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Portillo EGD, Olivares-Hernández A, Gudino LC, Félix LC, Hernández LB, Domínguez LP, Jiménez DL, Sarmiento RG, Morillo EDB, Sánchez EF, Miramontes-Gonzáleze JP. Evaluation of the effect of metformin as a radiosensitiser in solid tumours: A systematic review. Clin Transl Radiat Oncol 2025; 52:100930. [PMID: 40028423 PMCID: PMC11871473 DOI: 10.1016/j.ctro.2025.100930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 01/13/2025] [Accepted: 02/03/2025] [Indexed: 03/05/2025] Open
Abstract
Background Metformin is an antidiabetic drug that has shown its benefit in increasing the effect of radiotherapy in the treatment of solid tumors in preclinical studies. The objective of this systematic review is to study the effect of metformin as a radiosensitizer in studies carried out in clinical practice. Methods Systematic review carried out according to PRISMA criteria of clinical trials, systematic reviews and observational studies focused on the influence of metformin as a radiosensitizer in solid tumors. The studies were published between the years 2010 and 2022. The results of the studies have been analyzed in terms of survival (OS, PFS, DFS, DMFS) and response (ORR) between patients treated with metformin and without it. Results A total of 16 studies have been found in the literature (the most frequent tumor was prostate cancer, 5 studies). External radiotherapy was administered in all the studies and in two of them to greater brachytherapy. The use of metformin with radiotherapy showed a consistent benefit in terms of survival and response in tumors of prostate, hepatic and gynecological origin. The benefit in the rest of the tumors analyzed (lung, rectal, and head and neck cancer) is doubtful, and the results are contradictory. The greatest benefits were observed in prostate tumors both in OS and SLE. Conclusions The use of metformin in combination with radiotherapy in solid tumors is one of the most promising treatments under development in oncology. The benefit observed in real-life studies makes it necessary to develop clinical trials that specifically evaluate its use in clinical practice in the future.
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Affiliation(s)
| | - Alejandro Olivares-Hernández
- Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain
- Department of Medical Oncology, University Hospital of Salamanca, Salamanca, Spain
| | - Luis Corral Gudino
- Internal Medicine Unit, Río Hortega Hospital, Valladolid, Spain
- Medicine Department, University of Valladolid Medical School, Spain
| | - Laura Corvo Félix
- Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain
- Department of Medical Oncology, University Hospital of Salamanca, Salamanca, Spain
| | - Lorena Bellido Hernández
- Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain
- Department of Medical Oncology, University Hospital of Salamanca, Salamanca, Spain
- Faculty of Medicine, University of Salamanca, Salamanca, Spain
| | - Luis Posado Domínguez
- Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain
- Department of Medical Oncology, University Hospital of Salamanca, Salamanca, Spain
| | | | - Rogelio González Sarmiento
- Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain
- Internal Medicine Unit, Río Hortega Hospital, Valladolid, Spain
| | - Edel del Barco Morillo
- Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain
- Department of Medical Oncology, University Hospital of Salamanca, Salamanca, Spain
- Faculty of Medicine, University of Salamanca, Salamanca, Spain
| | - Emilio Fonseca Sánchez
- Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain
- Department of Medical Oncology, University Hospital of Salamanca, Salamanca, Spain
- Internal Medicine Unit, Río Hortega Hospital, Valladolid, Spain
| | - José Pablo Miramontes-Gonzáleze
- Internal Medicine Unit, Río Hortega Hospital, Valladolid, Spain
- Medicine Department, University of Valladolid Medical School, Spain
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Caprara G, Pallavi R, Sanyal S, Pelicci PG. Dietary Restrictions and Cancer Prevention: State of the Art. Nutrients 2025; 17:503. [PMID: 39940361 PMCID: PMC11820753 DOI: 10.3390/nu17030503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 01/22/2025] [Accepted: 01/25/2025] [Indexed: 02/16/2025] Open
Abstract
Worldwide, almost 10 million cancer deaths occurred in 2022, a number that is expected to rise to 16.3 million by 2040. Primary prevention has long been acknowledged as a crucial approach to reducing cancer incidence. In fact, between 30 and 50 percent of all tumors are known to be preventable by eating a healthy diet, staying active, avoiding alcohol, smoking, and being overweight. Accordingly, many international organizations have created tumor prevention guidelines, which underlie the importance of following a diet that emphasizes eating plant-based foods while minimizing the consumption of red/processed meat, sugars, processed foods, and alcohol. However, further research is needed to define the relationship between the effect of specific diets or nutritional components on cancer prevention. Interestingly, reductions in food intake and dietetic restrictions can extend the lifespan of yeast, nematodes, flies, and rodents. Despite controversial results in humans, those approaches have the potential to ameliorate health via direct and indirect effects on specific signaling pathways involved in cancer onset. Here, we describe the latest knowledge on the cancer-preventive potential of dietary restrictions and the biochemical processes involved. Molecular, preclinical, and clinical studies evaluating the effects of different fasting strategies will also be reviewed.
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Affiliation(s)
- Greta Caprara
- Department of Experimental Oncology, European Institute of Oncology (IEO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 20139 Milan, Italy
| | - Rani Pallavi
- Department of Experimental Oncology, European Institute of Oncology (IEO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 20139 Milan, Italy
- Brien Holden Eye Research Centre, L. V. Prasad Eye Institute, Hyderabad 500034, India
- The Operation Eyesight Universal Institute for Eye Cancer, L. V. Prasad Eye Institute, Hyderabad 500034, India; (R.P.); (S.S.)
| | - Shalini Sanyal
- Brien Holden Eye Research Centre, L. V. Prasad Eye Institute, Hyderabad 500034, India
- The Operation Eyesight Universal Institute for Eye Cancer, L. V. Prasad Eye Institute, Hyderabad 500034, India; (R.P.); (S.S.)
| | - Pier Giuseppe Pelicci
- Department of Experimental Oncology, European Institute of Oncology (IEO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 20139 Milan, Italy
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Takemori S, Morisada T, Osaka M, Watanabe M, Tajima A, Tanigaki S, Kobayashi Y. Assessing the antitumor effects of metformin on ovarian clear cell carcinoma. Hum Cell 2024; 37:1462-1474. [PMID: 39115639 DOI: 10.1007/s13577-024-01116-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 07/31/2024] [Indexed: 08/23/2024]
Abstract
Developing novel therapies that outperform the existing chemotherapeutic treatments is required for treatment-resistant ovarian clear cell carcinoma. We investigated the antitumor effect of metformin on ovarian clear cell carcinoma, enhancement of the antitumor effect by its combination with chemotherapy, and its molecular regulatory mechanism. First, we evaluated the viability of ovarian clear cell carcinoma lines using the water-soluble tetrazolium-1 assay and found that metformin suppressed cell viability. Cell viability was significantly suppressed by co-treatment with cisplatin and metformin. In contrast, co-treatment with paclitaxel and metformin showed no significant difference in viability compared with the group without metformin. Western blot analysis showed increased phosphorylation of AMP-activated protein kinase in some cell lines and suppressed phosphorylation of the mammalian target of rapamycin in a particular cell line. Flow cytometry analysis revealed a significant increase in the rate of apoptosis in the metformin-treated group and rate of cell cycle arrest at the G2/M phase in a particular cell line. These results indicated that metformin may be effective against cultured ovarian clear cell carcinoma cells, particularly in combination with cisplatin.
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Affiliation(s)
- Satoshi Takemori
- Department of Obstetrics and Gynecology, Faculty of Medicine, Kyorin University, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan
| | - Tohru Morisada
- Department of Obstetrics and Gynecology, Faculty of Medicine, Kyorin University, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan.
| | - Makoto Osaka
- Department of Obstetrics and Gynecology, Faculty of Medicine, Kyorin University, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan
| | - Momoe Watanabe
- Department of Obstetrics and Gynecology, Faculty of Medicine, Kyorin University, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan
| | - Atsushi Tajima
- Department of Obstetrics and Gynecology, Faculty of Medicine, Kyorin University, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan
| | - Shinji Tanigaki
- Department of Obstetrics and Gynecology, Faculty of Medicine, Kyorin University, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan
| | - Yoichi Kobayashi
- Department of Obstetrics and Gynecology, Faculty of Medicine, Kyorin University, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan
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Peppas S, Doumas S, Suvarnakar A, Chou J, Arafat A, Ahmad AI, Lewis JH. Clinical outcomes with metformin use in diabetic patients with compensated cirrhosis: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol 2024; 36:674-682. [PMID: 38477839 DOI: 10.1097/meg.0000000000002754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/14/2024]
Abstract
BACKGROUND Previous studies have demonstrated a beneficial effect of metformin in patients with cirrhosis, but no improvement in liver histology. AIM To investigate the impact of metformin on mortality and hepatic decompensation in people with diabetes with compensated cirrhosis. METHODS Medline, Embase and Cochrane databases were searched from inception to February 2023 for studies reporting results regarding the impact of metformin on all-cause mortality and hepatic decompensation in people with diabetes with compensated cirrhosis. The risk of bias was assessed by ROBINS-I Cochrane tool. R software 4.3.1 was used for all analyses. RESULTS Six observational studies were included in the final analysis. Metformin use was associated with reduced all-cause mortality or liver transplantation [hazard ratio (HR): 0.55; 95% confidence interval (CI) 0.37-0.82], while no benefit was shown in the prevention of hepatic decompensation (HR: 0.97; 95% CI: 0.77-1.22). In the subgroup analysis, metformin use was associated with reduced all-cause mortality or liver transplantation (HR: 0.50; 95% CI 0.38-0.65) in patients with metabolic-associated steatohepatitis cirrhosis, while two studies reported no survival benefit in patients with cirrhosis due to hepatitis C (HR: 0.39; 95% CI 0.12-1.20). CONCLUSION Metformin use is associated with reduced all-cause mortality, but not with the prevention of hepatic decompensation in people with diabetes with compensated cirrhosis. The mortality benefit is most likely driven by better diabetes and cardiovascular health control.
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Affiliation(s)
- Spyros Peppas
- Department of Medicine, MedStar Washington Hospital Center
| | - Stavros Doumas
- Department of Internal Medicine, MedStar Georgetown University Medical Center
| | | | - Jiling Chou
- MedStar Research Health Institute, Hyattsville, Maryland
| | - Ayah Arafat
- MedStar Research Health Institute, Hyattsville, Maryland
| | - Akram I Ahmad
- Divsion of Gastroenterology & Hepatology, Cleveland Clinic Florida, Weston, Florida
| | - James H Lewis
- Division of Gastroenterology & Hepatology, MedStar Georgetown University Medical Center, Washington, DC, USA
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Nassar K, El-Mekawey D, Elmasry AE, Refaey MS, El-Sayed Ghoneim M, Elshaier YAMM. The significance of caloric restriction mimetics as anti-aging drugs. Biochem Biophys Res Commun 2024; 692:149354. [PMID: 38091837 DOI: 10.1016/j.bbrc.2023.149354] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 11/26/2023] [Accepted: 11/30/2023] [Indexed: 01/06/2024]
Abstract
Aging is an intricate process characterized by the gradual deterioration of the physiological integrity of a living organism. This unfortunate phenomenon inevitably leads to a decline in functionality and a heightened susceptibility to the ultimate fate of mortality. Therefore, it is of utmost importance to implement interventions that possess the capability to reverse or preempt age-related pathology. Caloric restriction mimetics (CRMs) refer to a class of molecules that have been observed to elicit advantageous outcomes on both health and longevity in various model organisms and human subjects. Notably, these compounds offer a promising alternative to the arduous task of adhering to a caloric restriction diet and mitigate the progression of the aging process and extend the duration of life in laboratory animals and human population. A plethora of molecular signals have been linked to the practice of caloric restriction, encompassing Insulin-like Growth Factor 1 (IGF1), Mammalian Target of Rapamycin (mTOR), the Adenosine Monophosphate-Activated Protein Kinase (AMPK) pathway, and Sirtuins, with particular emphasis on SIRT1. Therefore, this review will center its focus on several compounds that act as CRMs, highlighting their molecular targets, chemical structures, and mechanisms of action. Moreover, this review serves to underscore the significant relationship between post COVID-19 syndrome, antiaging, and importance of utilizing CRMs. This particular endeavor will serve as a comprehensive guide for medicinal chemists and other esteemed researchers, enabling them to meticulously conceive and cultivate novel molecular entities with the potential to function as efficacious antiaging pharmaceutical agents.
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Affiliation(s)
- Khloud Nassar
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Menoufia, 32897, Egypt
| | - Doaa El-Mekawey
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Sadat City, Menoufia, 32897, Egypt
| | - Ahmed E Elmasry
- Department Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Sadat City, Menoufia, 32897, Egypt
| | - Mohamed S Refaey
- Department of Pharmacognosy, Faculty of Pharmacy, University of Sadat City, Menoufia, 32897, Egypt
| | - Mai El-Sayed Ghoneim
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Sadat City, Menoufia, 32897, Egypt.
| | - Yaseen A M M Elshaier
- Department Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Sadat City, Menoufia, 32897, Egypt
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Banisharif Dehkordi F, Ghatrehsamani M, Abdolvand M, Soltani A, Masoumi SH. Impact of Combination Therapy with Chemical Drugs and Megavoltage X-ray Exposure on Breast Cancer Stem Cells' Viability and Proliferation of MCF-7 and MDA-MB-231 Cell Lines. Curr Pharm Des 2024; 30:1341-1353. [PMID: 38676476 DOI: 10.2174/0113816128287325240329085055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 02/07/2024] [Accepted: 02/29/2024] [Indexed: 04/29/2024]
Abstract
BACKGROUND Breast Cancer (BC) is a serious malignancy among women. However, chemotherapy is an important tool for cancer treatments, but the long-term use of chemotherapy drugs may lead to drug resistance and tumor recurrence. Since Breast Cancer Stem Cells (BCSCs) can be the main factor to induce BC treatment resistance and recurrence, investigation of BCSCs signaling pathways can be an effective modality to enhance cancer treatment efficiency. OBJECTIVE In this study, the effect of metformin, SB203580, and takinib alone or in combination with radiotherapy on MCF-7 and MDA-MB-231 breast cancer cell lines was evaluated. METHODS MCF-7 and MDA-MB-231 breast cancer cell lines were treated with metformin, SB203580, and takinib for 24 or 48 hours, followed by X-ray exposure. The MTT assay and flow cytometry analysis were performed to assess cell growth inhibition and cellular death, CXCr4 expression, and BCSCs, respectively. RESULTS The results showed the combination of takinib/SB203580 with radiotherapy to remarkably reduce the CXCR4 expression and BCSCs levels in the MCF-7 cell line. Also, the concurrent administration of takinib/metformin/radiotherapy significantly reduced BCSCs and CXCR4 metastatic markers in the MDA-MB- 231 cells. Since the MAPK signaling pathway has an important role in inducing drug resistance and cell proliferation, the use of SB203580 as an inhibitor of p38 MAPK can improve breast cancer treatment. Furthermore, metformin and ionizing radiation by suppression of the mTOR signaling pathway can control AMPK activation and cellular proliferation. CONCLUSION Anti-cancer and cytotoxic effects of metformin can be effective in this strategy. In conclusion, the combination of conventional chemotherapeutic drugs, including SB203580, metformin, and takinib with X-ray exposure can be a new approach to diminish the drug resistance of breast cancer.
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Affiliation(s)
- Fatemeh Banisharif Dehkordi
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Mahdi Ghatrehsamani
- Department of Microbiology and Immunology, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Maryam Abdolvand
- Department of Microbiology and Immunology, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Amin Soltani
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Seyed Hossein Masoumi
- Medical Physics School of Allied Medical Sciences, Shahrekord University of Medical Sciences, Shahrekord, Iran
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Tang Z, Zhang Y, Yu Z, Luo Z. Metformin Suppresses Stemness of Non-Small-Cell Lung Cancer Induced by Paclitaxel through FOXO3a. Int J Mol Sci 2023; 24:16611. [PMID: 38068934 PMCID: PMC10705988 DOI: 10.3390/ijms242316611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 11/13/2023] [Accepted: 11/15/2023] [Indexed: 12/18/2023] Open
Abstract
Cancer stem cells (CSCs) play a pivotal role in drug resistance and metastasis. Among the key players, Forkhead box O3a (FOXO3a) acts as a tumor suppressor. This study aimed to unravel the role of FOXO3a in mediating the inhibitory effect of metformin on cancer stemness derived from paclitaxel (PTX)-resistant non-small-cell lung cancer (NSCLC) cells. We showed that CSC-like features were acquired by the chronic induction of resistance to PTX, concurrently with inactivation of FOXO3a. In line with this, knockdown of FOXO3a in PTX-sensitive cells led to changes toward stemness, while overexpression of FOXO3a in PTX-resistant cells mitigated stemness in vitro and remarkably curbed the tumorigenesis of NSCLC/PTX cells in vivo. Furthermore, metformin suppressed the self-renewal ability of PTX-resistant cells, reduced the expression of stemness-related markers (c-MYC, Oct4, Nanog and Notch), and upregulated FOXO3a, events concomitant with the activation of AMP-activated protein kinase (AMPK). All these changes were recapitulated by silencing FOXO3a in PTX-sensitive cells. Intriguingly, the introduction of the AMPK dominant negative mutant offset the inhibitory effect of metformin on the stemness of PTX-resistant cells. In addition, FOXO3a levels were elevated by the treatment of PTX-resistant cells with MK2206 (an Akt inhibitor) and U0126 (a MEK inhibitor). Collectively, our findings indicate that metformin exerts its effect on FOXO3a through the activation of AMPK and the inhibition of protein kinase B (Akt) and MAPK/extracellular signal-regulated kinase (MEK), culminating in the suppression of stemness in paclitaxel-resistant NSCLC cells.
