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Yeom S, Lee DH, Song J. Therapeutic Potential of Anti-Diabetes Drugs and Anti-Dyslipidemia Drugs to Mitigate Head and Neck Cancer Risk in Metabolic Syndrome. CNS Neurosci Ther 2025; 31:e70446. [PMID: 40387523 PMCID: PMC12087305 DOI: 10.1111/cns.70446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2025] [Revised: 04/24/2025] [Accepted: 05/06/2025] [Indexed: 05/20/2025] Open
Abstract
BACKGROUND Head and neck cancer (HNC) encompasses a heterogeneous group of malignancies originating in the oral cavity, pharynx, nasopharynx, larynx, paranasal sinuses, and salivary glands. Accumulating evidence indicates that metabolic syndrome (MetS) characterized by a constellation of conditions including central adiposity, hyperglycemia, dyslipidemia, hypertension, and insulin resistance, may significantly influence cancer pathogenesis and progression. RESULTS MetS has been epidemiologically linked to elevated risk for multiple malignancies through various metabolic mechanisms involving chronic systemic inflammation, insulin resistance, and dysregulated lipid metabolism. Especially in HNC, recent studies demonstrated that MetS and metabolic imbalance conditions may contribute to carcinogenesis, disease progression, and clinical outcomes, but the exact mechanisms behind the association between excess fat accumulation and HNC risk remain unclear. Considering previous studies, pharmacological agents targeting metabolic pathways, including biguanides (metformin), thiazolidinediones, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and HMG-CoA reductase inhibitors (statins) are being investigated for potential repurposing in cancer prevention and adjuvant therapy. CONCLUSIONS Here, we summarize the latest evidence on the relationship between MetS and HNC, highlighting the therapeutic potential of anti-diabetes drugs and anti-dyslipidemia drugs in ameliorating various pathological problems in HNC patients with MetS.
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Affiliation(s)
- Sujung Yeom
- Department of Otolaryngology‐Head and Neck SurgeryChonnam National University Medical School & Hwasun HospitalHwasunRepublic of Korea
| | - Dong Hoon Lee
- Department of Otolaryngology‐Head and Neck SurgeryChonnam National University Medical School & Hwasun HospitalHwasunRepublic of Korea
| | - Juhyun Song
- Department of AnatomyChonnam National University Medical SchoolHwasunRepublic of Korea
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2
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Ciaramicoli LM, Kwon HY, Im CY, Kim N, Oh Y, Chang YT, Kang NY. Label-Free Enrichment of Highly Metastatic Tumor-Initiating Cells up to a Monoclonal State. Biomater Res 2025; 29:0168. [PMID: 40177028 PMCID: PMC11964298 DOI: 10.34133/bmr.0168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 12/30/2024] [Accepted: 02/25/2025] [Indexed: 04/05/2025] Open
Affiliation(s)
- Larissa M. Ciaramicoli
- Department of Chemistry,
Pohang University of Science and Technology, Pohang 37673, Republic of Korea
| | - Haw-Young Kwon
- Department of Chemistry,
Pohang University of Science and Technology, Pohang 37673, Republic of Korea
- SenPro Inc.,
Pohang University of Science and Technology, Pohang, Gyeongbuk 37673, Republic of Korea
| | - Chun Y. Im
- New Drug Development Center,
Daegu-Gyeongbuk Medical Innovation Foundation (K-MEDIhub), Daegu 41061, Republic of Korea
| | - Namhui Kim
- New Drug Development Center,
Daegu-Gyeongbuk Medical Innovation Foundation (K-MEDIhub), Daegu 41061, Republic of Korea
| | - Yoojin Oh
- New Drug Development Center,
Daegu-Gyeongbuk Medical Innovation Foundation (K-MEDIhub), Daegu 41061, Republic of Korea
| | - Young-Tae Chang
- Department of Chemistry,
Pohang University of Science and Technology, Pohang 37673, Republic of Korea
- SenPro Inc.,
Pohang University of Science and Technology, Pohang, Gyeongbuk 37673, Republic of Korea
| | - Nam-Young Kang
- SenPro Inc.,
Pohang University of Science and Technology, Pohang, Gyeongbuk 37673, Republic of Korea
- Department of Convergence I.T. Engineering,
Pohang University of Science and Technology (POSTECH), Pohang 37673, Republic of Korea
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3
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Villegas-Vazquez EY, Marín-Carrasco FP, Reyes-Hernández OD, Báez-González AS, Bustamante-Montes LP, Padilla-Benavides T, Quintas-Granados LI, Figueroa-González G. Revolutionizing ovarian cancer therapy by drug repositioning for accelerated and cost-effective treatments. Front Oncol 2025; 14:1514120. [PMID: 39876896 PMCID: PMC11772297 DOI: 10.3389/fonc.2024.1514120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Accepted: 12/23/2024] [Indexed: 01/31/2025] Open
Abstract
Drug repositioning, the practice of identifying novel applications for existing drugs beyond their originally intended medical indications, stands as a transformative strategy revolutionizing pharmaceutical productivity. In contrast to conventional drug development approaches, this innovative method has proven to be exceptionally effective. This is particularly relevant for cancer therapy, where the demand for groundbreaking treatments continues to grow. This review focuses on drug repositioning for ovarian cancer treatment, showcasing a comprehensive exploration grounded in thorough in vitro experiments across diverse cancer cell lines, which are validated through preclinical in vivo models. These insights not only shed light on the efficacy of these drugs but also expand in potential synergies with other pharmaceutical agents, favoring the development of cost-effective treatments for cancer patients.
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Affiliation(s)
- Edgar Yebran Villegas-Vazquez
- Laboratorio de Farmacogenética, UMIEZ, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Francisco Pável Marín-Carrasco
- Laboratorio de Farmacogenética, UMIEZ, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Octavio Daniel Reyes-Hernández
- Laboratorio de Farmacogenética, UMIEZ, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Andrea S. Báez-González
- Department of Molecular Biology and Biochemistry, Wesleyan University, Middletown, CT, United States
| | | | | | - Laura Itzel Quintas-Granados
- Colegio de Ciencias y Humanidades, Plantel Cuautepec, Universidad Autónoma de la Ciudad de México, Ciudad de México, Mexico
| | - Gabriela Figueroa-González
- Laboratorio de Farmacogenética, UMIEZ, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
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4
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Stanciu AE, Bolovan ML, Zamfir-Chiru-Anton A, Voiosu C, Dabla PK, Stanciu MM, Serdarevic N, Gherghe M. The Interplay Between High Cumulative Doses of Radioactive Iodine and Type 2 Diabetes Mellitus: A Complex Cardiovascular Challenge. Int J Mol Sci 2024; 26:37. [PMID: 39795891 PMCID: PMC11720250 DOI: 10.3390/ijms26010037] [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: 12/03/2024] [Revised: 12/19/2024] [Accepted: 12/23/2024] [Indexed: 01/13/2025] Open
Abstract
Starting from the metabolic profile of type 2 diabetes mellitus (T2DM), we hypothesized that the mechanisms of ¹³¹I-induced cardiotoxicity differ between patients diagnosed with differentiated thyroid cancer (DTC) with/without T2DM, with metformin potentially acting as a cardioprotective agent by mitigating inflammation in patients with T2DM. To address this hypothesis, we quantified, using ELISA, the serum concentration of several key biomarkers that reflect cardiac injury (NT-proBNP, NT-proANP, ST2/IL-33R, and cTn I) in 74 female patients with DTC/-T2DM and 25 with DTC/+T2DM treated with metformin. All patients received a cumulative oral dose of 131I exceeding 150 mCi (5.55 GBq) over approximately 53 months. Our results showed the following: (i) In DTC/-T2DM patients, high-cumulative 131I doses promote a pro-inflammatory state that accelerates the development of cardiotoxicity. Monitoring NT-proBNP, ST2/IL-33R, and cTn I in these patients may help identify those at risk of developing cardiac complications. (ii) In patients with DTC/+T2DM, high-cumulative 131I doses lead to the release of NT-proANP (r = 0.63), which signals that the atria are under significant stress. (iii) In patients with DTC/+T2DM, metformin suppresses inflammation, leading to a dose-dependent reduction in cTn I (r = -0.59). Monitoring cTn I and NT-proANP, and considering the use of metformin as part of the therapeutic strategy, could help manage cardiotoxicity in T2DM patients undergoing 131I therapy.