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Affiliation(s)
- Zhimin Tang
- Jiangxi Provincial Key Laboratory of Tumor Pathogens and Molecular Pathology, Department of Pathophysiology, School of Basic Medical Sciences, Nanchang University, Nanchang 330031, China;
| | - Yilan Zhang
- Nanchang Joint Program, Queen Mary School, Nanchang University, Nanchang 330031, China; (Y.Z.); (Z.Y.)
| | - Zhengyi Yu
- Nanchang Joint Program, Queen Mary School, Nanchang University, Nanchang 330031, China; (Y.Z.); (Z.Y.)
| | - Zhijun Luo
- Jiangxi Provincial Key Laboratory of Tumor Pathogens and Molecular Pathology, Department of Pathophysiology, School of Basic Medical Sciences, Nanchang University, Nanchang 330031, China;
- Nanchang Joint Program, Queen Mary School, Nanchang University, Nanchang 330031, China; (Y.Z.); (Z.Y.)
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Dai G, Li Y, Zhang M, Lu P, Zhang Y, Wang H, Shi L, Cao M, Shen R, Rui Y. The Regulation of the AMPK/mTOR Axis Mitigates Tendon Stem/Progenitor Cell Senescence and Delays Tendon Aging. Stem Cell Rev Rep 2023; 19:1492-1506. [PMID: 36917311 DOI: 10.1007/s12015-023-10526-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/03/2023] [Indexed: 03/16/2023]
Abstract
Age-related tendon disorders are closely linked with tendon stem/progenitor cell (TSPC) senescence. However, the underlying mechanisms of TSPC senescence and promising therapeutic strategies for rejuvenation of TSPC senescence remain unclear. In this study, the senescent state of TSPCs increased with age. It was also verified that the AMPK inhibition/mTOR activation is correlated with the senescent state of TSPCs. Furthermore, a low dose of metformin mitigated TSPC senescence and restored senescence-related functions, including proliferation, colony-forming ability, migration ability and tenogenic differentiation ability at the early stage of aging. The protective effects of metformin on TSPCs were regulated through the AMPK/mTOR axis. An in vivo study showed that metformin treatment postpones tendon aging and enhances AMPK phosphorylation but reduces mTOR phosphorylation in a natural aging rat model. Our study revealed new insight and mechanistic exploration of TSPC senescence and proposed a novel therapeutic treatment for age-related tendon disorders by targeting the AMPK/mTOR axis at the early stage of aging.
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Affiliation(s)
- Guangchun Dai
- Department of Orthopaedics, School of Medicine, Zhongda Hospital, Southeast University, NO.87 Ding Jia Qiao, 210009, Nanjing, Jiangsu, PR China
- School of Medicine, Southeast University, N0.87 Ding Jia Qiao, 210009, Nanjing, PR China
- Trauma Center, Zhongda Hospital, Southeast University, 210009, Nanjing, Jiangsu, PR China
- Orthopaedic Trauma Institute (OTI), Southeast University, 210009, Nanjing, Jiangsu, PR China
| | - Yingjuan Li
- Department of Geriatrics, School of Medicine, Zhongda Hospital, Southeast University, NO.87 Ding Jia Qiao, Nanjing, PR China
| | - Ming Zhang
- Department of Orthopaedics, School of Medicine, Zhongda Hospital, Southeast University, NO.87 Ding Jia Qiao, 210009, Nanjing, Jiangsu, PR China
- School of Medicine, Southeast University, N0.87 Ding Jia Qiao, 210009, Nanjing, PR China
- Trauma Center, Zhongda Hospital, Southeast University, 210009, Nanjing, Jiangsu, PR China
- Orthopaedic Trauma Institute (OTI), Southeast University, 210009, Nanjing, Jiangsu, PR China
| | - Panpan Lu
- Department of Orthopaedics, School of Medicine, Zhongda Hospital, Southeast University, NO.87 Ding Jia Qiao, 210009, Nanjing, Jiangsu, PR China
- School of Medicine, Southeast University, N0.87 Ding Jia Qiao, 210009, Nanjing, PR China
- Trauma Center, Zhongda Hospital, Southeast University, 210009, Nanjing, Jiangsu, PR China
- Orthopaedic Trauma Institute (OTI), Southeast University, 210009, Nanjing, Jiangsu, PR China
| | - Yuanwei Zhang
- Department of Orthopaedics, School of Medicine, Zhongda Hospital, Southeast University, NO.87 Ding Jia Qiao, 210009, Nanjing, Jiangsu, PR China
- School of Medicine, Southeast University, N0.87 Ding Jia Qiao, 210009, Nanjing, PR China
- Trauma Center, Zhongda Hospital, Southeast University, 210009, Nanjing, Jiangsu, PR China
- Orthopaedic Trauma Institute (OTI), Southeast University, 210009, Nanjing, Jiangsu, PR China
| | - Hao Wang
- Department of Orthopaedics, School of Medicine, Zhongda Hospital, Southeast University, NO.87 Ding Jia Qiao, 210009, Nanjing, Jiangsu, PR China
- School of Medicine, Southeast University, N0.87 Ding Jia Qiao, 210009, Nanjing, PR China
- Trauma Center, Zhongda Hospital, Southeast University, 210009, Nanjing, Jiangsu, PR China
- Orthopaedic Trauma Institute (OTI), Southeast University, 210009, Nanjing, Jiangsu, PR China
| | - Liu Shi
- Department of Orthopaedics, School of Medicine, Zhongda Hospital, Southeast University, NO.87 Ding Jia Qiao, 210009, Nanjing, Jiangsu, PR China
- Trauma Center, Zhongda Hospital, Southeast University, 210009, Nanjing, Jiangsu, PR China
- Orthopaedic Trauma Institute (OTI), Southeast University, 210009, Nanjing, Jiangsu, PR China
| | - Mumin Cao
- Department of Orthopaedics, School of Medicine, Zhongda Hospital, Southeast University, NO.87 Ding Jia Qiao, 210009, Nanjing, Jiangsu, PR China
- School of Medicine, Southeast University, N0.87 Ding Jia Qiao, 210009, Nanjing, PR China
- Trauma Center, Zhongda Hospital, Southeast University, 210009, Nanjing, Jiangsu, PR China
- Orthopaedic Trauma Institute (OTI), Southeast University, 210009, Nanjing, Jiangsu, PR China
| | - Renwang Shen
- Department of Orthopaedics, School of Medicine, Zhongda Hospital, Southeast University, NO.87 Ding Jia Qiao, 210009, Nanjing, Jiangsu, PR China
- School of Medicine, Southeast University, N0.87 Ding Jia Qiao, 210009, Nanjing, PR China
- Trauma Center, Zhongda Hospital, Southeast University, 210009, Nanjing, Jiangsu, PR China
- Orthopaedic Trauma Institute (OTI), Southeast University, 210009, Nanjing, Jiangsu, PR China
| | - Yunfeng Rui
- Department of Orthopaedics, School of Medicine, Zhongda Hospital, Southeast University, NO.87 Ding Jia Qiao, 210009, Nanjing, Jiangsu, PR China.
- Trauma Center, Zhongda Hospital, Southeast University, 210009, Nanjing, Jiangsu, PR China.
- Orthopaedic Trauma Institute (OTI), Southeast University, 210009, Nanjing, Jiangsu, PR China.
- China Orthopedic Regenerative Medicine Group, 310000, Hangzhou, Zhejiang, PR China.
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Ghavami G, Kiasari RE, Pakzad F, Sardari S. Effect of metformin alone and in combination with etoposide and epirubicin on proliferation, apoptosis, necrosis, and migration of B-CPAP and SW cells as thyroid cancer cell lines. Res Pharm Sci 2023; 18:185-201. [PMID: 36873273 PMCID: PMC9976061 DOI: 10.4103/1735-5362.367797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Revised: 08/27/2022] [Accepted: 01/07/2023] [Indexed: 01/20/2023] Open
Abstract
Background and purpose There has not been a comprehensive study on the simultaneous effects of metformin, etoposide, and epirubicin on thyroid cancer cells. Hence, the current research proposed the in vitro study on the effect of metformin alone and in combination with etoposide and epirubicin on the rate of proliferation, apoptosis, necrosis, and migration against B-CPAP and SW-1736 cells as thyroid cancer cell lines. Experimental approach MTT-based proliferation assay, combination index method, flow cytometry, and scratch wound healing assays were used to evaluate the simultaneous effects of the three approved drugs against thyroid cancer cells. Findings/Results This study showed that the toxic concentration of metformin on normal Hu02 cells was more than 10 folds higher than B-CPAP and SW cancerous cells. Metformin in combination with epirubicin and etoposide could increase percentages of B-CPAP and SW cells in early and late apoptosis and necrosis phases in comparison with their single concentrations, significantly. Metformin in combination with epirubicin and etoposide could arrest the S phase in B-CPAP and SW cells, significantly. Metformin in combination with epirubicin and etoposide could reduce ~100% migration rate, whereas single concentrations of epirubicin and etoposide could reduce ~50% migration rate. Conclusion and implication Combined treatment of metformin with anticancer drugs epirubicin and etoposide can increase the mortality in thyroid cancer cell lines and reduce the toxicity of these drugs on the normal cell line, which could be the starting point for proposing a new combination strategy in the therapy of thyroid cancer to induce more potency and reduce acute toxicity.
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Affiliation(s)
- Ghazaleh Ghavami
- Drug Design and Bioinformatics Unit, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, I.R. Iran
| | - Ramin Ebrahimi Kiasari
- Drug Design and Bioinformatics Unit, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, I.R. Iran
| | - Faezeh Pakzad
- Drug Design and Bioinformatics Unit, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, I.R. Iran
| | - Soroush Sardari
- Drug Design and Bioinformatics Unit, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, I.R. Iran
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10
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Shete MB, Deshpande AS, Shende PK. Nanostructured lipid carrier-loaded metformin hydrochloride: Design, optimization, characterization, assessment of cytotoxicity and ROS evaluation. Chem Phys Lipids 2023; 250:105256. [PMID: 36372117 DOI: 10.1016/j.chemphyslip.2022.105256] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 10/29/2022] [Accepted: 11/08/2022] [Indexed: 11/13/2022]
Abstract
Metformin hydrochloride (MET) is commonly used in diabetes treatment. Recently, it has gained interest for its anticancer potential against a wide range of cancers. Owing to its hydrophilic nature, the delivery and clinical actions of MET are limited. Therefore, the present work aims to develop MET-encapsulated NLCs using the hot-melt emulsification and probe-sonication method. The optimization was accomplished by 33 BB design wherein lipid ratio, surfactant concentration, and sonication time were independent variables while the PS (nm), PDI, and EE (%) were dependent variables. The PS, PDI, % EE and ZP of optimized GMSMET-NLCs were found to be 114.9 ± 1.32 nm, 0.268 ± 0.04 %, 60.10 ± 2.23 %, and ZP - 15.76 mV, respectively. The morphological features, DSC and PXRD, and FTIR analyses suggested the confirmation of formation of the NLCs. Besides, optimized GMSMET-NLCs showed up to 88 % MET release in 24 h. Moreover, GMSMET-NLCs showed significant cell cytotoxicity against KB oral cancer cells compared with MET solution as shown by the reduction of IC50 values. Additionally, GMSMET-NLCs displayed significantly increased intracellular ROS levels suggesting the GMSMET-NLCs induced cell death in KB cells. GMSMET-NLCs can therefore be explored to deliver MET through different routes of administration for the effective treatment of oral cancer.
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Affiliation(s)
- Meghanath B Shete
- School of Pharmacy & Technology Management, SVKM'S NMIMS, Shirpur, Maharashtra, India; Department of Pharmaceutical Quality Assurance, R C Patel Institute of Pharmaceutical Education and Research, Shirpur, Dist., Dhule 425405, Maharashtra, India
| | - Ashwini S Deshpande
- School of Pharmacy & Technology Management, SVKM'S NMIMS, Polepally SEZ, TSIIC Jadcherla, Hyderabad 509301, India
| | - Pravin K Shende
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM'S NMIMS, Vile-Parle (W), Mumbai, Maharashtra, India.
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11
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Sanati M, Aminyavari S, Mollazadeh H, Motamed-Sanaye A, Bibak B, Mohtashami E, Teng Y, Afshari AR, Sahebkar A. The Potential Therapeutic Impact of Metformin in Glioblastoma Multiforme. Curr Med Chem 2023; 30:857-877. [PMID: 35796457 DOI: 10.2174/0929867329666220707103525] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 03/13/2022] [Accepted: 04/16/2022] [Indexed: 02/08/2023]
Abstract
In terms of frequency and aggressiveness, glioblastoma multiforme (GBM) is undoubtedly the most frequent and fatal primary brain tumor. Despite advances in clinical management, the response to current treatments is dismal, with a 2-year survival rate varying between 6 and 12 percent. Metformin, a derivative of biguanide widely used in treating type 2 diabetes, has been shown to extend the lifespan of patients with various malignancies. There is limited evidence available on the long-term survival of GBM patients who have taken metformin. This research examined the literature to assess the connection between metformin's anticancer properties and GBM development. Clinical findings, together with the preclinical data from animal models and cell lines, are included in the present review. This comprehensive review covers not only the association of hyperactivation of the AMPK pathway with the anticancer activity of metformin but also other mechanisms underpinning its role in apoptosis, cell proliferation, metastasis, as well as its chemo-radio-sensitizing behavior against GBM. Current challenges and future directions for developments and applications of metformin-based therapeutics are also discussed.
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Affiliation(s)
- Mehdi Sanati
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Birjand University of Medical Sciences, Birjand, Iran
| | - Samaneh Aminyavari
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamid Mollazadeh
- Department of Physiology and Pharmacology, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Ali Motamed-Sanaye
- Student Research Committee, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Bahram Bibak
- Department of Physiology and Pharmacology, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Elmira Mohtashami
- Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Yong Teng
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA30322, USA
| | - Amir R Afshari
- Department of Physiology and Pharmacology, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- School of Medicine, The University of Western Australia, Perth, Australia
- Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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12
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A Novel Biguanide Derivative, IM176, Induces Prostate Cancer Cell Death via AMPK-mTOR Pathway and Androgen Receptor Signalling Pathway. Prostate Int 2022. [DOI: 10.1016/j.prnil.2022.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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13
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Gu L, Ma G, Li C, Lin J, Zhao G. New insights into the prognosis of intraocular malignancy: Interventions for association mechanisms between cancer and diabetes. Front Oncol 2022; 12:958170. [PMID: 36003786 PMCID: PMC9393514 DOI: 10.3389/fonc.2022.958170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 07/12/2022] [Indexed: 11/19/2022] Open
Abstract
The intraocular malignancies, which mostly originate from the retina and uvea, exhibit a high incidence of blindness and even death. Uveal melanoma (UM) and retinoblastoma (RB) are the most common intraocular malignancies in adults and children, respectively. The high risks of distant metastases lead to an extremely poor prognosis. Nowadays, various epidemiological studies have demonstrated that diabetes is associated with the high incidence and mortality of cancers, such as liver cancer, pancreatic cancer, and bladder cancer. However, the mechanisms and interventions associated with diabetes and intraocular malignancies have not been reviewed. In this review, we have summarized the associated mechanisms between diabetes and intraocular malignancy. Diabetes mellitus is a chronic metabolic disease characterized by prolonged periods of hyperglycemia. Recent studies have reported that the abnormal glucose metabolism, insulin resistance, and the activation of the IGF/insulin-like growth factor-1 receptor (IGF-1R) signaling axis in diabetes contribute to the genesis, growth, proliferation, and metastases of intraocular malignancy. In addition, diabetic patients are more prone to suffer severe complications and poor prognosis after radiotherapy for intraocular malignancy. Based on the common pathogenesis shared by diabetes and intraocular malignancy, they may be related to interventions and treatments. Therefore, interventions targeting the abnormal glucose metabolism, insulin resistance, and IGF-1/IGF-1R signaling axis show therapeutic potentials to treat intraocular malignancy.
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Affiliation(s)
- Lingwen Gu
- Department of Ophthalmology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Guofeng Ma
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Cui Li
- Department of Ophthalmology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jing Lin
- Department of Ophthalmology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Guiqiu Zhao
- Department of Ophthalmology, The Affiliated Hospital of Qingdao University, Qingdao, China
- *Correspondence: Guiqiu Zhao,
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14
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Triggle CR, Mohammed I, Bshesh K, Marei I, Ye K, Ding H, MacDonald R, Hollenberg MD, Hill MA. Metformin: Is it a drug for all reasons and diseases? Metabolism 2022; 133:155223. [PMID: 35640743 DOI: 10.1016/j.metabol.2022.155223] [Citation(s) in RCA: 135] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Revised: 05/22/2022] [Accepted: 05/25/2022] [Indexed: 12/15/2022]
Abstract
Metformin was first used to treat type 2 diabetes in the late 1950s and in 2022 remains the first-choice drug used daily by approximately 150 million people. An accumulation of positive pre-clinical and clinical data has stimulated interest in re-purposing metformin to treat a variety of diseases including COVID-19. In polycystic ovary syndrome metformin improves insulin sensitivity. In type 1 diabetes metformin may help reduce the insulin dose. Meta-analysis and data from pre-clinical and clinical studies link metformin to a reduction in the incidence of cancer. Clinical trials, including MILES (Metformin In Longevity Study), and TAME (Targeting Aging with Metformin), have been designed to determine if metformin can offset aging and extend lifespan. Pre-clinical and clinical data suggest that metformin, via suppression of pro-inflammatory pathways, protection of mitochondria and vascular function, and direct actions on neuronal stem cells, may protect against neurodegenerative diseases. Metformin has also been studied for its anti-bacterial, -viral, -malaria efficacy. Collectively, these data raise the question: Is metformin a drug for all diseases? It remains unclear as to whether all of these putative beneficial effects are secondary to its actions as an anti-hyperglycemic and insulin-sensitizing drug, or result from other cellular actions, including inhibition of mTOR (mammalian target for rapamycin), or direct anti-viral actions. Clarification is also sought as to whether data from ex vivo studies based on the use of high concentrations of metformin can be translated into clinical benefits, or whether they reflect a 'Paracelsus' effect. The environmental impact of metformin, a drug with no known metabolites, is another emerging issue that has been linked to endocrine disruption in fish, and extensive use in T2D has also raised concerns over effects on human reproduction. The objectives for this review are to: 1) evaluate the putative mechanism(s) of action of metformin; 2) analyze the controversial evidence for metformin's effectiveness in the treatment of diseases other than type 2 diabetes; 3) assess the reproducibility of the data, and finally 4) reach an informed conclusion as to whether metformin is a drug for all diseases and reasons. We conclude that the primary clinical benefits of metformin result from its insulin-sensitizing and antihyperglycaemic effects that secondarily contribute to a reduced risk of a number of diseases and thereby enhancing healthspan. However, benefits like improving vascular endothelial function that are independent of effects on glucose homeostasis add to metformin's therapeutic actions.