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Affiliation(s)
- Adina Elena Stanciu
- Carcinogenesis and Molecular Biology Department, Institute of Oncology Bucharest, 022328 Bucharest, Romania;
- Faculty of Biology, University of Bucharest, 050095 Bucharest, Romania
| | - Madalina Lucica Bolovan
- Carcinogenesis and Molecular Biology Department, Institute of Oncology Bucharest, 022328 Bucharest, Romania;
| | - Adina Zamfir-Chiru-Anton
- ENT Department, “Grigore Alexandrescu” Children’s Emergency Hospital, 011743 Bucharest, Romania;
| | - Catalina Voiosu
- ENT Department, University of Medicine and Pharmacy “Carol Davila” Bucharest, 050474 Bucharest, Romania;
- ENT Department, “Prof. Dr. Dorin Hociota” Institute of Phonoaudiology and Functional ENT Surgery, 050751 Bucharest, Romania
| | - Pradeep Kumar Dabla
- G.B. Pant Institute of Postgraduate Medical Education & Research (GIPMER), Delhi 110002, India;
| | - Marcel Marian Stanciu
- Electrical Engineering Faculty, University “Politehnica” of Bucharest, 060042 Bucharest, Romania;
| | - Nafija Serdarevic
- Institute for Clinical Chemistry and Biochemistry, University of Sarajevo Clinics Center, 7100 Sarajevo, Bosnia and Herzegovina;
| | - Mirela Gherghe
- Nuclear Medicine Department, University of Medicine and Pharmacy “Carol Davila” Bucharest, 050474 Bucharest, Romania;
- Nuclear Medicine Department, Institute of Oncology Bucharest, 022328 Bucharest, Romania
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5
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Son B, Lee W, Kim H, Shin H, Park HH. Targeted therapy of cancer stem cells: inhibition of mTOR in pre-clinical and clinical research. Cell Death Dis 2024; 15:696. [PMID: 39349424 PMCID: PMC11442590 DOI: 10.1038/s41419-024-07077-8] [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: 12/29/2023] [Revised: 09/10/2024] [Accepted: 09/13/2024] [Indexed: 10/02/2024]
Abstract
Cancer stem cells (CSCs) are a type of stem cell that possesses not only the intrinsic abilities of stem cells but also the properties of cancer cells. Therefore, CSCs are known to have self-renewal and outstanding proliferation capacity, along with the potential to differentiate into specific types of tumor cells. Cancers typically originate from CSCs, making them a significant target for tumor treatment. Among the related cascades of the CSCs, mammalian target of rapamycin (mTOR) pathway is regarded as one of the most important signaling pathways because of its association with significant upstream signaling: phosphatidylinositol 3‑kinase/protein kinase B (PI3K/AKT) pathway and mitogen‑activated protein kinase (MAPK) cascade, which influence various activities of stem cells, including CSCs. Recent studies have shown that the mTOR pathway not only affects generation of CSCs but also the maintenance of their pluripotency. Furthermore, the maintenance of pluripotency or differentiation into specific types of cancer cells depends on the regulation of the mTOR signal in CSCs. Consequently, the clinical potential and importance of mTOR in effective cancer therapy are increasing. In this review, we demonstrate the association between the mTOR pathway and cancer, including CSCs. Additionally, we discuss a new concept for anti-cancer drug development aimed at overcoming existing drawbacks, such as drug resistance, by targeting CSCs through mTOR inhibition.
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Affiliation(s)
- Boram Son
- Department of Bioengineering, Hanyang University, Seoul, 04763, Republic of Korea
- Department of Bio and Fermentation Convergence Technology, Kookmin University, Seoul, 02707, Republic of Korea
| | - Wonhwa Lee
- Department of Chemistry, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - Hyeonjeong Kim
- Department of Bioengineering, Hanyang University, Seoul, 04763, Republic of Korea
| | - Heungsoo Shin
- Department of Bioengineering, Hanyang University, Seoul, 04763, Republic of Korea.
| | - Hee Ho Park
- Department of Bioengineering, Hanyang University, Seoul, 04763, Republic of Korea.
- Research Institute for Convergence of Basic Science, Hanyang University, Seoul, 04763, Republic of Korea.
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6
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Gómez-Villanueva Á, Martínez-Gómez SI, González-Mendoza DE, Ramos-Gutiérrez EA, Hernández-Ramírez RG, Delgado-Villarejo LD, Garduño-García JJ. Findings on Age at Onset of Cancer in Diabetic and Non-diabetic Populations. Cureus 2024; 16:e65719. [PMID: 39082041 PMCID: PMC11287237 DOI: 10.7759/cureus.65719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/29/2024] [Indexed: 08/02/2024] Open
Abstract
Background Diabetes mellitus and cancer are two associated chronic diseases. Despite being a widely researched topic, the underlying mechanisms of this association remain unclear. One of the poorly explored topics regarding diabetes and cancer is the relation between the age of cancer onset and diabetes mellitus status; therefore, this research exposes the difference in the age of cancer diagnosis in both groups. Methods We conducted a retrospective study by reviewing the clinical files on a secondary care hospital's database. Files from first-time consultations of patients over 18 diagnosed using a histopathological report were included. The present study aimed to determine whether there is a difference in age at the onset of cancer in diabetic and non-diabetic individuals. Moreover, we calculated the average BMI at the onset for both populations. Results Our study included 8,741 patients; 1,551 (17.8%) were diabetic, and 7,190 (82.2%) were non-diabetic. From 28 types of cancer, 27 showed a difference in the age at the onset of cancer when diabetic and non-diabetic subjects were compared. This difference is significant as it suggests a potential link between diabetes and cancer, which could have implications for early detection and prevention strategies. Out of the 27 types, 17 showed statistical significance with p-values ranging from 0.048 to <0.0001 considering a 95% CI. Among those, the most significant types of cancer were breast, cervical, lung, ovarian, rectal, thyroid, and sarcoma, reporting p-values <0.0001. The mean age at onset of cancer in diabetic and non-diabetic populations was 62.7 years (SD ± 3.9) and 55.3 years (SD ± 7.9), respectively, showing a difference of 7.4 years in both groups. The BMI was statistically significant in patients with breast (p = 0.006), endometrial (p = 0.007), head and neck (p=0.014), and thyroid (p = 0.022) cancer types. Conclusion The data offer a critical view of the relationship between cancer and diabetes. Since virtually no one has produced a similar report, there is a broad field for researching the causal factors implicated in the pathway of diabetic and non-diabetic individuals who develop cancer. Research regarding metformin, diabetic neuropathy, and other possible causes must be addressed to determine whether they are involved in this process.
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Affiliation(s)
- Ángel Gómez-Villanueva
- Oncology, Hospital General Regional No. 251, Instituto Mexicano del Seguro Social (IMSS), Metepec, MEX
| | - Sharon I Martínez-Gómez
- Internal Medicine, Hospital General de Zona No. 194, Instituto Mexicano del Seguro Social (IMSS), Naucalpan, MEX
| | | | - Edgar A Ramos-Gutiérrez
- Geriatrics, Hospital General Regional No. 251, Instituto Mexicano del Seguro Social (IMSS), Metepec, MEX
| | | | | | - José J Garduño-García
- Internal Medicine, Hospital General Regional No. 251, Instituto Mexicano del Seguro Social (IMSS), Metepec, MEX
- Medicine, Universidad Autónoma del Estado de México (UAEMex), Toluca, MEX
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7
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Viglianisi G, Polizzi A, Grippaudo C, Cocuzza S, Leonardi R, Isola G. Chemopreventive and Biological Strategies in the Management of Oral Potentially Malignant and Malignant Disorders. Bioengineering (Basel) 2024; 11:65. [PMID: 38247942 PMCID: PMC10813134 DOI: 10.3390/bioengineering11010065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 12/28/2023] [Accepted: 01/05/2024] [Indexed: 01/23/2024] Open
Abstract
Oral potentially malignant disorders (OPMD) and oral squamous cell carcinoma (OSCC) represent a significant global health burden due to their potential for malignant transformation and the challenges associated with their diagnosis and treatment. Chemoprevention, an innovative approach aimed at halting or reversing the neoplastic process before full malignancy, has emerged as a promising avenue for mitigating the impact of OPMD and OSCC. The pivotal role of chemopreventive strategies is underscored by the need for effective interventions that go beyond traditional therapies. In this regard, chemopreventive agents offer a unique opportunity to intercept disease progression by targeting the molecular pathways implicated in carcinogenesis. Natural compounds, such as curcumin, green tea polyphenols, and resveratrol, exhibit anti-inflammatory, antioxidant, and anti-cancer properties that could make them potential candidates for curtailing the transformation of OPMD to OSCC. Moreover, targeted therapies directed at specific molecular alterations hold promise in disrupting the signaling cascades driving OSCC growth. Immunomodulatory agents, like immune checkpoint inhibitors, are gaining attention for their potential to harness the body's immune response against early malignancies, thus impeding OSCC advancement. Additionally, nutritional interventions and topical formulations of chemopreventive agents offer localized strategies for preventing carcinogenesis in the oral cavity. The challenge lies in optimizing these strategies for efficacy, safety, and patient compliance. This review presents an up to date on the dynamic interplay between molecular insights, clinical interventions, and the broader goal of reducing the burden of oral malignancies. As research progresses, the synergy between early diagnosis, non-invasive biomarker identification, and chemopreventive therapy is poised to reshape the landscape of OPMD and OSCC management, offering a glimpse of a future where these diseases are no longer insurmountable challenges but rather preventable and manageable conditions.
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Affiliation(s)
- Gaia Viglianisi
- Department of General Surgery and Surgical-Medical Specialties, School of Dentistry, University of Catania, Via S. Sofia 68, 95124 Catania, Italy; (G.V.); (A.P.); (R.L.); (G.I.)
| | - Alessandro Polizzi
- Department of General Surgery and Surgical-Medical Specialties, School of Dentistry, University of Catania, Via S. Sofia 68, 95124 Catania, Italy; (G.V.); (A.P.); (R.L.); (G.I.)
| | - Cristina Grippaudo
- Head and Neck Department, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli 8, 00168 Rome, Italy
| | - Salvatore Cocuzza
- Department of Medical and Surgical Sciences and Advanced Technologies “GF Ingrassia” ENT Section, University of Catania, Via S. Sofia 68, 95124 Catania, Italy;
| | - Rosalia Leonardi
- Department of General Surgery and Surgical-Medical Specialties, School of Dentistry, University of Catania, Via S. Sofia 68, 95124 Catania, Italy; (G.V.); (A.P.); (R.L.); (G.I.)
| | - Gaetano Isola
- Department of General Surgery and Surgical-Medical Specialties, School of Dentistry, University of Catania, Via S. Sofia 68, 95124 Catania, Italy; (G.V.); (A.P.); (R.L.); (G.I.)
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Sharma N, Dhingra R. Clinical potentials of metformin in cancer therapy. JOURNAL OF DIABETOLOGY 2023; 14:186-192. [DOI: 10.4103/jod.jod_84_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Accepted: 09/28/2023] [Indexed: 01/05/2025] Open
Abstract
Abstract
Diabetes is a prevalent metabolic disorder that results in several comorbidities including cancer. Cancer becomes the most severe complication of diabetes patients. Growing evidence proved that impaired glucose homeostasis is an independent risk factor for the occurrence of various types of cancers including liver, pancreatic, gastric (stomach), colorectal, kidney, and breast cancers, and influences cancer prognosis. Diabetes mellitus and cancer have a bidirectional relationship, thus there is a need to look for drugs that can be beneficial in treating both diseases. Therefore, more research is focusing on evaluating the role of antihyperglycemic agents in the treatment of various types of cancers. Metformin, an FDA-approved first-line antihyperglycemic agent can be used as a monotherapy or as an adjuvant to chemotherapeutic agents in the treatment of various types of cancer. However, the exact mechanism of metformin as an anticancer agent is still unknown, the majority of the described putative mechanisms focus on promoting the activity of the AMP-activated protein kinase (AMPK) pathway. This review article thus gives insights into the prognosis of cancer in diabetes patients and aims to explore the possible mechanism of action of metformin in the prevention and treatment of cancer.
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Affiliation(s)
- Nidhi Sharma
- Department of Pharmacy, School of Medical and Allied Sciences, G.D. Goenka University, Sohna, Haryana, India
| | - Richa Dhingra
- Department of Pharmacy, School of Medical and Allied Sciences, G.D. Goenka University, Sohna, Haryana, India
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Boutaud M, Auger C, Verdier M, Christou N. Metformin Treatment Reduces CRC Aggressiveness in a Glucose-Independent Manner: An In Vitro and Ex Vivo Study. Cancers (Basel) 2023; 15:3724. [PMID: 37509386 PMCID: PMC10378121 DOI: 10.3390/cancers15143724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 07/13/2023] [Accepted: 07/20/2023] [Indexed: 07/30/2023] Open
Abstract
(1) Background: Metformin, an anti-diabetic drug, seems to protect against aggressive acquisition in colorectal cancers (CRCs). However, its mechanisms are still really unknown, raising questions about the possibility of its positive impact on non-diabetic patients with CRC. (2) Methods: An in vitro study based on human colon cancer cell lines and an ex vivo study with different colon cancer stages with proteomic and transcriptomic analyses were initiated. (3) Results: Metformin seems to protect from colon cancer invasive acquisition, irrespective of glucose concentration. (4) Conclusions: Metformin could be used as an adjuvant treatment to surgery for both diabetic and non-diabetic patients in order to prevent the acquisition of aggressiveness and, ultimately, recurrences.
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Affiliation(s)
- Marie Boutaud
- UMR-INSERM 1308 CAPTuR, Faculté de Médecine, Institut OmegaHealth, Université de Limoges, 2 Rue du Dr Raymond Marcland, CEDEX, 87025 Limoges, France
| | - Clément Auger
- UMR-INSERM 1308 CAPTuR, Faculté de Médecine, Institut OmegaHealth, Université de Limoges, 2 Rue du Dr Raymond Marcland, CEDEX, 87025 Limoges, France
| | - Mireille Verdier
- UMR-INSERM 1308 CAPTuR, Faculté de Médecine, Institut OmegaHealth, Université de Limoges, 2 Rue du Dr Raymond Marcland, CEDEX, 87025 Limoges, France
| | - Niki Christou
- UMR-INSERM 1308 CAPTuR, Faculté de Médecine, Institut OmegaHealth, Université de Limoges, 2 Rue du Dr Raymond Marcland, CEDEX, 87025 Limoges, France
- Service de Chirurgie Digestive, Centre Hospitalier Universitaire de Limoges, 2 Av. Martin Luther King, CEDEX, 87000 Limoges, France
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10
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Amicone L, Marchetti A, Cicchini C. The lncRNA HOTAIR: a pleiotropic regulator of epithelial cell plasticity. J Exp Clin Cancer Res 2023; 42:147. [PMID: 37308974 DOI: 10.1186/s13046-023-02725-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 05/30/2023] [Indexed: 06/14/2023] Open
Abstract
The epithelial-to-mesenchymal transition (EMT) is a trans-differentiation process that endows epithelial cells with mesenchymal properties, including motility and invasion capacity; therefore, its aberrant reactivation in cancerous cells represents a critical step to gain a metastatic phenotype. The EMT is a dynamic program of cell plasticity; many partial EMT states can be, indeed, encountered and the full inverse mesenchymal-to-epithelial transition (MET) appears fundamental to colonize distant secondary sites. The EMT/MET dynamics is granted by a fine modulation of gene expression in response to intrinsic and extrinsic signals. In this complex scenario, long non-coding RNAs (lncRNAs) emerged as critical players. This review specifically focuses on the lncRNA HOTAIR, as a master regulator of epithelial cell plasticity and EMT in tumors. Molecular mechanisms controlling its expression in differentiated as well as trans-differentiated epithelial cells are highlighted here. Moreover, current knowledge about HOTAIR pleiotropic functions in regulation of both gene expression and protein activities are described. Furthermore, the relevance of the specific HOTAIR targeting and the current challenges of exploiting this lncRNA for therapeutic approaches to counteract the EMT are discussed.
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Affiliation(s)
- Laura Amicone
- Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Dipartimento di Medicina Molecolare, Sapienza University of Rome, Viale Regina Elena 324, Rome, 00161, Italy
| | - Alessandra Marchetti
- Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Dipartimento di Medicina Molecolare, Sapienza University of Rome, Viale Regina Elena 324, Rome, 00161, Italy
| | - Carla Cicchini
- Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Dipartimento di Medicina Molecolare, Sapienza University of Rome, Viale Regina Elena 324, Rome, 00161, Italy.
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11
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Lee CS, Lam SY, Liu A, Sison C, Zhu XH. A Retrospective Study of the Effect of Metformin on Patients with Metastatic Prostate Cancer. Clin Med Insights Oncol 2023; 17:11795549231152073. [PMID: 36744171 PMCID: PMC9896090 DOI: 10.1177/11795549231152073] [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: 07/12/2022] [Accepted: 01/05/2023] [Indexed: 02/04/2023] Open
Abstract
Introduction Previous studies demonstrated that metformin could lead to an inhibition of proliferation of cancer cells through a shift from anabolic to catabolic metabolism. In this study, we seek to investigate the effect of metformin in metastatic prostate cancer. Methods Patients followed at Northwell Health Zuckerberg Cancer Center during 2014-2018 were included if they were diagnosed with metastatic hormone-sensitive prostate cancer (mHSPC) or metastatic castration-resistant prostate cancer (mCRPC), with ⩾6 months follow-up with and without metformin treatment. The primary outcomes, 6-month prostate-specific antigen (PSA) response, overall survival (OS), and radiographic progression free survival (rPFS), were evaluated. Results There were 267 patients included in the final analysis; 196 patients had mHSPC (73.2%) and 71 had mCRPC (26.8%). Within the mHSPC subjects, there was a significant difference in OS between metformin vs nonmetformin groups (148.5 vs 85.6 months; P < .046) in a univariate analysis; patients who took metformin had a significantly longer OS than subjects who did not (median OS: 148.5 vs 86 months; P < .046). There was no significant difference between the 2 groups with respect to either PSA response rate at 6 months or rPFS or OS in patients with mHSPC in both univariate and multivariate analysis. Within the mCRPC subjects, there was no significant difference between metformin and nonmetformin groups with respect to OS (43.3 vs 51.5 months; P < 0.160) or PSA response at 6 months (38.5% vs 57.1%; p < 0.24); however, patients on metformin had a significantly shorter rPFS in both the univariate analysis (7.3 vs 17.4; P < .0002) and in the multivariate analysis (HR = 2.52; 95% CI: 1.24m 5.11; P < .0109). Conclusions Among patients with mHSPC, use of metformin was not significantly associated with improved OS in the multivariate analysis.