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Affiliation(s)
- Chris R Triggle
- Department of Pharmacology, Weill Cornell Medicine in Qatar, P.O. Box 24144, Education City, Doha, Qatar; Department of Medical Education, Weill Cornell Medicine in Qatar, P.O. Box 24144, Education City, Doha, Qatar.
| | - Ibrahim Mohammed
- Department of Medical Education, Weill Cornell Medicine in Qatar, P.O. Box 24144, Education City, Doha, Qatar
| | - Khalifa Bshesh
- Department of Medical Education, Weill Cornell Medicine in Qatar, P.O. Box 24144, Education City, Doha, Qatar
| | - Isra Marei
- Department of Pharmacology, Weill Cornell Medicine in Qatar, P.O. Box 24144, Education City, Doha, Qatar
| | - Kevin Ye
- Department of Biomedical Physiology & Kinesiology, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada
| | - Hong Ding
- Department of Pharmacology, Weill Cornell Medicine in Qatar, P.O. Box 24144, Education City, Doha, Qatar; Department of Medical Education, Weill Cornell Medicine in Qatar, P.O. Box 24144, Education City, Doha, Qatar
| | - Ross MacDonald
- Distribution eLibrary, Weill Cornell Medicine in Qatar, P.O. Box 24144, Education City, Doha, Qatar
| | - Morley D Hollenberg
- Department of Physiology & Pharmacology, a Cumming School of Medicine, University of Calgary, T2N 4N1, Canada
| | - Michael A Hill
- Dalton Cardiovascular Research Center, Department of Medical Pharmacology & Physiology, School of Medicine, University of Missouri, Columbia 65211, MO, USA
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15
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Cancer Stem Cells: From an Insight into the Basics to Recent Advances and Therapeutic Targeting. Stem Cells Int 2022; 2022:9653244. [PMID: 35800881 PMCID: PMC9256444 DOI: 10.1155/2022/9653244] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 06/07/2022] [Indexed: 12/22/2022] Open
Abstract
Cancer is characterized by an abnormal growth of the cells in an uncontrolled manner. These cells have the potential to invade and can eventually turn into malignancy, leading to highly fatal forms of tumor. Small subpopulations of cancer cells that are long-lived with the potential of excessive self-renewal and tumor formation are called cancer stem cells (CSCs) or cancer-initiating cells or tumor stem cells. CSCs can be found in tissues, such as breast, brain, lung, liver, ovary, and testis; however, their origin is still a matter of debate. These cells can differentiate and possess self-renewal capacity maintained by numerous intracellular signal transduction pathways, such as the Wnt/β-catenin signaling, Notch signaling, transforming growth factor-β signaling, and Hedgehog signaling. They can also contribute to numerous malignancies and are an important reason for tumor recurrence and metastasis because they are resistant to the known therapeutic strategies that mainly target the bulk of the tumor cells. This review contains collected and compiled information after analyzing published works of the last three decades. The goal was to gather information of recent breakthroughs related to CSCs, strategies to target CSCs' niche (e.g., nanotechnology with tumor biology), and their signaling pathways for cancer therapy. Moreover, the role of metformin, an antidiabetic drug, acting as a chemotherapeutic agent on CSCs by inhibiting cellular transformation and its selective killing is also addressed.
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16
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Ali MA, Khalil MM, Al-Mokaddem AK, Aljuaydi SH, Ahmed M, Khalil HM. Differential effects of cancer modifying agents during radiation therapy on Ehrlich solid tumor-bearing mice: A comparative investigation of metformin and ascorbic acid. Appl Radiat Isot 2022; 187:110305. [DOI: 10.1016/j.apradiso.2022.110305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 05/15/2022] [Accepted: 05/18/2022] [Indexed: 11/02/2022]
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17
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Zhang J, Kuang L, Li Y, Wang Q, Xu H, Liu J, Zhou X, Li Y, Zhang B. Metformin Regulates TET2 Expression to Inhibit Endometrial Carcinoma Proliferation: A New Mechanism. Front Oncol 2022; 12:856707. [PMID: 35480097 PMCID: PMC9035737 DOI: 10.3389/fonc.2022.856707] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 03/07/2022] [Indexed: 11/30/2022] Open
Abstract
Objectives To investigate the relationship between TET2 expression and endometrial cancer’s clinicopathological features and prognosis, and the effect of metformin on TET2 and 5hmC levels in endometrial cancer cells. Methods The clinical significance of TET2 expression in endometrial carcinoma was analyzed from TCGA public database. Eighty-eight patients with endometrial cancer and 20 patients with normal proliferative endometrium were enrolled in this study. TET2 and 5hmC were respectively detected by Immunohistochemistry and ELISA in endometrial tissues. Kaplan-Meier and Cox proportional hazard regression models were used to analyze relationships between TET2 and 5hmC and the overall survival of EC patients. Endometrial cell proliferation was assessed after TET2 gene knockdown. Western blotting and real-time PCR were used to detect the effect of metformin on TET2 expression and to explore whether AMPK is involved in metformin-mediated TET2 regulation. Results The clinical significance of expression of TET2 in endometrial cancer from TCGA public database confirmed that TET2 expression was significantly down-regulated in cancer samples and TET2 expression was also significantly different among different histopathological samples and TET2 is down-regulated in advanced, high-grade, and relapsed endometrial carcinoma tissues(P<0.05). Immunohistochemical analysis showed that TET2 and 5hmC levels were significantly lower in endometrial adenocarcinoma(P<0.05). TET2 expression was correlated with the degree of EC differentiation (P < 0.05). 5hmC levels were associated with clinical stage, differentiation, the depth of myometrial invasion, and lymph node metastasis (P < 0.05). The mean survival time of patients with negative staining for TET2 and 5hmC was shorter than that of patients with positive staining for both markers (P<0.05). Multivariate Cox regression analysis showed that TET2 expression was an independent risk factor for prognosis in patients with endometrial adenocarcinoma (HR = 14.520, 95% CI was 1.From 060 to 198.843, P = 0.045). siRNA-mediated TET2 knockdown increased the proliferation of EC cells. Metformin increased the levels of TET2 and 5hmC in EC cells. AMPK was involved in the regulation of TET2 by metformin. Conclusions TET2 may play an important role in EC development and may be a prognostic marker. Moreover, TET2 may be involved in a novel mechanism by which metformin inhibits EC cell proliferation.
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Affiliation(s)
- Jingbo Zhang
- Department of Obstetrics and Gynecology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, China
| | - Lei Kuang
- Department of Obstetrics and Gynecology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, China
| | - Yanyu Li
- Department of Obstetrics and Gynecology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, China
| | - Qing Wang
- Department of Obstetrics and Gynecology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, China
| | - Hui Xu
- Department of Obstetrics and Gynecology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, China
| | - Jianwei Liu
- Department of Obstetrics and Gynecology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, China
| | - Xueyan Zhou
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Yang Li
- Xuzhou Institute of Medical Science, Xuzhou, China
- *Correspondence: Bei Zhang, ; Yang Li,
| | - Bei Zhang
- Department of Obstetrics and Gynecology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, China
- *Correspondence: Bei Zhang, ; Yang Li,
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18
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Nikitchenko YV, Klochkov VK, Kavok NS, Averchenko KA, Karpenko NA, Nikitchenko IV, Yefimova SL, Bozhkov AI. Anti-aging Effects of Antioxidant Rare-Earth Orthovanadate Nanoparticles in Wistar Rats. Biol Trace Elem Res 2021; 199:4183-4192. [PMID: 33409911 DOI: 10.1007/s12011-020-02531-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Accepted: 12/03/2020] [Indexed: 12/16/2022]
Abstract
Biomedical application of rare-earth-based nanoparticles attracts much attention due to their unique optical and redox properties and quite low toxicity. Earlier, we found age-related beneficial effects of rare-earth-based orthovanadate nanoparticles (OV NPs) on the prooxidant/antioxidant balance in liver and blood of Wistar rats, as reported by Nikitchenko et al. (Biol Trace Elem Res (2020). https://doi.org/10.1007/s12011-020-02196-7 ). However, the question remained unclear whether OV NPs' redox activity directly defines the protection ability. In the present work, antiradical, antioxidant, and membrane-protective properties of GdYVO4/Eu3+ NPs (1-2 nm), GdVO4/Eu3+ NPs (8 × 25 nm), LaVO4/Eu3+ (57 × 8 nm) were assayed in a comparative manner in various model systems. All OV NPs demonstrated the protective properties, but extra-small GdYVO4/Eu3+ NPs revealed the weakest antioxidant efficacy. In isolated mitochondria, OV NPs lowered (most evidently-extra-small NPs) respiration and oxidative phosphorylation, as well as ATP concentration. We conclude that not only the direct antioxidant effect but also slight suppression of bioenergetic processes by the OV NPs as well as the triggering of GSH-dependent antioxidant system may represent the principal mechanisms of their beneficial influences in an aged organism. This statement is consistent with improvement of the oxidative balance of 33-month-old rats due to prolonged administration of GdVO4 /Eu3+ NPs (for 11 months) accompanied by retention of the GSH signaling of the old rats at the level of 12 months mature animals. Consequently, an increase of antioxidant defense upon prolonged usage of OV NPs will lead to oxidative balance stabilization increasing the health span and survival of an organism.
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Affiliation(s)
- Yuri V Nikitchenko
- Karazin Kharkiv National University, 4 Svobody Sq., Kharkiv, 61022, Ukraine
| | - Vladimir K Klochkov
- Institute for Scintillation Materials, National Academy of Sciences of Ukraine, 60 Nauky Ave, Kharkiv, 61072, Ukraine
| | - Nataliya S Kavok
- Institute for Scintillation Materials, National Academy of Sciences of Ukraine, 60 Nauky Ave, Kharkiv, 61072, Ukraine.
| | - Kateryna A Averchenko
- Institute for Scintillation Materials, National Academy of Sciences of Ukraine, 60 Nauky Ave, Kharkiv, 61072, Ukraine
| | - Nina A Karpenko
- Institute for Scintillation Materials, National Academy of Sciences of Ukraine, 60 Nauky Ave, Kharkiv, 61072, Ukraine
| | | | - Svetlana L Yefimova
- Institute for Scintillation Materials, National Academy of Sciences of Ukraine, 60 Nauky Ave, Kharkiv, 61072, Ukraine
| | - Anatoly I Bozhkov
- Karazin Kharkiv National University, 4 Svobody Sq., Kharkiv, 61022, Ukraine
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19
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Xu Y, Liu Y, Liu Q, Lu S, Chen X, Xu W, Shi F. Co-delivery of bufalin and nintedanib via albumin sub-microspheres for synergistic cancer therapy. J Control Release 2021; 338:705-718. [PMID: 34481023 DOI: 10.1016/j.jconrel.2021.08.049] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 08/20/2021] [Accepted: 08/30/2021] [Indexed: 12/31/2022]
Abstract
Albumin nanoparticles represent an approved anti-tumor drug delivery system. However, there is only one albumin nanoparticle product (paclitaxel-albumin nanoparticle) on the market. The application of albumin carriers is limited by the lack of universal preparation technology and insufficient targeting effect. Herein, we developed multifunctional albumin sub-microspheres prepared by coaxial-electrospray technology to co-delivery bufalin and nintedanib for tumor-targeted combination therapy. The biguanide and ursodeoxycholic acid dual-modified multifunctional albumin was synthesized to enhance the anti-tumor effect and tumor target efficiency. Coaxial-electrospray technology was utilized in preparing albumin sub-microspheres with a core-shell structure that enables payload efficiency and stability. More importantly, the in vitro and in vivo experiments demonstrated that the multifunctional albumin sub-microspheres possessed superior tumor target efficiency. Furthermore, nintedanib and bufalin combined therapy relieved the tumor microenvironment and exerted a synergistic therapeutic effect. Therefore, this work provides a novel method for fabricating an albumin-based drug delivery system and a potential efficient combination therapeutic strategy for tumor treatment.
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Affiliation(s)
- Ying Xu
- College of Pharmacy, Jiangsu University, Zhenjiang 212013, China.
| | - Yulong Liu
- College of Pharmacy, Jiangsu University, Zhenjiang 212013, China
| | - Qi Liu
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Shengzhe Lu
- College of Pharmacy, Jiangsu University, Zhenjiang 212013, China; Chia Tai Tianqing Pharmaceutical Group Co., Ltd, Lianyungang, Jiangsu 222062, China
| | - Xiaolin Chen
- College of Pharmacy, Jiangsu University, Zhenjiang 212013, China
| | - Wenrong Xu
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, China
| | - Feng Shi
- College of Pharmacy, Jiangsu University, Zhenjiang 212013, China.
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20
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Metformin and sodium dichloroacetate effects on proliferation, apoptosis, and metabolic activity tested alone and in combination in a canine prostate and a bladder cancer cell line. PLoS One 2021; 16:e0257403. [PMID: 34570803 PMCID: PMC8476037 DOI: 10.1371/journal.pone.0257403] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 08/31/2021] [Indexed: 01/26/2023] Open
Abstract
An important approach in tumor therapy is combining substances with different action mechanisms aiming to enhance the antineoplastic effect, decrease the therapeutic dosage, and avoid resistance mechanisms. Moreover, evaluating compounds already approved for the treatment of non-neoplastic diseases is promising for new antineoplastic therapies. Sodium dichloroacetate (DCA) reactivates oxidative phosphorylation in the cancer cell mitochondria, reducing apoptosis resistance in cancer cells. Furthermore, metformin inhibits the proliferation of tumor cells and CD133+ cancer -stem-like cells. In the present study, we evaluated the independent and synergistic effect of metformin and DCA on the metabolic activity, cell proliferation, and apoptosis of a canine prostate adenocarcinoma (Adcarc1258) and a transitional cell carcinoma cell line (TCC1506) in comparison to a primary canine fibroblast culture. Determining metformin uptake in tumor cells was performed by quantitative HPLC. Depending on the dosage, metformin as a single agent inhibited the metabolic activity and cell proliferation of the tumor cells, showing only minor effects on the fibroblasts. Furthermore, 1 mM metformin increased apoptosis over 96 h in the tumor cell lines but not in fibroblasts. Additionally, metformin uptake into the tumor cells in vitro was measurable by quantitative HPLC. Synergistic effects for the combination therapy were observed in both neoplastic cell lines as well as in the fibroblasts. Based on these results, metformin might be a promising therapeutic agent for canine urogenital tumors. Further studies on kinetics, toxicology, bioavailability, and application of metformin in dogs are necessary.
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21
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Metformin Potentiates the Anticancer Effect of Everolimus on Cervical Cancer In Vitro and In Vivo. Cancers (Basel) 2021; 13:cancers13184612. [PMID: 34572837 PMCID: PMC8468269 DOI: 10.3390/cancers13184612] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 09/07/2021] [Accepted: 09/10/2021] [Indexed: 01/14/2023] Open
Abstract
Simple Summary Recent studies have shown that metformin combined with clinical chemotherapeutic drugs could cause decreased cell toxicity and attenuate tumor resistance in various types of cancer. The aim of the present study was to elucidate whether combined treatment with metformin and everolimus has a synergistic anticancer effect in human cervical cancer in vitro and in vivo. The results showed that this combined treatment synergistically inhibited the growth of human cervical cancer cell lines and xenografts in nude mice, and induced caspase-dependent apoptosis, promoting sub-G1- and G0/G1-phase arrest and enhancing mtROS production. Combined treatment also synergistically inactivated PI3K/AKT signaling and activated MAPKs signaling in cervical cancer. Our data suggested that metformin potentiates the anticancer effect of everolimus on cervical cancer, and combined treatment provides a novel therapeutic strategy for patients with cervical cancer. Abstract Cervical cancer is globally the fourth most common cancer in women. Metformin is a widely used drug for the treatment of type II diabetes and has been shown to possess important anticancer properties in cervical cancer. Everolimus is an mTOR inhibitor and is widely used to treat NETs, RCC, TSC, and breast cancers. The present study investigated the anticancer effects of metformin and everolimus in cervical cancer, when used alone or in combination. CaSki and C33A human cervical cancer cells were treated with different concentrations of everolimus alone or in combination with metformin. Cell viability was assessed using a CCK-8 assay. Cell apoptosis, cell-cycle, and mtROS analyses were conducted using flow cytometry. Target protein levels were analyzed by Western blotting. Related mechanisms were confirmed using appropriate inhibitors (z-VAD-fmk and BIRB796). The in vitro results were further confirmed in a xenograft tumor study. Both metformin and everolimus, when used alone, were moderately effective in inhibiting cell proliferation and inducing cell apoptosis of CaSki and C33A cells. When used in combination, these two drugs synergistically inhibited the growth of human cervical cancer cells and xenografts in nude mice, promoted sub-G1- and G0/G1-phase cell-cycle arrest, and enhanced mtROS production. The protein expressions of PI3K (p110α) and p-AKT were significantly downregulated, while P27, P21, p-p38, p-ERK, and p-JNK were upregulated following combined treatment. These results revealed that metformin potentiates the anticancer effect of everolimus on cervical cancer, and combination treatment with metformin and everolimus provides a novel therapeutic strategy for patients with cervical cancer.
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Chen YH, Huang YC, Yang SF, Yen HH, Tsai HD, Hsieh MC, Hsiao YH. Pitavastatin and metformin synergistically activate apoptosis and autophagy in pancreatic cancer cells. ENVIRONMENTAL TOXICOLOGY 2021; 36:1491-1503. [PMID: 33886150 DOI: 10.1002/tox.23146] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 03/12/2021] [Accepted: 04/02/2021] [Indexed: 06/12/2023]
Abstract
Pancreatic cancer is the seventh leading cause of cancer-related deaths globally. Metformin is the standard first-line of treatment for hyperglycemia in Type 2 diabetes, whereas pitavastatin is a cholesterol-lowering drug used to prevent cardiovascular diseases. Both these agents evidently exert anticancer effects on pancreatic cancer; however, it remains unclear whether cotreatment using them has additive or synergistic anticancer effects on pancreatic cancer. Thus, we herein used the ASPC-1 and PANC-1 cells and treated them with metformin and/or pitavastatin. We performed the cell viability assay, transwell migration assay, and cell cycle analysis using flow cytometry. Western blotting was used to determine protein levels. We found that cotreatment with metformin (30 mM) and pitavastatin (10 μM) significantly reduced cell viability; caused G0/G1 cell cycle arrest; upregulated the expression levels of Bax, PCNA, cleaved PARP-1, cleaved caspase-3, LC3 II, and p27 Kip1 /p21Cip1 ; and inhibited cell migration. The combination index value for cell viability indicated a synergistic interaction between metformin and pitavastatin. Moreover, cotreating the cells with metformin (30 mM) and pitavastatin (10 μM) could preserve mitochondrial function, activate AMPK, and inhibit PI3K/mTOR than treatment with metformin or pitavastatin alone. These findings clearly indicated that metformin plus pitavastatin had a synergistic anticancer effect on pancreatic cancer cells, potentially caused due to the activation of AMPK and inhibition of PI3K/mTOR signaling. Altogether, our results provide that use of metformin plus pitavastatin maybe serve as a chemotherapeutic agent for human pancreatic cancer in future.
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Affiliation(s)
- Ya-Hui Chen
- Women's Health Research Laboratory, Changhua Christian Hospital, Changhua, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Ying-Chih Huang
- Department of Research, Changhua Christian Hospital, Changhua, Taiwan
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Hsu-Heng Yen
- Division of Gastroenterology, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan
| | - Horng-Der Tsai
- Department of Obstetrics and Gynecology, Changhua Christian Hospital, Changhua, Taiwan
| | - Ming-Chia Hsieh
- Intelligent Diabetes Metabolism and Exercise Center, China Medical University Hospital, Taichung, Taiwan
| | - Yi-Hsuan Hsiao
- Women's Health Research Laboratory, Changhua Christian Hospital, Changhua, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Obstetrics and Gynecology, Changhua Christian Hospital, Changhua, Taiwan
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Biguanides drugs: Past success stories and promising future for drug discovery. Eur J Med Chem 2021; 224:113726. [PMID: 34364161 DOI: 10.1016/j.ejmech.2021.113726] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 07/27/2021] [Accepted: 07/27/2021] [Indexed: 12/13/2022]
Abstract
Biguanides have attracted much attention a century ago and showed resurgent interest in recent years after a long period of dormancy. They constitute an important class of therapeutic agents suitable for the treatment of a wide spectrum of diseases. Therapeutic indications of biguanides include antidiabetic, antimalarial, antiviral, antiplaque, and bactericidal applications. This review presents an extensive overview of the biological activity of biguanides and different mechanisms of action of currently marketed biguanide-containing drugs, as well as their pharmacological properties when applicable. We highlight the recent developments in research on biguanide compounds, with a primary focus on studies on metformin in the field of oncology. We aim to provide a critical overview of all main bioactive biguanide compounds and discuss future perspectives for the design of new drugs based on the biguanide fragment.
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24
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Nasry WHS, Martin CK. Intersecting Mechanisms of Hypoxia and Prostaglandin E2-Mediated Inflammation in the Comparative Biology of Oral Squamous Cell Carcinoma. Front Oncol 2021; 11:539361. [PMID: 34094895 PMCID: PMC8175905 DOI: 10.3389/fonc.2021.539361] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Accepted: 04/22/2021] [Indexed: 12/12/2022] Open
Abstract
The importance of inflammation in the pathogenesis of cancer was first proposed by Rudolph Virchow over 150 years ago, and our understanding of its significance has grown over decades of biomedical research. The arachidonic acid pathway of inflammation, including cyclooxygenase (COX) enzymes, PGE2 synthase enzymes, prostaglandin E2 (PGE2) and PGE2 receptors has been extensively studied and has been associated with different diseases and different types of cancers, including oral squamous cell carcinoma (OSCC). In addition to inflammation in the tumour microenvironment, low oxygen levels (hypoxia) within tumours have also been shown to contribute to tumour progression. Understandably, most of our OSCC knowledge comes from study of this aggressive cancer in human patients and in experimental rodent models. However, domestic animals develop OSCC spontaneously and this is an important, and difficult to treat, form of cancer in veterinary medicine. The primary goal of this review article is to explore the available evidence regarding interaction between hypoxia and the arachidonic acid pathway of inflammation during malignant behaviour of OSCC. Overlapping mechanisms in hypoxia and inflammation can contribute to tumour growth, angiogenesis, and, importantly, resistance to therapy. The benefits and controversies of anti-inflammatory and anti-angiogenic therapies for human and animal OSCC patients will be discussed, including conventional pharmaceutical agents as well as natural products.
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Affiliation(s)
- Walaa Hamed Shaker Nasry
- Department of Pathology and Microbiology, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PEI, Canada
| | - Chelsea K Martin
- Department of Pathology and Microbiology, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PEI, Canada
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25
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Zhang AM, Wellberg EA, Kopp JL, Johnson JD. Hyperinsulinemia in Obesity, Inflammation, and Cancer. Diabetes Metab J 2021; 45:285-311. [PMID: 33775061 PMCID: PMC8164941 DOI: 10.4093/dmj.2020.0250] [Citation(s) in RCA: 118] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 12/23/2020] [Indexed: 12/13/2022] Open
Abstract
The relative insufficiency of insulin secretion and/or insulin action causes diabetes. However, obesity and type 2 diabetes mellitus can be associated with an absolute increase in circulating insulin, a state known as hyperinsulinemia. Studies are beginning to elucidate the cause-effect relationships between hyperinsulinemia and numerous consequences of metabolic dysfunctions. Here, we review recent evidence demonstrating that hyperinsulinemia may play a role in inflammation, aging and development of cancers. In this review, we will focus on the consequences and mechanisms of excess insulin production and action, placing recent findings that have challenged dogma in the context of the existing body of literature. Where relevant, we elaborate on the role of specific signal transduction components in the actions of insulin and consequences of chronic hyperinsulinemia. By discussing the involvement of hyperinsulinemia in various metabolic and other chronic diseases, we may identify more effective therapeutics or lifestyle interventions for preventing or treating obesity, diabetes and cancer. We also seek to identify pertinent questions that are ripe for future investigation.
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Affiliation(s)
- Anni M.Y. Zhang
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
| | - Elizabeth A. Wellberg
- Department of Pathology, University of Oklahoma Health Sciences Center, Stephenson Cancer Center, Harold Hamm Diabetes Center, Oklahoma City, OK, USA
| | - Janel L. Kopp
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
| | - James D. Johnson
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
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26
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Mauvais-Jarvis F, Berthold HK, Campesi I, Carrero JJ, Dakal S, Franconi F, Gouni-Berthold I, Heiman ML, Kautzky-Willer A, Klein SL, Murphy A, Regitz-Zagrosek V, Reue K, Rubin JB. Sex- and Gender-Based Pharmacological Response to Drugs. Pharmacol Rev 2021; 73:730-762. [PMID: 33653873 PMCID: PMC7938661 DOI: 10.1124/pharmrev.120.000206] [Citation(s) in RCA: 108] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
In humans, the combination of all sex-specific genetic, epigenetic, and hormonal influences of biologic sex produces different in vivo environments for male and female cells. We dissect how these influences of sex modify the pharmacokinetics and pharmacodynamics of multiple drugs and provide examples for common drugs acting on specific organ systems. We also discuss how gender of physicians and patients may influence the therapeutic response to drugs. We aim to highlight sex as a genetic modifier of the pharmacological response to drugs, which should be considered as a necessary step toward precision medicine that will benefit men and women. SIGNIFICANCE STATEMENT: This study discusses the influences of biologic sex on the pharmacokinetics and pharmacodynamics of drugs and provides examples for common drugs acting on specific organ systems. This study also discusses how gender of physicians and patients influence the therapeutic response to drugs.
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Affiliation(s)
- Franck Mauvais-Jarvis
- Section of Endocrinology, John W. Deming Department of Medicine, Diabetes Discovery and Sex-Based Medicine Laboratory, Tulane University School of Medicine and Southeast Louisiana Veterans Health Care System Medical Center, New Orleans, Louisiana (F.M.-J.); Department of Internal Medicine and Geriatrics, Bethel Clinic (EvKB), Bielefeld, Germany (H.K.B.); Department of Biomedical Sciences, University of Sassari, Sassari, Italy (I.C.); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (J.-J.C.); W. Harry Feinstone Department of Molecular Microbiology and Immunology, the Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (S.D., S.L.K.); Laboratory of Sex-Gender Medicine, National Institute of Biostructures and Biosystems, Sassari, Italy (F.F.); Polyclinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University of Cologne, Cologne, Germany (I.G.-B.); Scioto Biosciences, Indianapolis, Indiana (M.L.H.); Department of Internal Medicine III, Clinical Division of Endocrinology, Metabolism and Gender Medicine, Medical University of Vienna, Vienna and Gender Institute Gars am Kamp, Vienna, Austria (A.K.-W.); Neuroscience Institute, Georgia State University, Atlanta, Georgia (A.M.); Berlin Institute of Gender Medicine, Charité, Universitätsmedizin Berlin, Berlin, Germany and University of Zürich, Switzerland (V.R.-Z.); Department of Human Genetics, David Geffen School of Medicine, and the Molecular Biology Institute, University of California, Los Angeles, California (K.R.); and Departments of Medicine, Pediatrics, and Neuroscience, Washington University School of Medicine, St. Louis, Missouri (J.B.R.)
| | - Heiner K Berthold
- Section of Endocrinology, John W. Deming Department of Medicine, Diabetes Discovery and Sex-Based Medicine Laboratory, Tulane University School of Medicine and Southeast Louisiana Veterans Health Care System Medical Center, New Orleans, Louisiana (F.M.-J.); Department of Internal Medicine and Geriatrics, Bethel Clinic (EvKB), Bielefeld, Germany (H.K.B.); Department of Biomedical Sciences, University of Sassari, Sassari, Italy (I.C.); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (J.-J.C.); W. Harry Feinstone Department of Molecular Microbiology and Immunology, the Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (S.D., S.L.K.); Laboratory of Sex-Gender Medicine, National Institute of Biostructures and Biosystems, Sassari, Italy (F.F.); Polyclinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University of Cologne, Cologne, Germany (I.G.-B.); Scioto Biosciences, Indianapolis, Indiana (M.L.H.); Department of Internal Medicine III, Clinical Division of Endocrinology, Metabolism and Gender Medicine, Medical University of Vienna, Vienna and Gender Institute Gars am Kamp, Vienna, Austria (A.K.-W.); Neuroscience Institute, Georgia State University, Atlanta, Georgia (A.M.); Berlin Institute of Gender Medicine, Charité, Universitätsmedizin Berlin, Berlin, Germany and University of Zürich, Switzerland (V.R.-Z.); Department of Human Genetics, David Geffen School of Medicine, and the Molecular Biology Institute, University of California, Los Angeles, California (K.R.); and Departments of Medicine, Pediatrics, and Neuroscience, Washington University School of Medicine, St. Louis, Missouri (J.B.R.)
| | - Ilaria Campesi
- Section of Endocrinology, John W. Deming Department of Medicine, Diabetes Discovery and Sex-Based Medicine Laboratory, Tulane University School of Medicine and Southeast Louisiana Veterans Health Care System Medical Center, New Orleans, Louisiana (F.M.-J.); Department of Internal Medicine and Geriatrics, Bethel Clinic (EvKB), Bielefeld, Germany (H.K.B.); Department of Biomedical Sciences, University of Sassari, Sassari, Italy (I.C.); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (J.-J.C.); W. Harry Feinstone Department of Molecular Microbiology and Immunology, the Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (S.D., S.L.K.); Laboratory of Sex-Gender Medicine, National Institute of Biostructures and Biosystems, Sassari, Italy (F.F.); Polyclinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University of Cologne, Cologne, Germany (I.G.-B.); Scioto Biosciences, Indianapolis, Indiana (M.L.H.); Department of Internal Medicine III, Clinical Division of Endocrinology, Metabolism and Gender Medicine, Medical University of Vienna, Vienna and Gender Institute Gars am Kamp, Vienna, Austria (A.K.-W.); Neuroscience Institute, Georgia State University, Atlanta, Georgia (A.M.); Berlin Institute of Gender Medicine, Charité, Universitätsmedizin Berlin, Berlin, Germany and University of Zürich, Switzerland (V.R.-Z.); Department of Human Genetics, David Geffen School of Medicine, and the Molecular Biology Institute, University of California, Los Angeles, California (K.R.); and Departments of Medicine, Pediatrics, and Neuroscience, Washington University School of Medicine, St. Louis, Missouri (J.B.R.)
| | - Juan-Jesus Carrero
- Section of Endocrinology, John W. Deming Department of Medicine, Diabetes Discovery and Sex-Based Medicine Laboratory, Tulane University School of Medicine and Southeast Louisiana Veterans Health Care System Medical Center, New Orleans, Louisiana (F.M.-J.); Department of Internal Medicine and Geriatrics, Bethel Clinic (EvKB), Bielefeld, Germany (H.K.B.); Department of Biomedical Sciences, University of Sassari, Sassari, Italy (I.C.); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (J.-J.C.); W. Harry Feinstone Department of Molecular Microbiology and Immunology, the Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (S.D., S.L.K.); Laboratory of Sex-Gender Medicine, National Institute of Biostructures and Biosystems, Sassari, Italy (F.F.); Polyclinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University of Cologne, Cologne, Germany (I.G.-B.); Scioto Biosciences, Indianapolis, Indiana (M.L.H.); Department of Internal Medicine III, Clinical Division of Endocrinology, Metabolism and Gender Medicine, Medical University of Vienna, Vienna and Gender Institute Gars am Kamp, Vienna, Austria (A.K.-W.); Neuroscience Institute, Georgia State University, Atlanta, Georgia (A.M.); Berlin Institute of Gender Medicine, Charité, Universitätsmedizin Berlin, Berlin, Germany and University of Zürich, Switzerland (V.R.-Z.); Department of Human Genetics, David Geffen School of Medicine, and the Molecular Biology Institute, University of California, Los Angeles, California (K.R.); and Departments of Medicine, Pediatrics, and Neuroscience, Washington University School of Medicine, St. Louis, Missouri (J.B.R.)
| | - Santosh Dakal
- Section of Endocrinology, John W. Deming Department of Medicine, Diabetes Discovery and Sex-Based Medicine Laboratory, Tulane University School of Medicine and Southeast Louisiana Veterans Health Care System Medical Center, New Orleans, Louisiana (F.M.-J.); Department of Internal Medicine and Geriatrics, Bethel Clinic (EvKB), Bielefeld, Germany (H.K.B.); Department of Biomedical Sciences, University of Sassari, Sassari, Italy (I.C.); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (J.-J.C.); W. Harry Feinstone Department of Molecular Microbiology and Immunology, the Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (S.D., S.L.K.); Laboratory of Sex-Gender Medicine, National Institute of Biostructures and Biosystems, Sassari, Italy (F.F.); Polyclinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University of Cologne, Cologne, Germany (I.G.-B.); Scioto Biosciences, Indianapolis, Indiana (M.L.H.); Department of Internal Medicine III, Clinical Division of Endocrinology, Metabolism and Gender Medicine, Medical University of Vienna, Vienna and Gender Institute Gars am Kamp, Vienna, Austria (A.K.-W.); Neuroscience Institute, Georgia State University, Atlanta, Georgia (A.M.); Berlin Institute of Gender Medicine, Charité, Universitätsmedizin Berlin, Berlin, Germany and University of Zürich, Switzerland (V.R.-Z.); Department of Human Genetics, David Geffen School of Medicine, and the Molecular Biology Institute, University of California, Los Angeles, California (K.R.); and Departments of Medicine, Pediatrics, and Neuroscience, Washington University School of Medicine, St. Louis, Missouri (J.B.R.)