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Affiliation(s)
- Chung-Shien Lee
- Department of Clinical Health
Professions, College of Pharmacy and Health Sciences, St. John’s University, Queens,
NY, USA,Division of Medical Oncology and
Hematology, Northwell Health Cancer Institute, Donald & Barbara Zucker School of
Medicine at Hofstra/Northwell, Lake Success, NY, USA
| | - So Yi Lam
- Department of Clinical Health
Professions, College of Pharmacy and Health Sciences, St. John’s University, Queens,
NY, USA
| | - Angel Liu
- Department of Clinical Health
Professions, College of Pharmacy and Health Sciences, St. John’s University, Queens,
NY, USA
| | - Cristina Sison
- Biostatistics Unit, The Feinstein
Institutes for Medical Research, Manhasset, NY, USA,Department of Molecular Medicine,
Donald & Barbara Zucker School of Medicine at Hofstra/Northwell, Northwell
Health, Manhasset, NY, USA
| | - Xin-Hua Zhu
- Division of Medical Oncology and
Hematology, Northwell Health Cancer Institute, Donald & Barbara Zucker School of
Medicine at Hofstra/Northwell, Lake Success, NY, USA,Xin-Hua Zhu, Division of Medical Oncology
and Hematology, Northwell Health Cancer Institute, Donald & Barbara Zucker
School of Medicine at Hofstra/Northwell, 450 Lakeville Road, Lake Success, NY
11042, USA.
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12
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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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13
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Cerebrolysin Alleviating Effect on Glutamate-Mediated Neuroinflammation Via Glutamate Transporters and Oxidative Stress. J Mol Neurosci 2022; 72:2292-2302. [PMID: 36333611 DOI: 10.1007/s12031-022-02078-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 10/14/2022] [Indexed: 11/06/2022]
Abstract
Glutamate, one of the most important excitatory neurotransmitters, acts as a signal transducer in peripheral tissues and endocrine cells. Excessive glutamate secretion has been shown to cause excitotoxicity and neurodegenerative disease. Cerebrolysin is a mixture of enzymatically treated peptides derived from pig brain including neurotrophic factors, like brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and ciliary neurotrophic factor (CNTF). The present study investigated the protective effects of cerebrolysin on glutamate transporters (EAAT 1, EAAT 2) and cytokines (IL-1β and IL-10) activity in glutamate-mediated neurotoxicity. Primary cortex neuron culture was exposed to glutamate and successively treated with various cerebrolysin concentrations for 24 and 48 h. Our data showed that cerebrolysin primarily protects neurons by decreasing glutamate concentration in the synaptic cleft. In addition, Cerebrolysin can decrease oxidative stress and neuron cell damage by increasing antioxidant activity and decreasing inflammation cytokine levels.
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14
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Kang J, Lee D, Lee KJ, Yoon JE, Kwon JH, Seo Y, Kim J, Chang SY, Park J, Kang EA, Park SJ, Park JJ, Cheon JH, Kim TI. Tumor-Suppressive Effect of Metformin via the Regulation of M2 Macrophages and Myeloid-Derived Suppressor Cells in the Tumor Microenvironment of Colorectal Cancer. Cancers (Basel) 2022; 14:2881. [PMID: 35740547 PMCID: PMC9220791 DOI: 10.3390/cancers14122881] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 06/08/2022] [Accepted: 06/09/2022] [Indexed: 11/16/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) and M2 macrophages in the tumor microenvironment contribute to tumor progression by inducing immune tolerance to tumor antigens and cancer cells. Metformin, one of the most common diabetes drugs, has shown anti-inflammatory and anti-tumor effects. However, the effects of metformin on inflammatory cells of the tumor microenvironment and its underlying mechanisms remain unclarified. In this study, we investigated the effect of metformin on M2 macrophages and MDSCs using monocyte THP-1 cells and a dextran sodium sulfate (DSS)-treated ApcMin/+ mouse model of colon cancer. Metformin decreased the fractions of MDSCs expressing CD33 and arginase, as well as M2 macrophages expressing CD206 and CD163. The inhibitory effect of metformin and rapamycin on MDSCs and M2 macrophages was reversed by the co-treatment of Compound C (an AMP-activated protein kinase (AMPK) inhibitor) or mevalonate. To examine the effect of protein prenylation and cholesterol synthesis (the final steps of the mevalonate pathway) on the MDSC and M2 macrophage populations, we used respective inhibitors (YM53601; SQLE inhibitor, FTI-277; farnesyl transferase inhibitor, GGTI-298; geranylgeranyl transferase inhibitor) and found that the MDSC and M2 populations were suppressed by the protein prenylation inhibitors. In the DSS-treated ApcMin/+ mouse colon cancer model, metformin reduced the number and volume of colorectal tumors with decreased populations of MDSCs and M2 macrophages in the tumor microenvironment. In conclusion, the inhibitory effect of metformin on MDSCs and M2 macrophages in the tumor microenvironment of colon cancers is mediated by AMPK activation and subsequent mTOR inhibition, leading to the downregulation of the mevalonate pathway.
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Affiliation(s)
- Joyeon Kang
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea; (J.K.); (D.L.); (K.J.L.); (J.E.Y.); (J.-H.K.); (Y.S.); (J.K.); (S.Y.C.); (J.P.); (E.A.K.); (S.J.P.); (J.J.P.); (J.H.C.)
- Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Doyeon Lee
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea; (J.K.); (D.L.); (K.J.L.); (J.E.Y.); (J.-H.K.); (Y.S.); (J.K.); (S.Y.C.); (J.P.); (E.A.K.); (S.J.P.); (J.J.P.); (J.H.C.)
| | - Kyoung Jin Lee
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea; (J.K.); (D.L.); (K.J.L.); (J.E.Y.); (J.-H.K.); (Y.S.); (J.K.); (S.Y.C.); (J.P.); (E.A.K.); (S.J.P.); (J.J.P.); (J.H.C.)
| | - Jaepil Eric Yoon
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea; (J.K.); (D.L.); (K.J.L.); (J.E.Y.); (J.-H.K.); (Y.S.); (J.K.); (S.Y.C.); (J.P.); (E.A.K.); (S.J.P.); (J.J.P.); (J.H.C.)
| | - Ji-Hee Kwon
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea; (J.K.); (D.L.); (K.J.L.); (J.E.Y.); (J.-H.K.); (Y.S.); (J.K.); (S.Y.C.); (J.P.); (E.A.K.); (S.J.P.); (J.J.P.); (J.H.C.)
| | - Yoojeong Seo
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea; (J.K.); (D.L.); (K.J.L.); (J.E.Y.); (J.-H.K.); (Y.S.); (J.K.); (S.Y.C.); (J.P.); (E.A.K.); (S.J.P.); (J.J.P.); (J.H.C.)
- Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Janghyun Kim
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea; (J.K.); (D.L.); (K.J.L.); (J.E.Y.); (J.-H.K.); (Y.S.); (J.K.); (S.Y.C.); (J.P.); (E.A.K.); (S.J.P.); (J.J.P.); (J.H.C.)
| | - Shin Young Chang
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea; (J.K.); (D.L.); (K.J.L.); (J.E.Y.); (J.-H.K.); (Y.S.); (J.K.); (S.Y.C.); (J.P.); (E.A.K.); (S.J.P.); (J.J.P.); (J.H.C.)
- Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Jihye Park
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea; (J.K.); (D.L.); (K.J.L.); (J.E.Y.); (J.-H.K.); (Y.S.); (J.K.); (S.Y.C.); (J.P.); (E.A.K.); (S.J.P.); (J.J.P.); (J.H.C.)
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Eun Ae Kang
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea; (J.K.); (D.L.); (K.J.L.); (J.E.Y.); (J.-H.K.); (Y.S.); (J.K.); (S.Y.C.); (J.P.); (E.A.K.); (S.J.P.); (J.J.P.); (J.H.C.)
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Soo Jung Park
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea; (J.K.); (D.L.); (K.J.L.); (J.E.Y.); (J.-H.K.); (Y.S.); (J.K.); (S.Y.C.); (J.P.); (E.A.K.); (S.J.P.); (J.J.P.); (J.H.C.)
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Jae Jun Park
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea; (J.K.); (D.L.); (K.J.L.); (J.E.Y.); (J.-H.K.); (Y.S.); (J.K.); (S.Y.C.); (J.P.); (E.A.K.); (S.J.P.); (J.J.P.); (J.H.C.)
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Jae Hee Cheon
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea; (J.K.); (D.L.); (K.J.L.); (J.E.Y.); (J.-H.K.); (Y.S.); (J.K.); (S.Y.C.); (J.P.); (E.A.K.); (S.J.P.); (J.J.P.); (J.H.C.)