| | - Flavia Franconi
- Section of Endocrinology, John W. Deming Department of Medicine, Diabetes Discovery and Sex-Based Medicine Laboratory, Tulane University School of Medicine and Southeast Louisiana Veterans Health Care System Medical Center, New Orleans, Louisiana (F.M.-J.); Department of Internal Medicine and Geriatrics, Bethel Clinic (EvKB), Bielefeld, Germany (H.K.B.); Department of Biomedical Sciences, University of Sassari, Sassari, Italy (I.C.); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (J.-J.C.); W. Harry Feinstone Department of Molecular Microbiology and Immunology, the Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (S.D., S.L.K.); Laboratory of Sex-Gender Medicine, National Institute of Biostructures and Biosystems, Sassari, Italy (F.F.); Polyclinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University of Cologne, Cologne, Germany (I.G.-B.); Scioto Biosciences, Indianapolis, Indiana (M.L.H.); Department of Internal Medicine III, Clinical Division of Endocrinology, Metabolism and Gender Medicine, Medical University of Vienna, Vienna and Gender Institute Gars am Kamp, Vienna, Austria (A.K.-W.); Neuroscience Institute, Georgia State University, Atlanta, Georgia (A.M.); Berlin Institute of Gender Medicine, Charité, Universitätsmedizin Berlin, Berlin, Germany and University of Zürich, Switzerland (V.R.-Z.); Department of Human Genetics, David Geffen School of Medicine, and the Molecular Biology Institute, University of California, Los Angeles, California (K.R.); and Departments of Medicine, Pediatrics, and Neuroscience, Washington University School of Medicine, St. Louis, Missouri (J.B.R.)
| | - Ioanna Gouni-Berthold
- Section of Endocrinology, John W. Deming Department of Medicine, Diabetes Discovery and Sex-Based Medicine Laboratory, Tulane University School of Medicine and Southeast Louisiana Veterans Health Care System Medical Center, New Orleans, Louisiana (F.M.-J.); Department of Internal Medicine and Geriatrics, Bethel Clinic (EvKB), Bielefeld, Germany (H.K.B.); Department of Biomedical Sciences, University of Sassari, Sassari, Italy (I.C.); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (J.-J.C.); W. Harry Feinstone Department of Molecular Microbiology and Immunology, the Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (S.D., S.L.K.); Laboratory of Sex-Gender Medicine, National Institute of Biostructures and Biosystems, Sassari, Italy (F.F.); Polyclinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University of Cologne, Cologne, Germany (I.G.-B.); Scioto Biosciences, Indianapolis, Indiana (M.L.H.); Department of Internal Medicine III, Clinical Division of Endocrinology, Metabolism and Gender Medicine, Medical University of Vienna, Vienna and Gender Institute Gars am Kamp, Vienna, Austria (A.K.-W.); Neuroscience Institute, Georgia State University, Atlanta, Georgia (A.M.); Berlin Institute of Gender Medicine, Charité, Universitätsmedizin Berlin, Berlin, Germany and University of Zürich, Switzerland (V.R.-Z.); Department of Human Genetics, David Geffen School of Medicine, and the Molecular Biology Institute, University of California, Los Angeles, California (K.R.); and Departments of Medicine, Pediatrics, and Neuroscience, Washington University School of Medicine, St. Louis, Missouri (J.B.R.)
| | - Mark L Heiman
- Section of Endocrinology, John W. Deming Department of Medicine, Diabetes Discovery and Sex-Based Medicine Laboratory, Tulane University School of Medicine and Southeast Louisiana Veterans Health Care System Medical Center, New Orleans, Louisiana (F.M.-J.); Department of Internal Medicine and Geriatrics, Bethel Clinic (EvKB), Bielefeld, Germany (H.K.B.); Department of Biomedical Sciences, University of Sassari, Sassari, Italy (I.C.); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (J.-J.C.); W. Harry Feinstone Department of Molecular Microbiology and Immunology, the Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (S.D., S.L.K.); Laboratory of Sex-Gender Medicine, National Institute of Biostructures and Biosystems, Sassari, Italy (F.F.); Polyclinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University of Cologne, Cologne, Germany (I.G.-B.); Scioto Biosciences, Indianapolis, Indiana (M.L.H.); Department of Internal Medicine III, Clinical Division of Endocrinology, Metabolism and Gender Medicine, Medical University of Vienna, Vienna and Gender Institute Gars am Kamp, Vienna, Austria (A.K.-W.); Neuroscience Institute, Georgia State University, Atlanta, Georgia (A.M.); Berlin Institute of Gender Medicine, Charité, Universitätsmedizin Berlin, Berlin, Germany and University of Zürich, Switzerland (V.R.-Z.); Department of Human Genetics, David Geffen School of Medicine, and the Molecular Biology Institute, University of California, Los Angeles, California (K.R.); and Departments of Medicine, Pediatrics, and Neuroscience, Washington University School of Medicine, St. Louis, Missouri (J.B.R.)
| | - Alexandra Kautzky-Willer
- Section of Endocrinology, John W. Deming Department of Medicine, Diabetes Discovery and Sex-Based Medicine Laboratory, Tulane University School of Medicine and Southeast Louisiana Veterans Health Care System Medical Center, New Orleans, Louisiana (F.M.-J.); Department of Internal Medicine and Geriatrics, Bethel Clinic (EvKB), Bielefeld, Germany (H.K.B.); Department of Biomedical Sciences, University of Sassari, Sassari, Italy (I.C.); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (J.-J.C.); W. Harry Feinstone Department of Molecular Microbiology and Immunology, the Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (S.D., S.L.K.); Laboratory of Sex-Gender Medicine, National Institute of Biostructures and Biosystems, Sassari, Italy (F.F.); Polyclinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University of Cologne, Cologne, Germany (I.G.-B.); Scioto Biosciences, Indianapolis, Indiana (M.L.H.); Department of Internal Medicine III, Clinical Division of Endocrinology, Metabolism and Gender Medicine, Medical University of Vienna, Vienna and Gender Institute Gars am Kamp, Vienna, Austria (A.K.-W.); Neuroscience Institute, Georgia State University, Atlanta, Georgia (A.M.); Berlin Institute of Gender Medicine, Charité, Universitätsmedizin Berlin, Berlin, Germany and University of Zürich, Switzerland (V.R.-Z.); Department of Human Genetics, David Geffen School of Medicine, and the Molecular Biology Institute, University of California, Los Angeles, California (K.R.); and Departments of Medicine, Pediatrics, and Neuroscience, Washington University School of Medicine, St. Louis, Missouri (J.B.R.)
| | - Sabra L Klein
- Section of Endocrinology, John W. Deming Department of Medicine, Diabetes Discovery and Sex-Based Medicine Laboratory, Tulane University School of Medicine and Southeast Louisiana Veterans Health Care System Medical Center, New Orleans, Louisiana (F.M.-J.); Department of Internal Medicine and Geriatrics, Bethel Clinic (EvKB), Bielefeld, Germany (H.K.B.); Department of Biomedical Sciences, University of Sassari, Sassari, Italy (I.C.); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (J.-J.C.); W. Harry Feinstone Department of Molecular Microbiology and Immunology, the Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (S.D., S.L.K.); Laboratory of Sex-Gender Medicine, National Institute of Biostructures and Biosystems, Sassari, Italy (F.F.); Polyclinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University of Cologne, Cologne, Germany (I.G.-B.); Scioto Biosciences, Indianapolis, Indiana (M.L.H.); Department of Internal Medicine III, Clinical Division of Endocrinology, Metabolism and Gender Medicine, Medical University of Vienna, Vienna and Gender Institute Gars am Kamp, Vienna, Austria (A.K.-W.); Neuroscience Institute, Georgia State University, Atlanta, Georgia (A.M.); Berlin Institute of Gender Medicine, Charité, Universitätsmedizin Berlin, Berlin, Germany and University of Zürich, Switzerland (V.R.-Z.); Department of Human Genetics, David Geffen School of Medicine, and the Molecular Biology Institute, University of California, Los Angeles, California (K.R.); and Departments of Medicine, Pediatrics, and Neuroscience, Washington University School of Medicine, St. Louis, Missouri (J.B.R.)
| | - Anne Murphy
- Section of Endocrinology, John W. Deming Department of Medicine, Diabetes Discovery and Sex-Based Medicine Laboratory, Tulane University School of Medicine and Southeast Louisiana Veterans Health Care System Medical Center, New Orleans, Louisiana (F.M.-J.); Department of Internal Medicine and Geriatrics, Bethel Clinic (EvKB), Bielefeld, Germany (H.K.B.); Department of Biomedical Sciences, University of Sassari, Sassari, Italy (I.C.); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (J.-J.C.); W. Harry Feinstone Department of Molecular Microbiology and Immunology, the Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (S.D., S.L.K.); Laboratory of Sex-Gender Medicine, National Institute of Biostructures and Biosystems, Sassari, Italy (F.F.); Polyclinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University of Cologne, Cologne, Germany (I.G.-B.); Scioto Biosciences, Indianapolis, Indiana (M.L.H.); Department of Internal Medicine III, Clinical Division of Endocrinology, Metabolism and Gender Medicine, Medical University of Vienna, Vienna and Gender Institute Gars am Kamp, Vienna, Austria (A.K.-W.); Neuroscience Institute, Georgia State University, Atlanta, Georgia (A.M.); Berlin Institute of Gender Medicine, Charité, Universitätsmedizin Berlin, Berlin, Germany and University of Zürich, Switzerland (V.R.-Z.); Department of Human Genetics, David Geffen School of Medicine, and the Molecular Biology Institute, University of California, Los Angeles, California (K.R.); and Departments of Medicine, Pediatrics, and Neuroscience, Washington University School of Medicine, St. Louis, Missouri (J.B.R.)
| | - Vera Regitz-Zagrosek
- Section of Endocrinology, John W. Deming Department of Medicine, Diabetes Discovery and Sex-Based Medicine Laboratory, Tulane University School of Medicine and Southeast Louisiana Veterans Health Care System Medical Center, New Orleans, Louisiana (F.M.-J.); Department of Internal Medicine and Geriatrics, Bethel Clinic (EvKB), Bielefeld, Germany (H.K.B.); Department of Biomedical Sciences, University of Sassari, Sassari, Italy (I.C.); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (J.-J.C.); W. Harry Feinstone Department of Molecular Microbiology and Immunology, the Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (S.D., S.L.K.); Laboratory of Sex-Gender Medicine, National Institute of Biostructures and Biosystems, Sassari, Italy (F.F.); Polyclinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University of Cologne, Cologne, Germany (I.G.-B.); Scioto Biosciences, Indianapolis, Indiana (M.L.H.); Department of Internal Medicine III, Clinical Division of Endocrinology, Metabolism and Gender Medicine, Medical University of Vienna, Vienna and Gender Institute Gars am Kamp, Vienna, Austria (A.K.-W.); Neuroscience Institute, Georgia State University, Atlanta, Georgia (A.M.); Berlin Institute of Gender Medicine, Charité, Universitätsmedizin Berlin, Berlin, Germany and University of Zürich, Switzerland (V.R.-Z.); Department of Human Genetics, David Geffen School of Medicine, and the Molecular Biology Institute, University of California, Los Angeles, California (K.R.); and Departments of Medicine, Pediatrics, and Neuroscience, Washington University School of Medicine, St. Louis, Missouri (J.B.R.)
| | - Karen Reue
- Section of Endocrinology, John W. Deming Department of Medicine, Diabetes Discovery and Sex-Based Medicine Laboratory, Tulane University School of Medicine and Southeast Louisiana Veterans Health Care System Medical Center, New Orleans, Louisiana (F.M.-J.); Department of Internal Medicine and Geriatrics, Bethel Clinic (EvKB), Bielefeld, Germany (H.K.B.); Department of Biomedical Sciences, University of Sassari, Sassari, Italy (I.C.); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (J.-J.C.); W. Harry Feinstone Department of Molecular Microbiology and Immunology, the Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (S.D., S.L.K.); Laboratory of Sex-Gender Medicine, National Institute of Biostructures and Biosystems, Sassari, Italy (F.F.); Polyclinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University of Cologne, Cologne, Germany (I.G.-B.); Scioto Biosciences, Indianapolis, Indiana (M.L.H.); Department of Internal Medicine III, Clinical Division of Endocrinology, Metabolism and Gender Medicine, Medical University of Vienna, Vienna and Gender Institute Gars am Kamp, Vienna, Austria (A.K.-W.); Neuroscience Institute, Georgia State University, Atlanta, Georgia (A.M.); Berlin Institute of Gender Medicine, Charité, Universitätsmedizin Berlin, Berlin, Germany and University of Zürich, Switzerland (V.R.-Z.); Department of Human Genetics, David Geffen School of Medicine, and the Molecular Biology Institute, University of California, Los Angeles, California (K.R.); and Departments of Medicine, Pediatrics, and Neuroscience, Washington University School of Medicine, St. Louis, Missouri (J.B.R.)
| | - Joshua B Rubin
- Section of Endocrinology, John W. Deming Department of Medicine, Diabetes Discovery and Sex-Based Medicine Laboratory, Tulane University School of Medicine and Southeast Louisiana Veterans Health Care System Medical Center, New Orleans, Louisiana (F.M.-J.); Department of Internal Medicine and Geriatrics, Bethel Clinic (EvKB), Bielefeld, Germany (H.K.B.); Department of Biomedical Sciences, University of Sassari, Sassari, Italy (I.C.); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (J.-J.C.); W. Harry Feinstone Department of Molecular Microbiology and Immunology, the Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (S.D., S.L.K.); Laboratory of Sex-Gender Medicine, National Institute of Biostructures and Biosystems, Sassari, Italy (F.F.); Polyclinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University of Cologne, Cologne, Germany (I.G.-B.); Scioto Biosciences, Indianapolis, Indiana (M.L.H.); Department of Internal Medicine III, Clinical Division of Endocrinology, Metabolism and Gender Medicine, Medical University of Vienna, Vienna and Gender Institute Gars am Kamp, Vienna, Austria (A.K.-W.); Neuroscience Institute, Georgia State University, Atlanta, Georgia (A.M.); Berlin Institute of Gender Medicine, Charité, Universitätsmedizin Berlin, Berlin, Germany and University of Zürich, Switzerland (V.R.-Z.); Department of Human Genetics, David Geffen School of Medicine, and the Molecular Biology Institute, University of California, Los Angeles, California (K.R.); and Departments of Medicine, Pediatrics, and Neuroscience, Washington University School of Medicine, St. Louis, Missouri (J.B.R.)
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Kathuria D, Raul AD, Wanjari P, Bharatam PV. Biguanides: Species with versatile therapeutic applications. Eur J Med Chem 2021; 219:113378. [PMID: 33857729 DOI: 10.1016/j.ejmech.2021.113378] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Revised: 03/04/2021] [Accepted: 03/08/2021] [Indexed: 12/18/2022]
Abstract
Biguanides are compounds in which two guanidine moieties are fused to form a highly conjugated system. Biguanides are highly basic and hence they are available as salts mostly hydrochloride salts, these cationic species have been found to exhibit many therapeutic properties. This review covers the research and development carried out on biguanides and accounts the various therapeutic applications of drugs containing biguanide group-such as antimalarial, antidiabetic, antiviral, anticancer, antibacterial, antifungal, anti-tubercular, antifilarial, anti-HIV, as well as other biological activities. The aim of this review is to compile all the medicinal chemistry applications of this class of compounds so as to pave way for the accelerated efforts in finding the drug action mechanisms associated with this class of compounds. Importance has been given to the organic chemistry of these biguanide derivatives also.
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Affiliation(s)
- Deepika Kathuria
- University Center for Research and Development, Chandigarh University, Gharuan, Punjab, 140413, India
| | - Akshay D Raul
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar, 160 062, Punjab, India
| | - Pravin Wanjari
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar, 160 062, Punjab, India
| | - Prasad V Bharatam
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar, 160 062, Punjab, India.
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Mdkhana B, Zaher DM, Abdin SM, Omar HA. Tangeretin boosts the anticancer activity of metformin in breast cancer cells via curbing the energy production. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2021; 83:153470. [PMID: 33524703 DOI: 10.1016/j.phymed.2021.153470] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 12/31/2020] [Accepted: 01/14/2021] [Indexed: 06/12/2023]
Abstract
BACKGROUND Breast cancer is the first leading cause of women cancer-related deaths worldwide. While there are many proposed treatments for breast cancer, low efficacy, toxicity, and resistance are still major therapeutic obstacles. Thus, there is a need for safer and more effective therapeutic approaches. Because of the direct link between obesity and carcinogenesis, energy restriction mimetic agents (ERMAs) such as the antidiabetic agent, metformin was proposed as a novel antiproliferative agent. However, the anticancer dose of metformin alone is relatively high and impractical to be implemented safely in patients. The current work aimed to sensitize resistant breast cancer cells to metformin's antiproliferative effect using the natural potential anticancer agent, tangeretin. METHODS The possible synergistic combination between metformin and tangeretin was initially evaluated using MTT cell viability assay in different breast cancer cell lines (MCF-7, MDA-MB-231, and their resistant phenotype). The possible mechanisms of synergy were investigated via Western blotting analysis, reactive oxygen species (ROS) measurement, annexin/PI assay, cell cycle analysis, and wound healing assay. RESULTS The results indicated the ability of tangeretin to improve the anticancer activity of metformin. Interestingly, the improved activity was almost equally observed in both parental and resistant cancer cells, which underlines the importance of this combination in cases of the emergence of resistance. The synergy was mediated through the enhanced activation of AMPK and ROS generation in addition to the improved inhibition of cell migration, induction of cell cycle arrest, and apoptosis in cancer cells. CONCLUSION The current work underscores the importance of metformin as an ERMA in tackling breast cancer and as a novel approach to boost its anticancer activity via a synergistic combination with tangeretin.
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Affiliation(s)
- Bushra Mdkhana
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates; College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Dana M Zaher
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates; College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Shifaa M Abdin
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates; College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Hany A Omar
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates; College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62511 Egypt.
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29
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Behrouzi B, Zokaasadi M, Mohagheghi MA, Emami AH, Sadighi S. The Effect of Metformin on Survival Outcomes of Non-Metastatic Breast Cancer Patients with Type 2 Diabetes. Asian Pac J Cancer Prev 2021; 22:611-616. [PMID: 33639681 PMCID: PMC8190344 DOI: 10.31557/apjcp.2021.22.2.611] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND There are still inconsistencies about the role of metformin on breast cancer. This study was designed to assess metformin's effect on the prognosis of female breast cancer patients with type II diabetes. METHODS The present research was carried out as a retrospective cohort study between 2003 and 2014. Breast cancer patients with pre-existing type II diabetes mellitus were included. Overall survival (OS) and relapse-free survival (RFS) were measured as the main endpoints. Kaplan-Meier estimate was used to calculate survival rates. RESULTS 217 patients were included with a mean age of 53.32±11.10 years. 148 (68.2%) patients were prescribed metformin and 69 (31.8%) took other antidiabetic drugs (non-metformin group). Five-year OS and RFS rates for all patients were 82.5% (95% CI: 76.0%-87.4%) and 71.1% (95% CI: 64.2%-77.0%) respectively. Log-rank test showed that the metformin group had a significant advantage over the non-metformin group in terms of both OS and RFS rates (p.
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Affiliation(s)
- Bita Behrouzi
- Geisel School of Medicine at Dartmouth, Hanover, NH, USA
| | - Mohammad Zokaasadi
- Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Ali Mohagheghi
- The Cancer Research Center of the Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Hosein Emami
- Department of Hematology-Oncology, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, Iran
| | - Sanambar Sadighi
- Department of Hematology-Oncology, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, Iran
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30
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Jiang LL, Liu L. Effect of metformin on stem cells: Molecular mechanism and clinical prospect. World J Stem Cells 2020; 12:1455-1473. [PMID: 33505595 PMCID: PMC7789120 DOI: 10.4252/wjsc.v12.i12.1455] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 09/28/2020] [Accepted: 10/23/2020] [Indexed: 02/06/2023] Open
Abstract
Metformin is a first-line medication for type II diabetes. Numerous studies have shown that metformin not only has hypoglycemic effects, but also modulates many physiological and pathological processes ranging from aging and cancer to fracture healing. During these different physiological activities and pathological changes, stem cells usually play a core role. Thus, many studies have investigated the effects of metformin on stem cells. Metformin affects cell differentiation and has promising applications in stem cell medicine. It exerts anti-aging effects and can be applied to gerontology and regenerative medicine. The potential anti-cancer stem cell effect of metformin indicates that it can be an adjuvant therapy for cancers. Furthermore, metformin has beneficial effects against many other diseases including cardiovascular and autoimmune diseases. In this review, we summarize the effects of metformin on stem cells and provide an overview of its molecular mechanisms and clinical prospects.
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Affiliation(s)
- Lin-Li Jiang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Lei Liu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China.
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31
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Saguyod SJU, Alhallak I, Simmen RCM, Velarde MC. Metformin regulation of progesterone receptor isoform-B expression in human endometrial cancer cells is glucose-dependent. Oncol Lett 2020; 20:249. [PMID: 32994812 PMCID: PMC7509689 DOI: 10.3892/ol.2020.12112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 08/25/2020] [Indexed: 11/17/2022] Open
Abstract
Metformin (MET) constitutes the first-line treatment against type 2 diabetes. Growing evidence linking insulin resistance and cancer risk has expanded the therapeutic potential of MET to several cancer types. However, the oncostatic mechanisms of MET are not well understood. MET has been shown to promote the expression of progesterone receptor (PGR) and other antitumor biomarkers in patients with non-diabetic endometrial cancer (EC) and in Ishikawa EC cells cultured in normal glucose (5.5 mM) media. Therefore, the present study aimed to assess the effects of MET on EC cells under conditions simulating diabetes. Ishikawa cells treated with 10 nM 17β-estradiol (E2) and/or 100 µM MET and exposed to normal and high (17.5 mM) concentrations of glucose were evaluated for proliferative and PGR expression status. Under normal glucose conditions, MET attenuated E2-induced cell proliferation and cyclin D1 gene expression, and increased total PGR and PGR-B transcript levels. MET inhibited Ishikawa cell spheroid formation only in the absence of E2 treatment. In E2-treated cells under high glucose conditions, MET showed no effects on cell proliferation and spheroid formation, and increased total PGR but not PGR-B transcript levels. Transfection with Krüppel-like factor 9 small interfering RNA increased PGR-A transcript levels, irrespective of glucose environment. Medroxyprogesterone acetate downregulated PGR-A expression more effectively with metformin under high compared with normal glucose conditions. To evaluate the potential mechanisms underlying the targeting of PGR by MET, E2-treated cells were incubated with MET and the AMPK inhibitor Compound C, or with the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), under normal glucose conditions. Compound C abrogated the effects of MET on PGR-B while AICAR increased PGR-B transcript levels, albeit less effectively compared with MET. The present results demonstrate the glucose-dependent effects of MET on PGR-B isoform expression, which may inform the response to progestin therapy in diabetic women with EC.
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Affiliation(s)
- Sofia Jade U Saguyod
- Institute of Biology, College of Science, University of the Philippines Diliman, Quezon City, PH 1101, Philippines
| | - Iad Alhallak
- Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Rosalia C M Simmen
- Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.,The Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Michael C Velarde
- Institute of Biology, College of Science, University of the Philippines Diliman, Quezon City, PH 1101, Philippines
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Yari K, Akbari I, Yazdi SAV. Development and evaluation of sodium alginate-basil seeds mucilage beads as a suitable carrier for controlled release of metformin. Int J Biol Macromol 2020; 159:1-10. [PMID: 32330501 DOI: 10.1016/j.ijbiomac.2020.04.111] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 04/15/2020] [Accepted: 04/16/2020] [Indexed: 01/07/2023]
Abstract
Sodium alginate (SA) is a natural biopolymer that is used as biodegradable and non-toxic material in medical and pharmaceutical fields. Although crosslinked SA with calcium ions in the presence of monovalent salts are unstable. The aim of this work is to employe plant mucilage in combination of SA beads to improve the properties of SA beads. SA beads containing metformin drug (MET) were modified using basil seed mucilage (BSM) to achieve controlled release was investigated. The presence of BSM in the SA structure results in more stability, less swelling, and consequently lower release. The effect of pH 1.2 and pH 7.4 on its release and swelling of the beads was studied, and the results showed that the lowest swelling and release was from the acidic environment. Sodium Tripolyphosphate (TPP) as a cross-linker in the bead structure caused a lower release and swelling. The chemical structure of beads was confirmed by FTIR, SEM indicated the porous structure of SA bead and continuous structure of SA/BSM bead and DSC indicated that the presence of BSM in the bead structure decreased the chain motility. Also, cytotoxicity of BSM was investigated by MTT method, and the mucilage toxicity was not confirmed until 3 ml.
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Affiliation(s)
- Kasra Yari
- Chemical and Petroleum Engineering Department, Science and Research Branch, Islamic Azad University, 1477893855 Tehran, Iran
| | - Iman Akbari
- Chemical and Petroleum Engineering Department, Science and Research Branch, Islamic Azad University, 1477893855 Tehran, Iran.
| | - Seyed Ali Vaziri Yazdi
- Chemical and Petroleum Engineering Department, Science and Research Branch, Islamic Azad University, 1477893855 Tehran, Iran.
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Pabona JMP, Burnett AF, Brown DM, Quick CM, Simmen FA, Montales MTE, Liu SJ, Rose T, Alhallak I, Siegel ER, Simmen RC. Metformin Promotes Anti-tumor Biomarkers in Human Endometrial Cancer Cells. Reprod Sci 2020; 27:267-277. [PMID: 32046384 PMCID: PMC7077930 DOI: 10.1007/s43032-019-00019-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 03/28/2019] [Indexed: 12/13/2022]
Abstract
Metformin (MET) is increasingly implicated in reducing the incidence of multiple cancer types in patients with diabetes. However, similar effects of MET in non-diabetic women with endometrial cancer (EC) remain unknown. In a pilot study, obese non-diabetic women diagnosed with type 1, grade 1/2 EC, and consenting to participate were randomly assigned to receive MET or no MET (control (CON)) during the pre-surgical window between diagnosis and hysterectomy. Endometrial tumors obtained at surgery (MET, n = 4; CON, n = 4) were analyzed for proliferation (Ki67), apoptosis (TUNEL), and nuclear expression of ERα, PGR, PTEN, and KLF9 proteins in tumor glandular epithelial (GE) and stromal (ST) cells. The percentages of immunopositive cells for PGR and for KLF9 in GE and for PTEN in ST were higher while those for ERα in GE but not ST were lower, in tumors of MET vs. CON patients. The numbers of Ki67- and TUNEL-positive cells in tumor GE and ST did not differ between groups. In human Ishikawa endometrial cancer cells, MET treatment (60 μM) decreased cell numbers and elicited distinct temporal changes in ESR1, KLF9, PGR, PGR-B, KLF4, DKK1, and other tumor biomarker mRNA levels. In the context of reduced KLF9 expression (by siRNA targeting), MET rapidly amplified PGR, PGR-B, and KLF4 transcript levels. Our findings suggest that MET acts directly in EC cells to modify steroid receptor expression and signaling network and may constitute a preventative strategy against EC in high-risk non-diabetic women.
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Affiliation(s)
- John Mark P Pabona
- Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Alexander F Burnett
- Department of Obstetrics & Gynecology, Division of Gynecologic Oncology, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.,The Winthrop P Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Dustin M Brown
- Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Charles M Quick
- The Winthrop P Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.,Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Frank A Simmen
- Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.,The Winthrop P Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Maria Theresa E Montales
- Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Shi J Liu
- Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Tyler Rose
- Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Iad Alhallak
- Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Eric R Siegel
- Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Rosalia Cm Simmen
- Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, USA. .,The Winthrop P Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
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Wang X, Wang H, Zhang T, Cai L, Dai E, He J. Diabetes and its Potential Impact on Head and Neck Oncogenesis. J Cancer 2020; 11:583-591. [PMID: 31942181 PMCID: PMC6959048 DOI: 10.7150/jca.35607] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Accepted: 09/27/2019] [Indexed: 12/25/2022] Open
Abstract
In recent years, the incidence of diabetes mellitus and cancer has increased sharply; indeed, these have become the two most important diseases threatening health and survival. Head and neck (HN) tumors are the sixth most common malignancies in humans. Numerous studies have shown that there are many common risk factors for diabetes mellitus and HN squamous cell carcinoma, including advanced age, poor diet and lifestyle, and environmental factors. However, the mechanism linking the two diseases has not been identified. A number of studies have shown that diabetes affects the development, metastasis, and prognosis of HN cancer, potentially through the associated hyperglycemia, hyperinsulinemia and insulin resistance, or chronic inflammation. More recent studies show that metformin, the first-line drug for the treatment of type 2 diabetes, can significantly reduce the risk of HN tumor development and reduce mortality in diabetic patients. Here, we review recent progress in the study of the relationship between diabetes mellitus and HN carcinogenesis, and its potential mechanisms, in order to provide a scientific basis for the early diagnosis and effective treatment of these diseases.
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Affiliation(s)
- Xiaofeng Wang
- Department of Stomatology, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
- Pediatric Research Institute, Department of Pediatrics, The University of Louisville School of Medicine, Louisville, KY 40292, USA
| | - Huiyu Wang
- Department of Stomatology, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
| | - Tianfu Zhang
- Department of Stomatology, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
| | - Lu Cai
- Pediatric Research Institute, Department of Pediatrics, The University of Louisville School of Medicine, Louisville, KY 40292, USA
- Departments of Radiation Oncology, Pharmacology, and Toxicology, University of Louisville, Louisville, KY 40202, USA
| | - Enyong Dai
- Department of Oncology and Hematology, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
| | - Jinting He
- Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
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Samuel SM, Varghese E, Kubatka P, Triggle CR, Büsselberg D. Metformin: The Answer to Cancer in a Flower? Current Knowledge and Future Prospects of Metformin as an Anti-Cancer Agent in Breast Cancer. Biomolecules 2019; 9:E846. [PMID: 31835318 PMCID: PMC6995629 DOI: 10.3390/biom9120846] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 12/02/2019] [Accepted: 12/06/2019] [Indexed: 12/25/2022] Open
Abstract
Interest has grown in studying the possible use of well-known anti-diabetic drugs as anti-cancer agents individually or in combination with, frequently used, chemotherapeutic agents and/or radiation, owing to the fact that diabetes heightens the risk, incidence, and rapid progression of cancers, including breast cancer, in an individual. In this regard, metformin (1, 1-dimethylbiguanide), well known as 'Glucophage' among diabetics, was reported to be cancer preventive while also being a potent anti-proliferative and anti-cancer agent. While meta-analysis studies reported a lower risk and incidence of breast cancer among diabetic individuals on a metformin treatment regimen, several in vitro, pre-clinical, and clinical studies reported the efficacy of using metformin individually as an anti-cancer/anti-tumor agent or in combination with chemotherapeutic drugs or radiation in the treatment of different forms of breast cancer. However, unanswered questions remain with regards to areas such as cancer treatment specific therapeutic dosing of metformin, specificity to cancer cells at high concentrations, resistance to metformin therapy, efficacy of combinatory therapeutic approaches, post-therapeutic relapse of the disease, and efficacy in cancer prevention in non-diabetic individuals. In the current article, we discuss the biology of metformin and its molecular mechanism of action, the existing cellular, pre-clinical, and clinical studies that have tested the anti-tumor potential of metformin as a potential anti-cancer/anti-tumor agent in breast cancer therapy, and outline the future prospects and directions for a better understanding and re-purposing of metformin as an anti-cancer drug in the treatment of breast cancer.
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Affiliation(s)
- Samson Mathews Samuel
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar;
| | - Elizabeth Varghese
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar;
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia;
| | - Chris R. Triggle
- Department of Pharmacology, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar;
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar;
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Mathews Samuel S, Satheesh NJ, Ghosh S, Büsselberg D, Majeed Y, Ding H, Triggle CR. Treatment with a Combination of Metformin and 2-Deoxyglucose Upregulates Thrombospondin-1 in Microvascular Endothelial Cells: Implications in Anti-Angiogenic Cancer Therapy. Cancers (Basel) 2019; 11:E1737. [PMID: 31698699 PMCID: PMC6895998 DOI: 10.3390/cancers11111737] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 10/28/2019] [Accepted: 10/29/2019] [Indexed: 12/12/2022] Open
Abstract
Metformin, the most widely used anti-diabetic drug, also exhibits anti-cancer properties; however, the true potential of metformin as an anticancer drug remains largely unknown. In this study using mouse microvascular endothelial cells (MMECs), we investigated the effects of metformin alone or in combination with the glycolytic inhibitor, 2-deoxyglucose (2DG), on angiogenesis-a process known to be an integral part of tumor growth, cancer cell survival and metastasis. MMECs were exposed to 2DG (1-10 mM) for 48 h in the absence or presence of metformin (2 mM). The status of angiogenic and anti-angiogenic marker proteins, proteins of the mTOR pathway and cell-cycle-related proteins were quantified by Western blot analysis. Assays for cell proliferation, migration and tubulogenesis were also performed. We observed robust up-regulation of anti-angiogenic thrombospondin-1 (TSP1) and increased TSP1-CD36 co-localization with a marked decrease in the levels of phosphorylated vascular endothelial growth factor receptor-2 (pVEGFR2; Y1175) in 2DG (5 mM) exposed cells treated with metformin (2 mM). Additionally, treatment with metformin and 2DG (5 mM) inhibited the Akt/mTOR pathway and down-regulated the cell-cycle-related proteins such as p-cyclin B1 (S147) and cyclins D1 and D2 when compared to cells that were treated with either 2DG or metformin alone. Treatment with a combination of 2DG (5 mM) and metformin (2 mM) also significantly decreased cell proliferation, migration and tubulogenic capacity when compared to cells that were treated with either 2DG or metformin alone. The up-regulation of TSP1, inhibition of cell proliferation, migration and tubulogenesis provides support to the argument that the combination of metformin and 2DG may prove to be an appropriate anti-proliferative and anti-angiogenic therapeutic strategy for the treatment of some cancers.
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Affiliation(s)
- Samson Mathews Samuel
- Department of Pharmacology, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar; (N.J.S.); (S.G.); (Y.M.); (H.D.)
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar;
| | - Noothan Jyothi Satheesh
- Department of Pharmacology, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar; (N.J.S.); (S.G.); (Y.M.); (H.D.)
| | - Suparna Ghosh
- Department of Pharmacology, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar; (N.J.S.); (S.G.); (Y.M.); (H.D.)
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar;
| | - Yasser Majeed
- Department of Pharmacology, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar; (N.J.S.); (S.G.); (Y.M.); (H.D.)
| | - Hong Ding
- Department of Pharmacology, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar; (N.J.S.); (S.G.); (Y.M.); (H.D.)
- Department of Medical Education, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar
| | - Chris R. Triggle
- Department of Pharmacology, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar; (N.J.S.); (S.G.); (Y.M.); (H.D.)