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Tae Il Kim
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea; (J.K.); (D.L.); (K.J.L.); (J.E.Y.); (J.-H.K.); (Y.S.); (J.K.); (S.Y.C.); (J.P.); (E.A.K.); (S.J.P.); (J.J.P.); (J.H.C.)
- Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Korea
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea
- Cancer Prevention Center, Yonsei University College of Medicine, Seoul 03722, Korea
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15
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Khanlarkhani N, Azizi E, Amidi F, Khodarahmian M, Salehi E, Pazhohan A, Farhood B, Mortezae K, Goradel NH, Nashtaei MS. Metabolic risk factors of ovarian cancer: a review. JBRA Assist Reprod 2022; 26:335-347. [PMID: 34751020 PMCID: PMC9118962 DOI: 10.5935/1518-0557.20210067] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 08/29/2021] [Indexed: 11/20/2022] Open
Abstract
Ovarian cancer continues to be the leading cause of death from gynecological cancers. Despite inconsistent results, patients with metabolic abnormalities, including obesity and diabetes mellitus (DM), have poorer outcomes, showing a correlation with ovarian cancer incidence and ovarian cancer survival. Since ovarian cancer is the most common cancer in women, and considering the increasing prevalence of obesity and DM, this paper reviews the literature regarding the relationship between the aforementioned metabolic derangements and ovarian cancer, with a focus on ovarian cancer incidence, mortality, and likely mechanisms behind them. Several systematic reviews and meta-analyses have shown that obesity is associated with a higher incidence and poorer survival in ovarian cancer. Although more studies are required to investigate the etiological relation of DM and ovarian cancer, sufficient biological evidence indicates poorer outcomes and shorter survival in DM women with ovarian cancer. A variety of pathologic factors may contribute to ovarian cancer risk, development, and survival, including altered adipokine expression, increased levels of circulating growth factors, altered levels of sex hormones, insulin resistance, hyperinsulinemia, and chronic inflammation. Thus, obesity and DM, as changeable risk factors, can be targeted for intervention to prevent ovarian cancer and improve its outcomes.
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Affiliation(s)
- Neda Khanlarkhani
- Department of Physiology and Pharmacology, Karolinska Institute, Sweden
| | - Elham Azizi
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fardin Amidi
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahshad Khodarahmian
- Infertility department, Arash Women's Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Ensieh Salehi
- Department of Gynecology, School of Medicine, Fertility and Infertility Research Center, Dr. Ali Shariati Hospital, Shahid Mohammadi Hospital, Hormozgan University of Medical Sciences, Hormozgan, Iran
| | - Azar Pazhohan
- Infertility Center, Academic Center for Education, Culture and Research, East Azarbaijan, Tabriz, Iran. / Department of Midwifery, Urmia Branch, Islamic Azad University, Urmia, Iran
| | - Bagher Farhood
- Departments of Medical Physics and Radiology, Faculty of Paramedical Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Keywan Mortezae
- Department of Anatomy, School of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Nasser Hashemi Goradel
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Shabani Nashtaei
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. / Infertility Department, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
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16
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Chow E, Yang A, Chung CHL, Chan JCN. A Clinical Perspective of the Multifaceted Mechanism of Metformin in Diabetes, Infections, Cognitive Dysfunction, and Cancer. Pharmaceuticals (Basel) 2022; 15:ph15040442. [PMID: 35455439 PMCID: PMC9030054 DOI: 10.3390/ph15040442] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 03/30/2022] [Accepted: 03/30/2022] [Indexed: 12/16/2022] Open
Abstract
In type 2 diabetes, ecological and lifecourse factors may interact with the host microbiota to influence expression of his/her genomes causing perturbation of interconnecting biological pathways with diverse clinical course. Metformin is a plant-based or plant-derived medicinal product used for the treatment of type 2 diabetes for over 60 years and is an essential drug listed by the World Health Organization. By reducing mitochondrial oxidative phosphorylation and adenosine triphosphate (ATP) production, metformin increased AMP (adenosine monophosphate)-activated protein kinase (AMPK) activity and altered cellular redox state with reduced glucagon activity, endogenous glucose production, lipogenesis, and protein synthesis. Metformin modulated immune response by directly reducing neutrophil to lymphocyte ratio and improving the phagocytic function of immune cells. By increasing the relative abundance of mucin-producing and short-chain-fatty-acid-producing gut microbes, metformin further improved the host inflammatory and metabolic milieu. Experimentally, metformin promoted apoptosis and reduced proliferation of cancer cells by reducing their oxygen consumption and modulating the microenvironment. Both clinical and mechanistic studies support the pluripotent effects of metformin on reducing cardiovascular–renal events, infection, cancer, cognitive dysfunction, and all-cause death in type 2 diabetes, making this low-cost medication a fundamental therapy for individualization of other glucose-lowering drugs in type 2 diabetes. Further research into the effects of metformin on cognitive function, infection and cancer, especially in people without diabetes, will provide new insights into the therapeutic value of metformin in our pursuit of prevention and treatment of ageing-related as well as acute and chronic diseases beyond diabetes.
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Affiliation(s)
- Elaine Chow
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong 999077, China; (E.C.); (A.Y.); (C.H.L.C.)
- The Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong 999077, China
- Phase 1 Clinical Trial Centre, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong 999077, China
| | - Aimin Yang
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong 999077, China; (E.C.); (A.Y.); (C.H.L.C.)
- The Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong 999077, China
| | - Colin H. L. Chung
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong 999077, China; (E.C.); (A.Y.); (C.H.L.C.)
| | - Juliana C. N. Chan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong 999077, China; (E.C.); (A.Y.); (C.H.L.C.)
- The Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong 999077, China
- Correspondence: ; Tel.: +852-3505-3138
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17
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Udumula MP, Poisson LM, Dutta I, Tiwari N, Kim S, Chinna-Shankar J, Allo G, Sakr S, Hijaz M, Munkarah AR, Giri S, Rattan R. Divergent Metabolic Effects of Metformin Merge to Enhance Eicosapentaenoic Acid Metabolism and Inhibit Ovarian Cancer In Vivo. Cancers (Basel) 2022; 14:cancers14061504. [PMID: 35326656 PMCID: PMC8946838 DOI: 10.3390/cancers14061504] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 03/07/2022] [Accepted: 03/12/2022] [Indexed: 02/01/2023] Open
Abstract
Metformin is being actively repurposed for the treatment of gynecologic malignancies including ovarian cancer. We investigated if metformin induces analogous metabolic changes across ovarian cancer cells. Functional metabolic analysis showed metformin caused an immediate and sustained decrease in oxygen consumption while increasing glycolysis across A2780, C200, and SKOV3ip cell lines. Untargeted metabolomics showed metformin to have differential effects on glycolysis and TCA cycle metabolites, while consistent increased fatty acid oxidation intermediates were observed across the three cell lines. Metabolite set enrichment analysis showed alpha-linolenic/linoleic acid metabolism as being most upregulated. Downstream mediators of the alpha-linolenic/linoleic acid metabolism, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), were abundant in all three cell lines. EPA was more effective in inhibiting SKOV3 and CaOV3 xenografts, which correlated with inhibition of inflammatory markers and indicated a role for EPA-derived specialized pro-resolving mediators such as Resolvin E1. Thus, modulation of the metabolism of omega-3 fatty acids and their anti-inflammatory signaling molecules appears to be one of the common mechanisms of metformin's antitumor activity. The distinct metabolic signature of the tumors may indicate metformin response and aid the preclinical and clinical interpretation of metformin therapy in ovarian and other cancers.
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Affiliation(s)
- Mary P. Udumula
- Department of Women’s Health Services, Henry Ford Hospital, Henry Ford Cancer Institute, Detroit, MI 48202, USA; (M.P.U.); (N.T.); (J.C.-S.); (M.H.); (A.R.M.)
| | - Laila M. Poisson
- Center for Bioinformatics, Department of Public Health Services, Henry Ford Cancer Institute, Detroit, MI 48202, USA; (L.M.P.); (I.D.)
| | - Indrani Dutta
- Center for Bioinformatics, Department of Public Health Services, Henry Ford Cancer Institute, Detroit, MI 48202, USA; (L.M.P.); (I.D.)
| | - Nivedita Tiwari
- Department of Women’s Health Services, Henry Ford Hospital, Henry Ford Cancer Institute, Detroit, MI 48202, USA; (M.P.U.); (N.T.); (J.C.-S.); (M.H.); (A.R.M.)
| | - Seongho Kim
- Biostatistics and Bioinformatics Core, Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA;
| | - Jasdeep Chinna-Shankar
- Department of Women’s Health Services, Henry Ford Hospital, Henry Ford Cancer Institute, Detroit, MI 48202, USA; (M.P.U.); (N.T.); (J.C.-S.); (M.H.); (A.R.M.)
| | - Ghassan Allo
- Department of Pathology, Henry Ford Hospital, Henry Ford Cancer Institute, Detroit, MI 48202, USA;
| | - Sharif Sakr
- Department of Gynecology Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA;
| | - Miriana Hijaz
- Department of Women’s Health Services, Henry Ford Hospital, Henry Ford Cancer Institute, Detroit, MI 48202, USA; (M.P.U.); (N.T.); (J.C.-S.); (M.H.); (A.R.M.)
| | - Adnan R. Munkarah
- Department of Women’s Health Services, Henry Ford Hospital, Henry Ford Cancer Institute, Detroit, MI 48202, USA; (M.P.U.); (N.T.); (J.C.-S.); (M.H.); (A.R.M.)
| | - Shailendra Giri
- Department of Neurology, Henry Ford Hospital, Detroit, MI 48202, USA;
| | - Ramandeep Rattan
- Department of Women’s Health Services, Henry Ford Hospital, Henry Ford Cancer Institute, Detroit, MI 48202, USA; (M.P.U.); (N.T.); (J.C.-S.); (M.H.); (A.R.M.)