- Department of Medical Education, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar
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Lee JO, Kang MJ, Byun WS, Kim SA, Seo IH, Han JA, Moon JW, Kim JH, Kim SJ, Lee EJ, In Park S, Park SH, Kim HS. Metformin overcomes resistance to cisplatin in triple-negative breast cancer (TNBC) cells by targeting RAD51. Breast Cancer Res 2019; 21:115. [PMID: 31640742 PMCID: PMC6805313 DOI: 10.1186/s13058-019-1204-2] [Citation(s) in RCA: 96] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Accepted: 09/20/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Chemotherapy is a standard therapeutic regimen to treat triple-negative breast cancer (TNBC); however, chemotherapy alone does not result in significant improvement and often leads to drug resistance in patients. In contrast, combination therapy has proven to be an effective strategy for TNBC treatment. Whether metformin enhances the anticancer effects of cisplatin and prevents cisplatin resistance in TNBC cells has not been reported. METHODS Cell viability, wounding healing, and invasion assays were performed on Hs 578T and MDA-MB-231 human TNBC cell lines to demonstrate the anticancer effects of combined cisplatin and metformin treatment compared to treatment with cisplatin alone. Western blotting and immunofluorescence were used to determine the expression of RAD51 and gamma-H2AX. In an in vivo 4T1 murine breast cancer model, a synergistic anticancer effect of metformin and cisplatin was observed. RESULTS Cisplatin combined with metformin decreased cell viability and metastatic effect more than cisplatin alone. Metformin suppressed cisplatin-mediated RAD51 upregulation by decreasing RAD51 protein stability and increasing its ubiquitination. In contrast, cisplatin increased RAD51 expression in an ERK-dependent manner. In addition, metformin also increased cisplatin-induced phosphorylation of γ-H2AX. Overexpression of RAD51 blocked the metformin-induced inhibition of cell migration and invasion, while RAD51 knockdown enhanced cisplatin activity. Moreover, the combination of metformin and cisplatin exhibited a synergistic anticancer effect in an orthotopic murine model of 4T1 breast cancer in vivo. CONCLUSIONS Metformin enhances anticancer effect of cisplatin by downregulating RAD51 expression, which represents a novel therapeutic target in TNBC management.
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Affiliation(s)
- Jung Ok Lee
- Department of Anatomy, Korea University College of Medicine, 126-1, Anam-dong 5-ga, Seongbuk-gu, Seoul, Republic of Korea
| | - Min Ju Kang
- Department of Anatomy, Korea University College of Medicine, 126-1, Anam-dong 5-ga, Seongbuk-gu, Seoul, Republic of Korea
| | - Won Seok Byun
- Department of Anatomy, Korea University College of Medicine, 126-1, Anam-dong 5-ga, Seongbuk-gu, Seoul, Republic of Korea
| | - Shin Ae Kim
- Department of Anatomy, Korea University College of Medicine, 126-1, Anam-dong 5-ga, Seongbuk-gu, Seoul, Republic of Korea
| | - Il Hyeok Seo
- Department of Anatomy, Korea University College of Medicine, 126-1, Anam-dong 5-ga, Seongbuk-gu, Seoul, Republic of Korea
| | - Jeong Ah Han
- Department of Anatomy, Korea University College of Medicine, 126-1, Anam-dong 5-ga, Seongbuk-gu, Seoul, Republic of Korea
| | - Ji Wook Moon
- Department of Anatomy, Korea University College of Medicine, 126-1, Anam-dong 5-ga, Seongbuk-gu, Seoul, Republic of Korea
| | - Ji Hae Kim
- Department of Anatomy, Korea University College of Medicine, 126-1, Anam-dong 5-ga, Seongbuk-gu, Seoul, Republic of Korea
| | - Su Jin Kim
- Department of Anatomy, Korea University College of Medicine, 126-1, Anam-dong 5-ga, Seongbuk-gu, Seoul, Republic of Korea
| | - Eun Jung Lee
- Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, Republic of Korea
| | - Serk In Park
- Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, Republic of Korea
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Sun Hwa Park
- Department of Anatomy, Korea University College of Medicine, 126-1, Anam-dong 5-ga, Seongbuk-gu, Seoul, Republic of Korea
| | - Hyeon Soo Kim
- Department of Anatomy, Korea University College of Medicine, 126-1, Anam-dong 5-ga, Seongbuk-gu, Seoul, Republic of Korea.
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Courtois S, Lehours P, Bessède E. The therapeutic potential of metformin in gastric cancer. Gastric Cancer 2019; 22:653-662. [PMID: 30900101 DOI: 10.1007/s10120-019-00952-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 03/11/2019] [Indexed: 02/07/2023]
Abstract
Metformin is a biguanide molecule used since 1957 to treat type 2 diabetes patients. In addition to its hypoglycemic effects, epidemiological studies have shown that metformin can be associated with a decrease in cancer development risk in diabetic populations. Thus, since 2005 this molecule is largely studied for its antitumoural properties in different types of cancer. The potential antitumoural effect of metformin in gastric cancer has been poorly studied. Here, we detailed the different described mechanisms implicated in the antitumoural effect of metformin in gastric cancer, from the signalling pathways to the functional effects on gastric cancer cell lines and gastric cancer stem cells.
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Affiliation(s)
- Sarah Courtois
- INSERM, Univ. Bordeaux, UMR1053 Bordeaux Research In Translational Oncology, BaRITOn, 33000, Bordeaux, France.
| | - Philippe Lehours
- INSERM, Univ. Bordeaux, UMR1053 Bordeaux Research In Translational Oncology, BaRITOn, 33000, Bordeaux, France.,French National Reference Center for Campylobacters and Helicobacters in Bordeaux (CNRCH), University Hospital of Bordeaux, Bordeaux, France
| | - Emilie Bessède
- INSERM, Univ. Bordeaux, UMR1053 Bordeaux Research In Translational Oncology, BaRITOn, 33000, Bordeaux, France.,French National Reference Center for Campylobacters and Helicobacters in Bordeaux (CNRCH), University Hospital of Bordeaux, Bordeaux, France
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Metformin in breast cancer: preclinical and clinical evidence. Curr Probl Cancer 2019; 44:100488. [PMID: 31235186 DOI: 10.1016/j.currproblcancer.2019.06.003] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Revised: 03/25/2019] [Accepted: 06/08/2019] [Indexed: 12/11/2022]
Abstract
Metformin, a well-acknowledged biguanide, safety profile and multiaction drug with low cost for management of type 2 diabetes, makes a first-class candidate for repurposing. The off-patent drug draws huge attention for repositioned for anticancer drug delivery recently. Still few unanswered questions are challenging, among them one leading question; can metformin use as a generic therapy for all breast cancer subtypes? And is metformin able to get over the problem of drug resistance? The review focused on the mechanisms of metformin action specifically for breast cancer therapy and overcoming the resistance; also discusses preclinical and ongoing and completed clinical trials. The existing limitation such as therapeutic dose specifically for cancer treatment, resistance of metformin in breast cancer and organic cation transporters heterogeneity of the drug opens up a new pathway for improved understanding and successful application as repurposed effective chemotherapeutics for breast cancer. However, much more additional research is needed to confirm the accurate efficacy of metformin treatment for prevention of cancer and its recurrence.
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40
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Wang JC, Li GY, Wang B, Han SX, Sun X, Jiang YN, Shen YW, Zhou C, Feng J, Lu SY, Liu JL, Wang MD, Liu PJ. Metformin inhibits metastatic breast cancer progression and improves chemosensitivity by inducing vessel normalization via PDGF-B downregulation. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:235. [PMID: 31164151 PMCID: PMC6549289 DOI: 10.1186/s13046-019-1211-2] [Citation(s) in RCA: 95] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 05/03/2019] [Indexed: 12/29/2022]
Abstract
Background Vascular maturity and functionality are closely associated with tumor progression and chemosensitivity. The antidiabetic agent metformin has shown its ability to inhibit tumor angiogenesis in metastatic breast cancer models. However, it remains unclear if or how metformin remodels the abnormal vasculature of metastatic breast cancer, while inhibiting angiogenesis. Methods Metastatic breast cancer models were constructed to compare microvessel density (MVD), vascular maturity and function, lung metastasis and chemosensitivity in metformin-treated or untreated mice. Protein array assay and transcriptome sequencing were performed for genetic screening. Lentiviral shRNA-PDGF-B transfection was used for observing the contribution of PDGF-B knockdown to metformin’s vascular effects. Results Metastatic breast cancers were characterized by an excessively angiogenic, immature and morphologically abnormal vasculature. Compared to control, metformin significantly reduced MVD, leakage and hypoxia, and increased vascular mural cells coverage and perfusion, namely, “vessel normalization”. Metformin at human blood concentrations had no direct effect on the migration and proliferation of cancer cells. Based on that, reduced lung metastasis of the primary tumor and improved chemosensitization by metformin were assumed to be mediated via metformin’s vascular effects. Further results of genetic screening and in vivo experiments showed that the downregulation of platelet-derived growth factor B (PDGF-B) greatly contributed to the metformin-induced vessel normalization. Conclusions These findings provide pre-clinical evidences for the vascular mechanism of metformin-induced metastasis inhibition and the chemosensitization of metastatic breast cancers. Electronic supplementary material The online version of this article (10.1186/s13046-019-1211-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Ji-Chang Wang
- Department of Vascular Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China.,Center for Translational Medicine, First Affiliated Hospital of Xi'an Jiaotong University, No. 277 of the Western Yanta Road, Xi'an, 710061, Shaanxi Province, China
| | - Guang-Yue Li
- Department of Science and Technology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
| | - Bo Wang
- Center for Translational Medicine, First Affiliated Hospital of Xi'an Jiaotong University, No. 277 of the Western Yanta Road, Xi'an, 710061, Shaanxi Province, China
| | - Su-Xia Han
- Department of Oncological Radiotherapy, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
| | - Xin Sun
- Department of Thoracic Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
| | - Yi-Na Jiang
- Department of Pathology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
| | - Yan-Wei Shen
- Department of Breast Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
| | - Can Zhou
- Department of Medical Oncology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
| | - Jun Feng
- Department of Vascular Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
| | - Shao-Ying Lu
- Department of Vascular Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
| | - Jian-Lin Liu
- Department of Vascular Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
| | - Mao-De Wang
- Department of Neurosurgery, First Affiliated Hospital of Xi'an Jiaotong University, No. 277 of the Western Yanta Road, Xi'an, 710061, Shaanxi Province, China.
| | - Pei-Jun Liu
- Center for Translational Medicine, First Affiliated Hospital of Xi'an Jiaotong University, No. 277 of the Western Yanta Road, Xi'an, 710061, Shaanxi Province, China. .,Key Laboratory for Tumor Precision Medicine of Shaanxi Province, First Affiliated Hospital of Xi'an Jiaotong University, No. 277 of the Western Yanta Road, Xi'an, 710061, Shaanxi Province, China.
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Osama H, Sayed OM, Hussein RRS, Abdelrahim M, A. Elberry A. Design, optimization, characterization, and in vivo evaluation of sterosomes as a carrier of metformin for treatment of lung cancer. J Liposome Res 2019; 30:150-162. [DOI: 10.1080/08982104.2019.1610434] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Affiliation(s)
- Hasnaa Osama
- Department of Clinical Pharmacy, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Ossama M. Sayed
- Department of Pharmaceutics, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Raghda R. S. Hussein
- Department of Clinical Pharmacy, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Mohamed Abdelrahim
- Department of Clinical Pharmacy, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Ahmed A. Elberry
- Department of Clinical Pharmacology, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt
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Ferretti AC, Hidalgo F, Tonucci FM, Almada E, Pariani A, Larocca MC, Favre C. Metformin and glucose starvation decrease the migratory ability of hepatocellular carcinoma cells: targeting AMPK activation to control migration. Sci Rep 2019; 9:2815. [PMID: 30809021 PMCID: PMC6391381 DOI: 10.1038/s41598-019-39556-w] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Accepted: 01/17/2019] [Indexed: 12/22/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly metastatic cancer with very poor prognosis. AMP activated kinase (AMPK) constitutes a candidate to inhibit HCC progression. First, AMPK is downregulated in HCC. Second, glucose starvation induces apoptosis in HCC cells via AMPK. Correspondingly, metformin activates AMPK and inhibits HCC cell proliferation. Nevertheless, the effect of AMPK activation on HCC cell invasiveness remains elusive. Here, migration/invasion was studied in HCC cells exposed to metformin and glucose starvation. Cell viability, proliferation and differentiation, as well as AMPK and PKA activation were analyzed. In addition, invasiveness in mutants of the AMPKα activation loop was assessed. Metformin decreased cell migration, invasion and epithelial-mesenchymal transition, and interference with AMPKα expression avoided metformin actions. Those antitumor effects were potentiated by glucose deprivation. Metformin activated AMPK at the same time that inhibited PKA, and both effects were enhanced by glucose starvation. Given that AMPKα(S173) phosphorylation by PKA decreases AMPK activation, we hypothesized that the reduction of PKA inhibitory effect by metformin could explain the increased antitumor effects observed. Supporting this, in AMPK activating conditions, cell migration/invasion was further impaired in AMPKα(S173C) mutant cells. Metformin emerges as a strong inhibitor of migration/invasion in HCC cells, and glucose restriction potentiates this effect.
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Affiliation(s)
- Anabela C Ferretti
- Institute of Experimental Physiology, CONICET, School of Biochemical Sciences, University of Rosario, Rosario, Argentina
| | - Florencia Hidalgo
- Institute of Experimental Physiology, CONICET, School of Biochemical Sciences, University of Rosario, Rosario, Argentina
| | - Facundo M Tonucci
- Institute of Experimental Physiology, CONICET, School of Biochemical Sciences, University of Rosario, Rosario, Argentina
| | - Evangelina Almada
- Institute of Experimental Physiology, CONICET, School of Biochemical Sciences, University of Rosario, Rosario, Argentina
| | - Alejandro Pariani
- Institute of Experimental Physiology, CONICET, School of Biochemical Sciences, University of Rosario, Rosario, Argentina
| | - María C Larocca
- Institute of Experimental Physiology, CONICET, School of Biochemical Sciences, University of Rosario, Rosario, Argentina
| | - Cristián Favre
- Institute of Experimental Physiology, CONICET, School of Biochemical Sciences, University of Rosario, Rosario, Argentina.
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Lee BB, Kim Y, Kim D, Cho EY, Han J, Kim HK, Shim YM, Kim DH. Metformin and tenovin-6 synergistically induces apoptosis through LKB1-independent SIRT1 down-regulation in non-small cell lung cancer cells. J Cell Mol Med 2019; 23:2872-2889. [PMID: 30710424 PMCID: PMC6433689 DOI: 10.1111/jcmm.14194] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 11/26/2018] [Accepted: 01/02/2019] [Indexed: 12/20/2022] Open
Abstract
Sirtuin 1 (SIRT1) is known to play a role in a variety of tumorigenesis processes by deacetylating histone and non‐histone proteins; however, antitumour effects by suppressing SIRT1 activity in non‐small cell lung cancer (NSCLC) remain unclear. This study was designed to scrutinize clinicopathological significance of SIRT1 in NSCLC and investigate effects of metformin on SIRT1 inhibition. This study also evaluated new possibilities of drug combination using a SIRT1 inhibitor, tenovin‐6, in NSCLC cell lines. It was found that SIRT1 was overexpressed in 300 (62%) of 485 formalin‐fixed paraffin‐embedded NSCLC tissues. Its overexpression was significantly associated with reduced overall survival and poor recurrence‐free survival after adjusted for histology and pathologic stage. Thus, suppression of SIRT1 expression may be a reasonable therapeutic strategy for NSCLC. Metformin in combination with tenovin‐6 was found to be more effective in inhibiting cell growth than either agent alone in NSCLC cell lines with different liver kinase B1 (LKB1) status. In addition, metformin and tenovin‐6 synergistically suppressed SIRT1 expression in NSCLC cells regardless of LKB1 status. The marked reduction in SIRT1 expression by combination of metformin and tenovin‐6 increased acetylation of p53 at lysine 382 and enhanced p53 stability in LKB1‐deficient A549 cells. The combination suppressed SIRT1 promoter activity more effectively than either agent alone by up‐regulating hypermethylation in cancer 1 (HIC1) binding at SIRT1 promoter. Also, suppressed SIRT1 expression by the combination synergistically induced caspase‐3‐dependent apoptosis. The study concluded that metformin with tenovin‐6 may enhance antitumour effects through LKB1‐independent SIRT1 down‐regulation in NSCLC cells.
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Affiliation(s)
- Bo Bin Lee
- Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea
| | - Yujin Kim
- Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea
| | - Dongho Kim
- Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea
| | - Eun Yoon Cho
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Joungho Han
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hong Kwan Kim
- Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Young Mog Shim
- Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Duk-Hwan Kim
- Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea
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Xiong C, Yin D, Li J, Huang Q, Ravoori MK, Kundra V, Zhu H, Yang Z, Lu Y, Li C. Metformin Reduces Renal Uptake of Radiotracers and Protects Kidneys from Radiation-Induced Damage. Mol Pharm 2019; 16:808-815. [PMID: 30608713 DOI: 10.1021/acs.molpharmaceut.8b01091] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Metformin is the most widely prescribed drug for type 2 diabetes. Chemically, metformin is a hydrophilic base that functions as an organic cation, suggesting that it may have the capacity to inhibit the tubular reabsorption of peptide radiotracers. The purpose of this study was to investigate whether metformin could reduce renal uptake of peptidyl radiotracers and serve as a radioprotective agent for peptide receptor radionuclide therapy (PRRT). METHODS We used two radiolabeled peptides: a 68Ga-labeled cyclic (TNYL-RAW) peptide (68Ga-NOTA-c(TNYL-RAW) (NOTA: 1,4,7 triazacyclononane-1,4,7-trisacetic acid) targeting EphB4 receptors and an 111In- or 64Cu-labeled octreotide (111In/64Cu-DOTA-octreotide) (DOTA: 1,4,7,10 triazacyclododecane-1,4,7,10-tetraacetic acid) targeting somatostatin receptors. Each radiotracer was injected intravenously into normal Swiss mice or tumor-bearing nude mice in the presence or absence of metformin administered intravenously or orally. Micropositron emission tomography or microsingle-photon emission computed tomography images were acquired at different times after radiotracer injection, and biodistribution studies were performed at the end of the imaging session. To assess the radioprotective effect of metformin on the kidneys, normal Swiss mice received two doses of 111In-DOTA-octreotidein the presence or absence of metformin, and renal function was analyzed via blood chemistry and histology. RESULTS Intravenous injection of metformin with 68Ga-NOTA-c(TNYL-RAW) or 111In-DOTA-octreotide reduced the renal uptake of the radiotracer by 60% and 35%, respectively, compared to uptake without metformin. These reductions were accompanied by greater uptake in the tumors for both radiolabeled peptides. Moreover, the renal uptake of 111In-DOTA-octreotide was significantly reduced when metformin was administered via oral gavage. Significantly more radioactivity was recovered in the urine collected over a period of 24 h after intravenous injection of 64Cu-DOTA-octreotide in mice that received oral metformin than in mice that received vehicle. Finally, coadministration of 111In-DOTA-octreotide with metformin mitigated radio-nephrotoxicity. CONCLUSION Metformin inhibits kidney uptake of peptidyl radiotracers, protecting the kidney from nephrotoxicity. Further studies are needed to elucidate the mechanisms of these finding and to optimize mitigation of radiation-induced damage to kidney in PRRT.