- Department of Oncology, Wayne State School of Medicine, Detroit, MI 48201, USA
- Correspondence: ; Tel.: +313-876-7381; Fax: +313-876-3415
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18
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He L, Wick N, Germans SK, Peng Y. The Role of Breast Cancer Stem Cells in Chemoresistance and Metastasis in Triple-Negative Breast Cancer. Cancers (Basel) 2021; 13:cancers13246209. [PMID: 34944829 PMCID: PMC8699562 DOI: 10.3390/cancers13246209] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 12/05/2021] [Accepted: 12/08/2021] [Indexed: 02/05/2023] Open
Abstract
Triple negative breast cancer (TNBC) remains an aggressive disease due to the lack of targeted therapies and low rate of response to chemotherapy that is currently the main treatment modality for TNBC. Breast cancer stem cells (BCSCs) are a small subpopulation of breast tumors and recognized as drivers of tumorigenesis. TNBC tumors are characterized as being enriched for BCSCs. Studies have demonstrated the role of BCSCs as the source of metastatic disease and chemoresistance in TNBC. Multiple targets against BCSCs are now under investigation, with the considerations of either selectively targeting BCSCs or co-targeting BCSCs and non-BCSCs (majority of tumor cells). This review article provides a comprehensive overview of recent advances in the role of BCSCs in TNBC and the identification of cancer stem cell biomarkers, paving the way for the development of new targeted therapies. The review also highlights the resultant discovery of cancer stem cell targets in TNBC and the ongoing clinical trials treating chemoresistant breast cancer. We aim to provide insights into better understanding the mutational landscape of BCSCs and exploring potential molecular signaling pathways targeting BCSCs to overcome chemoresistance and prevent metastasis in TNBC, ultimately to improve the overall survival of patients with this devastating disease.
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Affiliation(s)
- Lin He
- Department of Pathology, University of Texas Southwestern Medical Center, 6201 Harry Hines Blvd, Dallas, TX 75235, USA; (L.H.); (N.W.); (S.K.G.)
| | - Neda Wick
- Department of Pathology, University of Texas Southwestern Medical Center, 6201 Harry Hines Blvd, Dallas, TX 75235, USA; (L.H.); (N.W.); (S.K.G.)
| | - Sharon Koorse Germans
- Department of Pathology, University of Texas Southwestern Medical Center, 6201 Harry Hines Blvd, Dallas, TX 75235, USA; (L.H.); (N.W.); (S.K.G.)
| | - Yan Peng
- Department of Pathology, University of Texas Southwestern Medical Center, 6201 Harry Hines Blvd, Dallas, TX 75235, USA; (L.H.); (N.W.); (S.K.G.)
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75235, USA
- Correspondence:
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19
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Shoshan-Barmatz V, Anand U, Nahon-Crystal E, Di Carlo M, Shteinfer-Kuzmine A. Adverse Effects of Metformin From Diabetes to COVID-19, Cancer, Neurodegenerative Diseases, and Aging: Is VDAC1 a Common Target? Front Physiol 2021; 12:730048. [PMID: 34671273 PMCID: PMC8521008 DOI: 10.3389/fphys.2021.730048] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 08/24/2021] [Indexed: 12/13/2022] Open
Abstract
Metformin has been used for treating diabetes mellitus since the late 1950s. In addition to its antihyperglycemic activity, it was shown to be a potential drug candidate for treating a range of other diseases that include various cancers, cardiovascular diseases, diabetic kidney disease, neurodegenerative diseases, renal diseases, obesity, inflammation, COVID-19 in diabetic patients, and aging. In this review, we focus on the important aspects of mitochondrial dysfunction in energy metabolism and cell death with their gatekeeper VDAC1 (voltage-dependent anion channel 1) as a possible metformin target, and summarize metformin's effects in several diseases and gut microbiota. We question how the same drug can act on diseases with opposite characteristics, such as increasing apoptotic cell death in cancer, while inhibiting it in neurodegenerative diseases. Interestingly, metformin's adverse effects in many diseases all show VDAC1 involvement, suggesting that it is a common factor in metformin-affecting diseases. The findings that metformin has an opposite effect on various diseases are consistent with the fact that VDAC1 controls cell life and death, supporting the idea that it is a target for metformin.
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Affiliation(s)
- Varda Shoshan-Barmatz
- Department of Life Sciences, Ben-Gurion University of the Negev, Beersheba, Israel
- National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beersheba, Israel
| | - Uttpal Anand
- Department of Life Sciences, Ben-Gurion University of the Negev, Beersheba, Israel
| | | | - Marta Di Carlo
- Institute for Biomedical Research and Innovation, National Research Council, Palermo, Italy
| | - Anna Shteinfer-Kuzmine
- National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beersheba, Israel
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20
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Durrani IA, Bhatti A, John P. The prognostic outcome of 'type 2 diabetes mellitus and breast cancer' association pivots on hypoxia-hyperglycemia axis. Cancer Cell Int 2021; 21:351. [PMID: 34225729 PMCID: PMC8259382 DOI: 10.1186/s12935-021-02040-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 06/24/2021] [Indexed: 12/24/2022] Open
Abstract
Type 2 diabetes mellitus and breast cancer are complex, chronic, heterogeneous, and multi-factorial diseases; with common risk factors including but not limited to diet, obesity, and age. They also share mutually inclusive phenotypic features such as the metabolic deregulations resulting from hyperglycemia, hypoxic conditions and hormonal imbalances. Although, the association between diabetes and cancer has long been speculated; however, the exact molecular nature of this link remains to be fully elucidated. Both the diseases are leading causes of death worldwide and a causal relationship between the two if not addressed, may translate into a major global health concern. Previous studies have hypothesized hyperglycemia, hyperinsulinemia, hormonal imbalances and chronic inflammation, as some of the possible grounds for explaining how diabetes may lead to cancer initiation, yet further research still needs to be done to validate these proposed mechanisms. At the crux of this dilemma, hyperglycemia and hypoxia are two intimately related states involving an intricate level of crosstalk and hypoxia inducible factor 1, at the center of this, plays a key role in mediating an aggressive disease state, particularly in solid tumors such as breast cancer. Subsequently, elucidating the role of HIF1 in establishing the diabetes-breast cancer link on hypoxia-hyperglycemia axis may not only provide an insight into the molecular mechanisms underlying the association but also, illuminate on the prognostic outcome of the therapeutic targeting of HIF1 signaling in diabetic patients with breast cancer or vice versa. Hence, this review highlights the critical role of HIF1 signaling in patients with both T2DM and breast cancer, potentiates its significance as a prognostic marker in comorbid patients, and further discusses the potential prognostic outcome of targeting HIF1, subsequently establishing the pressing need for HIF1 molecular profiling-based patient selection leading to more effective therapeutic strategies emerging from personalized medicine.
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Affiliation(s)
- Ilhaam Ayaz Durrani
- Atta-ur-Rehman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), H-12, Islamabad, Pakistan
| | - Attya Bhatti
- Atta-ur-Rehman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), H-12, Islamabad, Pakistan.
| | - Peter John
- Atta-ur-Rehman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), H-12, Islamabad, Pakistan
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21
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Farahi A, Abedini MR, Javdani H, Arzi L, Chamani E, Farhoudi R, Talebloo N, Hoshyar R. Crocin and Metformin suppress metastatic breast cancer progression via VEGF and MMP9 downregulations: in vitro and in vivo studies. Mol Cell Biochem 2021; 476:3341-3351. [PMID: 33929675 DOI: 10.1007/s11010-020-04043-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Accepted: 12/22/2020] [Indexed: 12/09/2022]
Abstract
Metastatic breast cancer remains a serious health concern and numerous investigations recommended medicinal plants as a complementary therapy. Crocin is one of the known anticancer bio-component. Recently, the inhibitory effect of metformin has been studied on the various aspects of cancer. However, no study reported their combination effects on metastatic breast cancer. In the present study, we have assessed their anti-metastatic effects on in vitro and in vivo breast cancer models. Using MTT assay, scratch, and adhesion tests, we have evaluated the cytotoxic, anti-invasive and anti-adhesion effects of crocin and metformin on 4T1 cell line, respectively. Their protective effects and MMP9 as well as VEGF protein expression levels (Western blotting) investigated in the 4T1 murine breast cancer model. Our results showed that both crocin and metformin reduced cell viability, delayed scratch healing and inhibited the cell adhesion, in vitro. While crocin alone restored the mice's weight reduction, crocin, metformin, and their combination significantly reduced the tumor volume size and enhanced animal survival rate in murine breast cancer model, responses that were associated with VEGF and MMP9 down-regulation. These findings suggest that a combination of crocin and metformin could serve as a novel therapeutic approach to enhance the effectiveness of metastatic breast cancer therapy.
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Affiliation(s)
- Ali Farahi
- Student Research Committee and Department of Molecular Medicine, Birjand University of Medical Sciences, Birjand, Iran.,Cellular and Molecular Research Center, Birjand University of Medical Sciences, P.O. Box 9717853577, Birjand, Iran
| | - Mohammad Reza Abedini
- Cellular and Molecular Research Center, Birjand University of Medical Sciences, P.O. Box 9717853577, Birjand, Iran. .,Department of Cellular and Molecular Medicine, University of Ottawa School of Medicine, Ottawa, ON, Canada.
| | - Hossein Javdani
- Student Research Committee and Department of Molecular Medicine, Birjand University of Medical Sciences, Birjand, Iran.,Cellular and Molecular Research Center, Birjand University of Medical Sciences, P.O. Box 9717853577, Birjand, Iran
| | - Laleh Arzi
- Department of Microbiology, Shahr-e-Qods Branch, Islamic Azad University, Tehran, Iran
| | - Elham Chamani
- Cellular and Molecular Research Center, Birjand University of Medical Sciences, P.O. Box 9717853577, Birjand, Iran
| | - Ramin Farhoudi
- Department of Viral Vaccine Production, Pasteur Institute of Iran, Research and Production Complex, Karaj, Iran
| | - Nazanin Talebloo
- Precision Health Program, Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI, USA.,Department of Chemistry, College of Natural Science, Michigan State University, East Lansing, MI, USA
| | - Reyhane Hoshyar
- Cellular and Molecular Research Center, Birjand University of Medical Sciences, P.O. Box 9717853577, Birjand, Iran. .,Microbiology and Molecular Genetics Department, Michigan State University, East Lansing, MI, 48824, USA.
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22
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Golshan M, Khaleghi S, Shafiee SM, Valaee S, Ghanei Z, Jamshidizad A, Dashtizad M, Shamsara M. Metformin modulates oncogenic expression of HOTAIR gene via promoter methylation and reverses epithelial-mesenchymal transition in MDA-MB-231 cells. J Cell Biochem 2020; 122:385-393. [PMID: 33164274 DOI: 10.1002/jcb.29867] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2019] [Revised: 10/06/2020] [Accepted: 10/28/2020] [Indexed: 12/11/2022]
Abstract
Epithelial-mesenchymal transition (EMT) is a biological event, which critically regulates migration and invasion of cancer cells. EMT is regulated by several protein and nonprotein factors (such as noncoding RNAs). HOTAIR is an oncogenic long noncoding RNA that stimulates EMT in cancers. In the current study, we investigated the effect of metformin on EMT behavior and HOTAIR expression in MDA-MB-231 breast cancer cells. The minimal effective concentrations of metformin (10 and 20 mM) were obtained by the MTT test. Cell migration and invasion in the metformin-containing medium were assayed in the scratch assay and transwell test. Meaningful decreases in both cell migration and invasion were observed in the presence of metformin. Vimentin, snail, β-catenin, and HOTAIR transcripts were quantified by real-time polymerase chain reaction (PCR). Reduction in the expression of vimentin, β-catenin, and HOTAIR was detected as the result of metformin treatment, but the snail showed a constant expression. Western blottingrevealed the downregulation of vimentin and β-catenin proteins. HOTAIR promoter methylation pattern was also investigated in metformin-exposed cells using bisulfite sequencing PCR which the result showed differences in the methylation profile of CpG islands between the treated and untreated cells. In conclusion, metformin modulated oncogenic expression of the HOTAIR gene in the MDA-MB-231 cells. This downregulation was associated with the modification of promoter methylation patterns. Since HOTAIR induces EMT in breast cancer, HOTAIR decline might be one of the mechanisms by which metformin reverses EMT.
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Affiliation(s)
- Mahsa Golshan
- Department of Animal Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
| | - Saeedeh Khaleghi
- Department of Animal Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran.,Department of Biochemistry, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Shiva Valaee
- Department of Animal Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
| | - Zahra Ghanei
- Department of Animal Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
| | - Abbas Jamshidizad
- Department of Animal Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
| | - Mojtaba Dashtizad
- Department of Animal Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
| | - Mehdi Shamsara
- Department of Animal Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
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23
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Samuel SM, Varghese E, Koklesová L, Líšková A, Kubatka P, Büsselberg D. Counteracting Chemoresistance with Metformin in Breast Cancers: Targeting Cancer Stem Cells. Cancers (Basel) 2020; 12:E2482. [PMID: 32883003 PMCID: PMC7565921 DOI: 10.3390/cancers12092482] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 08/19/2020] [Accepted: 08/22/2020] [Indexed: 12/12/2022] Open
Abstract
Despite the leaps and bounds in achieving success in the management and treatment of breast cancers through surgery, chemotherapy, and radiotherapy, breast cancer remains the most frequently occurring cancer in women and the most common cause of cancer-related deaths among women. Systemic therapeutic approaches, such as chemotherapy, although beneficial in treating and curing breast cancer subjects with localized breast tumors, tend to fail in metastatic cases of the disease due to (a) an acquired resistance to the chemotherapeutic drug and (b) the development of intrinsic resistance to therapy. The existence of cancer stem cells (CSCs) plays a crucial role in both acquired and intrinsic chemoresistance. CSCs are less abundant than terminally differentiated cancer cells and confer chemoresistance through a unique altered metabolism and capability to evade the immune response system. Furthermore, CSCs possess active DNA repair systems, transporters that support multidrug resistance (MDR), advanced detoxification processes, and the ability to self-renew and differentiate into tumor progenitor cells, thereby supporting cancer invasion, metastasis, and recurrence/relapse. Hence, current research is focusing on targeting CSCs to overcome resistance and improve the efficacy of the treatment and management of breast cancer. Studies revealed that metformin (1, 1-dimethylbiguanide), a widely used anti-hyperglycemic agent, sensitizes tumor response to various chemotherapeutic drugs. Metformin selectively targets CSCs and improves the hypoxic microenvironment, suppresses the tumor metastasis and inflammation, as well as regulates the metabolic programming, induces apoptosis, and reverses epithelial-mesenchymal transition and MDR. Here, we discuss cancer (breast cancer) and chemoresistance, the molecular mechanisms of chemoresistance in breast cancers, and metformin as a chemo-sensitizing/re-sensitizing agent, with a particular focus on breast CSCs as a critical contributing factor to acquired and intrinsic chemoresistance. The review outlines the prospects and directions for a better understanding and re-purposing of metformin as an anti-cancer/chemo-sensitizing drug in the treatment of breast cancer. It intends to provide a rationale for the use of metformin as a combinatory therapy in a clinical setting.
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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;
| | - Lenka Koklesová
- Department of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia; (L.K.); (A.L.)
| | - Alena Líšková
- Department of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia; (L.K.); (A.L.)
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia;
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar;
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24
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Associations between metabolic syndrome and gynecologic cancer. Obstet Gynecol Sci 2020; 63:215-224. [PMID: 32489965 PMCID: PMC7231948 DOI: 10.5468/ogs.2020.63.3.215] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 01/01/2020] [Accepted: 01/16/2020] [Indexed: 12/21/2022] Open
Abstract
Metabolic syndrome (MetS) is a group of risk factors that causes cardiovascular and diabetic morbidity and mortality, which is diagnosed by central obesity, dyslipidemia, hyperglycemia, and hypertension. Increasing epidemiological data and experimental results indicate that the presence of MetS increases the incidence of common malignancies and related mortality. Epidemiological studies have previously reported an association of endometrial cancer occurrence with MetS. Aromatization of androstenedione to estrogen, insulin resistance, and diabetes can cause increased levels of free estrogen, and the detrimental effect of elevated estrogen as a carcinogen is well studied in endometrial cancer. Medications used to manage MetS such as metformin and statins are suggested to reduce endometrial cancer risk and improve survival. Some large population-based epidemiological studies have suggested that the MetS is related to an increased risk of cervical carcinoma. MetS may contribute to viral-host interactions, which lead to persistent human papilloma virus (HPV) infection, although limited epidemiological data are available. Specific effects of obesity and diabetes on the occurrence of ovarian cancer have been suggested. However, the direct correlation between MetS and ovarian cancer is still lacking. Previous retrospective studies reported that the use of metformin, statins, and beta-blockers could be associated with cancer prevention or better prognosis. Proper diagnosis and management of the MetS should be a part of the strategies undertaken to prevent and treat gynecologic cancer. So far, only limited data is available on this subject, and further clinical and fundamental research is required to further clarify the effect of these therapies on gynecologic cancer treatment.