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Affiliation(s)
| | | | | | | | | | | | - Hua Zhu
- Department of Nuclear Medicine , Peking University Cancer Hospital & Institute , Beijing , 100142 , PR China
| | - Zhi Yang
- Department of Nuclear Medicine , Peking University Cancer Hospital & Institute , Beijing , 100142 , PR China
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Pan YH, Jiao L, Lin CY, Lu CH, Li L, Chen HY, Wang YB, He Y. Combined treatment with metformin and gefitinib overcomes primary resistance to EGFR-TKIs with EGFR mutation via targeting IGF-1R signaling pathway. Biologics 2018; 12:75-86. [PMID: 30154647 PMCID: PMC6108345 DOI: 10.2147/btt.s166867] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Aim Although EGFR tyrosine kinase inhibitors (TKIs) have shown dramatic effects against sensitizing EGFR mutations in non-small cell lung cancer (NSCLC), ~20%–30% of NSCLC patients with EGFR-sensitive mutation exhibit intrinsic resistance to EGFR-TKIs. The purpose of the current study was to investigate the enhanced antitumor effect of metformin (Met), a biguanide drug, in combination with gefitinib (Gef) in primary resistant human lung cancer cells and the associated molecular mechanism. Experimental design H1975 cell line was treated with Met and/or Gef to examine the inhibition of cell growth and potential mechanism of action by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Ki67 incorporation assay, flow cytometry analysis, small interfering RNA technology, Western blot analysis and xenograft implantation. Results Insulin-like growth factor-1 receptor (IGF-1R) signaling pathway was markedly activated in EGFR-TKI primary resistant H1975 cells as compared to EGFR-TKI acquired resistance cells (PC-9GR, H1650-M3) and EGFR-TKI sensitivity cells (PC-9, HCC827). Inhibition of IGF-1R activity by AG-1024 (a small molecule of IGF-1R inhibitor), as well as downregulation of IGF-1R by siRNA, significantly enhanced the ability of Gef to suppress proliferation and induce apoptosis in H1975 cells via the inhibition of AKT activation and subsequent upregulation of Bcl-2-interacting mediator of cell death (BIM). Interestingly, the observation showed that Met combined with Gef treatment had similar tumor growth suppression effects in comparison with the addition of AG-1024 to therapy with Gef. A clear synergistic antiproliferative interaction between Met and Gef was observed with a combination index (CI) value of 0.65. Notably, IGF-1R silencing mediated by RNA interference (RNAi) attenuated anticancer effects of Met without obviously resensitizing H1975 cells to Gef. Finally, Met-based combinatorial therapy effectively blocked tumor growth in the xenograft with TKI primary resistant lung cancer cells. Conclusion Our findings demonstrated that Met combined with Gef would be a promising strategy to overcome EGFR-TKI primary resistance via suppressing IGF-1R signaling pathway in NSCLC.
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Affiliation(s)
- Yong-Hong Pan
- Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing 400042, China,
| | - Lin Jiao
- Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing 400042, China,
| | - Cai-Yu Lin
- Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing 400042, China,
| | - Cong-Hua Lu
- Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing 400042, China,
| | - Li Li
- Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing 400042, China,
| | - Heng-Yi Chen
- Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing 400042, China,
| | - Yu-Bo Wang
- Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing 400042, China,
| | - Yong He
- Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing 400042, China,
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46
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Challenges and perspectives in the treatment of diabetes associated breast cancer. Cancer Treat Rev 2018; 70:98-111. [PMID: 30130687 DOI: 10.1016/j.ctrv.2018.08.004] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Revised: 08/02/2018] [Accepted: 08/09/2018] [Indexed: 12/12/2022]
Abstract
Type 2 diabetes mellitus is one of the most common chronic disease worldwide and affects all cross-sections of the society including children, women, youth and adults. Scientific evidence has linked diabetes to higher incidence, accelerated progression and increased aggressiveness of different cancers. Among the different forms of cancer, research has reinforced a link between diabetes and the risk of breast cancer. Some studies have specifically linked diabetes to the highly aggressive, triple negative breast cancers (TNBCs) which do not respond to conventional hormonal/HER2 targeted interventions, have chances of early recurrence, metastasize, tend to be more invasive in nature and develop drug resistance. Commonly used anti-diabetic drugs, such as metformin, have recently gained importance in the treatment of breast cancer due to their proposed anti-cancer properties. Here we discuss the link between diabetes and breast cancer, the metabolic disturbances in diabetes that support the development of breast cancer, the challenges involved and future perspective and directions. We link the three main metabolic disturbances (dyslipidemia, hyperinsulinemia and hyperglycemia) that occur in diabetes to potential aberrant molecular pathways that may lead to the development of an oncogenic phenotype of the breast tissue, thereby leading to acceleration of cell growth, proliferation, migration, inflammation, angiogenesis, EMT and metastasis and inhibition of apoptosis in breast cancer cells. Furthermore, managing diabetes and treating cancer using a combination of anti-diabetic and classical anti-cancer drugs should prove to be more efficient in the treatment diabetes associated cancers.
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Fang J, Yang J, Wu X, Zhang G, Li T, Wang X, Zhang H, Wang C, Liu G, Wang L. Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7. Aging Cell 2018; 17:e12765. [PMID: 29659168 PMCID: PMC6052468 DOI: 10.1111/acel.12765] [Citation(s) in RCA: 127] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/08/2018] [Indexed: 12/16/2022] Open
Abstract
Metformin, an FDA-approved antidiabetic drug, has been shown to elongate lifespan in animal models. Nevertheless, the effects of metformin on human cells remain unclear. Here, we show that low-dose metformin treatment extends the lifespan of human diploid fibroblasts and mesenchymal stem cells. We report that a low dose of metformin upregulates the endoplasmic reticulum-localized glutathione peroxidase 7 (GPx7). GP×7 expression levels are decreased in senescent human cells, and GPx7 depletion results in premature cellular senescence. We also indicate that metformin increases the nuclear accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2), which binds to the antioxidant response elements in the GPX7 gene promoter to induce its expression. Moreover, the metformin-Nrf2-GPx7 pathway delays aging in worms. Our study provides mechanistic insights into the beneficial effects of metformin on human cellular aging and highlights the importance of the Nrf2-GPx7 pathway in pro-longevity signaling.
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Affiliation(s)
- Jingqi Fang
- National Laboratory of BiomacromoleculesCAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijingChina
- College of Life SciencesUniversity of Chinese Academy of SciencesBeijingChina
| | - Jiping Yang
- National Laboratory of BiomacromoleculesCAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijingChina
- College of Life SciencesUniversity of Chinese Academy of SciencesBeijingChina
| | - Xun Wu
- National Laboratory of BiomacromoleculesCAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijingChina
- College of Life SciencesUniversity of Chinese Academy of SciencesBeijingChina
| | - Gangming Zhang
- National Laboratory of BiomacromoleculesCAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijingChina
- College of Life SciencesUniversity of Chinese Academy of SciencesBeijingChina
| | - Tao Li
- National Laboratory of BiomacromoleculesCAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijingChina
- College of Life SciencesUniversity of Chinese Academy of SciencesBeijingChina
| | - Xi'e Wang
- National Laboratory of BiomacromoleculesCAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijingChina
| | - Hong Zhang
- National Laboratory of BiomacromoleculesCAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijingChina
- College of Life SciencesUniversity of Chinese Academy of SciencesBeijingChina
| | - Chih‐chen Wang
- National Laboratory of BiomacromoleculesCAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijingChina
- College of Life SciencesUniversity of Chinese Academy of SciencesBeijingChina
| | - Guang‐Hui Liu
- National Laboratory of BiomacromoleculesCAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijingChina
- College of Life SciencesUniversity of Chinese Academy of SciencesBeijingChina
- National Clinical Research Center for Geriatric DisordersXuanwu Hospital of Capital Medical UniversityBeijingChina
| | - Lei Wang
- National Laboratory of BiomacromoleculesCAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijingChina
- College of Life SciencesUniversity of Chinese Academy of SciencesBeijingChina
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48
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Sena P, Mancini S, Benincasa M, Mariani F, Palumbo C, Roncucci L. Metformin Induces Apoptosis and Alters Cellular Responses to Oxidative Stress in Ht29 Colon Cancer Cells: Preliminary Findings. Int J Mol Sci 2018; 19:1478. [PMID: 29772687 PMCID: PMC5983851 DOI: 10.3390/ijms19051478] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Revised: 04/25/2018] [Accepted: 05/10/2018] [Indexed: 12/25/2022] Open
Abstract
Accumulating evidence suggests that metformin, used as an antidiabetic drug, possesses anti-cancer properties. Metformin reduced the incidence and growth of experimental tumors in vivo. In a randomized clinical trial among nondiabetic patients, metformin treatment significantly decreased the number of aberrant crypt foci compared to the untreated group with a follow-up of 1 month. In our study, HT29 cells were treated with graded concentrations of metformin, 10 mM/25 mM/50 mM for 24/48 h. We performed immunofluorescence experiments by means of confocal microscopy and western blot analysis to evaluate a panel of factors involved in apoptotic/autophagic processes and oxidative stress response. Moreover, HT29 cells treated with metformin were analyzed by a flow cytometry assay to detect the cell apoptotic rate. The results demonstrate that metformin exerts growth inhibitory effects on cultured HT29 cells by increasing both apoptosis and autophagy; moreover, it affects the survival of cultured cells inhibiting the transcriptional activation of Nuclear factor E2-related factor 2 (NRF-2) and nuclear factor-kappa B (NF-κB). The effects of metformin on HT29 cells were dose- and time-dependent. These results are very intriguing since metformin is emerging as a multi-faceted drug: It has a good safety profile and is associated with low cost and might be a promising candidate for the prevention or the treatment of colorectal cancer.
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Affiliation(s)
- Paola Sena
- Department of Biomedical, Metabolic and Neurosciences, Section of Human Morphology, University of Modena and Reggio Emilia, Policlinico, Via Del Pozzo 71, I-41125 Modena, Italy.
| | - Stefano Mancini
- Department of Diagnostic and Clinical Medicine, and Public Health, University of Modena and Reggio Emilia, Policlinico, Via Del Pozzo 71, I-41125 Modena, Italy.
| | - Marta Benincasa
- Department of Biomedical, Metabolic and Neurosciences, Section of Human Morphology, University of Modena and Reggio Emilia, Policlinico, Via Del Pozzo 71, I-41125 Modena, Italy.
| | - Francesco Mariani
- Department of Diagnostic and Clinical Medicine, and Public Health, University of Modena and Reggio Emilia, Policlinico, Via Del Pozzo 71, I-41125 Modena, Italy.
| | - Carla Palumbo
- Department of Biomedical, Metabolic and Neurosciences, Section of Human Morphology, University of Modena and Reggio Emilia, Policlinico, Via Del Pozzo 71, I-41125 Modena, Italy.
| | - Luca Roncucci
- Department of Diagnostic and Clinical Medicine, and Public Health, University of Modena and Reggio Emilia, Policlinico, Via Del Pozzo 71, I-41125 Modena, Italy.
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49
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Wang JC, Sun X, Ma Q, Fu GF, Cong LL, Zhang H, Fan DF, Feng J, Lu SY, Liu JL, Li GY, Liu PJ. Metformin's antitumour and anti-angiogenic activities are mediated by skewing macrophage polarization. J Cell Mol Med 2018; 22:3825-3836. [PMID: 29726618 PMCID: PMC6050465 DOI: 10.1111/jcmm.13655] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2018] [Accepted: 03/26/2018] [Indexed: 12/31/2022] Open
Abstract
Beneficial effects of metformin on cancer risk and mortality have been proved by epidemiological and clinical studies, thus attracting research interest in elucidating the underlying mechanisms. Recently, tumour‐associated macrophages (TAMs) appeared to be implicated in metformin‐induced antitumour activities. However, how metformin inhibits TAMs‐induced tumour progression remains ill‐defined. Here, we report that metformin‐induced antitumour and anti‐angiogenic activities were not or only partially contributed by its direct inhibition of functions of tumour and endothelial cells. By skewing TAM polarization from M2‐ to M1‐like phenotype, metformin inhibited both tumour growth and angiogenesis. Depletion of TAMs by clodronate liposomes eliminated M2‐TAMs‐induced angiogenic promotion, while also abrogating M1‐TAMs‐mediated anti‐angiogenesis, thus promoting angiogenesis in tumours from metformin treatment mice. Further in vitro experiments using TAMs‐conditioned medium and a coculture system were performed, which demonstrated an inhibitory effect of metformin on endothelial sprouting and tumour cell proliferation promoted by M2‐polarized RAW264.7 macrophages. Based on these results, metformin‐induced inhibition of tumour growth and angiogenesis is greatly contributed by skewing of TAMs polarization in microenvironment, thus offering therapeutic opportunities for metformin in cancer treatment.
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Affiliation(s)
- Ji-Chang Wang
- Department of Vascular Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.,Center for Translational Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Xin Sun
- Department of Thoracic Surgery and Oncology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Qiang Ma
- Department of Peripheral Vascular Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Gui-Feng Fu
- Medical Imaging Department, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Long-Long Cong
- Department of Vascular Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Hong Zhang
- Department of Neurology, First Hospital of Yulin City, Yulin City, Shaanxi Province, China
| | - De-Fu Fan
- Department of Neurosurgery, People's Hospital of Qu Wo Country, Linfen City, Shanxi Province, China
| | - Jun Feng
- Department of Vascular Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Shao-Ying Lu
- Department of Vascular Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Jian-Lin Liu
- Department of Vascular Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Guang-Yue Li
- Department of Science and Technology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Pei-Jun Liu
- Center for Translational Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.,Key Laboratory for Tumor Precision Medicine of Shaanxi Province, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
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50
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Chu D, Wu J, Wang K, Zhao M, Wang C, Li L, Guo R. Effect of metformin use on the risk and prognosis of endometrial cancer: a systematic review and meta-analysis. BMC Cancer 2018; 18:438. [PMID: 29669520 PMCID: PMC5907461 DOI: 10.1186/s12885-018-4334-5] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Accepted: 04/04/2018] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Previous studies have suggested that metformin may be useful for preventing and treating endometrial cancer (EC), while the results have been inconsistent. This systematic review and meta-analysis aimed to investigate the association between metformin use and risk and prognosis of patients with EC. METHODS PubMed, Embase, and the Cochrane Library databases were searched for observational studies evaluating the effect of metformin on EC prevention or treatment. The odds ratio (OR) was used for analyzing risks, and the hazard ratio (HR) was used for analyzing survival outcomes. A random-effects model was used for data analysis. RESULTS Seven studies reported data on EC risk. The pooled results suggested that metformin was not significantly associated with a lower risk of EC [OR = 1.05, 95% confidence interval (CI) 0.82-1.35, P = 0.70]. For patients with diabetes, metformin showed no advantage in reducing the EC risk compared with other interventions (OR = 0.99, 95% CI 0.78-1.26, P = 0.95). Further, seven studies were included for survival analysis. The pooled data showed that metformin could significantly improve the overall survival of patients with EC (HR = 0.61, 95% CI 0.48-0.77, P < 0.05) and reduce the risk of EC recurrence (OR = 0.50, 95% CI 0.28-0.92, P < 0.05) Finally, we noted metformin was associated with significantly improving the overall survival of EC patients among diabetes (HR = 0.47; 95%CI 0.33-0.67, P < 0.05). CONCLUSIONS This meta-analysis did not prove that metformin was beneficial for preventing EC. However, metformin could prolong the overall survival of patients with EC and reduce their risk of cancer relapse.
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Affiliation(s)
- Danxia Chu
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, NO.1, JianShe East Road, Zhengzhou, 450052 Henan China
| | - Jie Wu
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, NO.1, JianShe East Road, Zhengzhou, 450052 Henan China
| | - Kaili Wang
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, NO.1, JianShe East Road, Zhengzhou, 450052 Henan China
| | - Mengling Zhao
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, NO.1, JianShe East Road, Zhengzhou, 450052 Henan China
| | - Chunfang Wang
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, NO.1, JianShe East Road, Zhengzhou, 450052 Henan China
| | - Liuxia Li
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, NO.1, JianShe East Road, Zhengzhou, 450052 Henan China
| | - Ruixia Guo
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, NO.1, JianShe East Road, Zhengzhou, 450052 Henan China
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