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25
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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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26
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2-Amino-4-(1-piperidine) pyridine exhibits inhibitory effect on colon cancer through suppression of FOXA2 expression. 3 Biotech 2019; 9:384. [PMID: 31656722 DOI: 10.1007/s13205-019-1915-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Accepted: 09/21/2019] [Indexed: 12/27/2022] Open
Abstract
The present study was aimed to investigate the effect of 2-amino-4-(1-piperidine) pyridine on migration and invasion of colon cancer cells. Treatment of colon cancer cells with 2-amino-4-(1-piperidine) pyridine reduced viability in concentration-based manner. The migration potential of HCT116 and HT29 cells was also suppressed on treatment with 2-amino-4-(1-piperidine) pyridine. In HCT116 and HT29 cells, apoptotic cell proportion was increased significantly by 2-amino-4-(1-piperidine) pyridine treatment. The expression of EMT and Vimentin in HCT116 and HT29 cells was reduced markedly on treatment with 2-amino-4-(1-piperidine) pyridine. The expression of E-cadherin was increased in HCT116 and HT29 cells by 2-amino-4-(1-piperidine) pyridine treatment. Treatment with 2-amino-4-(1-piperidine) pyridine reduced the expression of FOXA2 in HCT116 and HT29 cells. The 2-amino-4-(1-piperidine) pyridine treatment reduced growth of tumor in vivo in mice model. In summary, 2-amino-4-(1-piperidine) pyridine treatment inhibits colon cancer cell proliferation through down-regulation of FOXA2 expression. Therefore, 2-amino-4-(1-piperidine) pyridine can be used for the treatment of colon cancer.
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27
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Choi YJ, Kim DJ, Shin S. Incident cancer risk in dipeptidyl peptidase-4 inhibitor-treated patients with type 2 diabetes mellitus. Cancer Manag Res 2019; 11:7427-7438. [PMID: 31496802 PMCID: PMC6689554 DOI: 10.2147/cmar.s215107] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 07/22/2019] [Indexed: 12/29/2022] Open
Abstract
Objective It is known that patients with diabetes are susceptible to cancer development due to long-standing diabetic conditions. This study aimed to investigate new-onset cancer risk associated with dipeptidyl peptidase-4 (DPP-4) inhibitors as compared to metformin, the first-line antidiabetic agent with promising anticancer activity, in patients with type 2 diabetes mellitus (T2DM). Methods A retrospective cohort study of adult T2DM patients was performed at a tertiary care hospital in Korea. Patients who received comparison therapies during 2008–2017 were propensity score (PS)-matched in a 1:1 ratio either to the DPP-4 inhibitors group or to the metformin group in accordance with their primary antidiabetic therapy. Results A total of 1538 patients (769 in each group) were found eligible for study entry. Although the rate of newly diagnosed malignancy, irrespective of specific sites or types, was numerically less frequent in the DPP-4 inhibitors group, the difference in overall cancer risk between groups was not statistically significant (HR=1.00, 95% CI=0.56–1.80, P=0.998). The PS-matched patients were further stratified by relevant patient factors and diabetes severity. No signal of increased risk of malignant complications among DPP-4 inhibitor-receiving diabetic patients was detected in any of the individual strata, nor in the subgroup patients where insulin-exposed patients were excluded from study analyses in consideration of its carcinogenic properties. Patient death or incident pancreatitis events were seldom encountered in both treatment groups; hence such risks were assessed as negligible with the use of either antidiabetic therapy. Conclusion This PS-matched cohort study demonstrated no elevated risk of malignant complications with DPP-4 inhibitor treatment relative to metformin treatment among T2DM patients, irrespective of patient sex, age, comorbid conditions, and diabetes severity status. Similar results were confirmed in the subgroup analyses where a potential confounding effect due to the between-group disparity in insulin co-therapy was eliminated by excluding insulin-exposed patients from risk assessments.
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Affiliation(s)
- Yeo Jin Choi
- Clinical Trial Center, Hallym University Hospital, Anyang, Republic of Korea
| | - Dae Jung Kim
- Department of Endocrinology and Metabolism, School of Medicine, Ajou University, Suwon, Republic of Korea
| | - Sooyoung Shin
- Department of Clinical Pharmacy, College of Pharmacy, Ajou University, Suwon, Republic of Korea.,Research Institute of Pharmaceutical Science and Technology (RIPST), Ajou University, Suwon, Republic of Korea
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28
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Ovarian Cancer Stem Cells: Role in Metastasis and Opportunity for Therapeutic Targeting. Cancers (Basel) 2019; 11:cancers11070934. [PMID: 31277278 PMCID: PMC6678643 DOI: 10.3390/cancers11070934] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Revised: 06/29/2019] [Accepted: 06/30/2019] [Indexed: 02/08/2023] Open
Abstract
Ovarian cancer (OC) is a heterogeneous disease usually diagnosed at a late stage. Cancer stem cells (CSCs) that exist within the bulk tumor survive first-line chemotherapy and contribute to resistant disease with metastasis. Understanding the key features of CSC biology provides valuable opportunities to develop OCSC-directed therapeutics, which will eventually improve the clinical outcomes of patients. Although significant developments have occurred since OCSCs were first described, the involvement of CSCs in ovarian tumor metastasis is not fully understood. Here, we discuss putative CSC markers and the fundamental role of CSCs in facilitating tumor dissemination in OC. Additionally, we focus on promising CSC-targeting strategies in preclinical and clinical studies of OC and discuss potential challenges in CSC research.
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29
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Brown SL, Kolozsvary A, Isrow DM, Al Feghali K, Lapanowski K, Jenrow KA, Kim JH. A Novel Mechanism of High Dose Radiation Sensitization by Metformin. Front Oncol 2019; 9:247. [PMID: 31024849 PMCID: PMC6465931 DOI: 10.3389/fonc.2019.00247] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Accepted: 03/18/2019] [Indexed: 12/15/2022] Open
Abstract
Introduction: Metformin, the most widely used treatment for diabetes, is lethal to cancer cells and increases in toxicity when used in combination with radiation. In addition to various molecular and metabolic mechanisms that have been previously proposed, the studies presented provide evidence of an additional, novel mechanism of sensitization following high dose radiotherapy; the magnitude of sensitization depends on the microenvironmental levels of glucose and oxygen which are in turn affected by high dose radiation. Methods: Cancer cells (A549 and MCF7) were studied in vitro under various controlled conditions. Endpoints included clonogenic cell survival and ROS expression measured by DHE and DCFDA. CD1 nu/nu athymic mice implanted with A549 cells received metformin alone (200 mg/kg, i.p.), radiation alone (15 Gy) or a combination of metformin and radiation; the effect of treatment sequence on efficacy was assessed by tumor growth delay and histology. In a separate set of experiments, tumor blood flow was measured using a tracer clearance technique using SPECT after the administration of metformin alone, radiation alone and the combined treatment. Results:In vivo, metformin provided equally effective tumor growth delay when given 24 h after radiation as when given 1 h or 4 h before radiation, an observation not previously reported and, in fact, unexpected based on published scientific literature. When drug followed radiation, the tumors were histologically characterized by massive cellular necrosis. In vitro, cancer cells when glucose depleted and/or hypoxic were preferentially killed by metformin, in a drug dose dependent manner. A549 cells exposed to 5.0 mM of metformin was reduced seven fold in survival when in a glucose deprived as compared to a low-glucose medium (0 vs. 1.0 g/L). Finally, using a SPECT detector to follow the washout of a radioactive tracer, it was shown that a high single dose of radiosurgery (15 Gy) could dramatically inhibit blood flow and presumably diminish glucose and oxygen. Discussion: Insight into the best timing of drug and radiation administration is gained through an understanding of the mechanisms of interaction. A new mechanism of metformin sensitization by high dose radiation is proposed based on the blood flow, glucose and oxygen.
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Affiliation(s)
- Stephen L Brown
- Department of Radiation Oncology, Henry Ford Hospital, Detroit, MI, United States
| | - Andrew Kolozsvary
- Department of Radiation Oncology, Henry Ford Hospital, Detroit, MI, United States
| | - Derek M Isrow
- Department of Radiation Oncology, Henry Ford Hospital, Detroit, MI, United States
| | - Karine Al Feghali
- Department of Radiation Oncology, Henry Ford Hospital, Detroit, MI, United States
| | - Karen Lapanowski
- Department of Radiation Oncology, Henry Ford Hospital, Detroit, MI, United States
| | - Kenneth A Jenrow
- Department of Radiation Oncology, Henry Ford Hospital, Detroit, MI, United States.,Department of Psychology, Central Michigan University, Mount Pleasant, MI, United States
| | - Jae Ho Kim
- Department of Radiation Oncology, Henry Ford Hospital, Detroit, MI, United States
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30
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Toledo-Guzmán ME, Bigoni-Ordóñez GD, Ibáñez Hernández M, Ortiz-Sánchez E. Cancer stem cell impact on clinical oncology. World J Stem Cells 2018; 10:183-195. [PMID: 30613312 PMCID: PMC6306557 DOI: 10.4252/wjsc.v10.i12.183] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 10/15/2018] [Accepted: 11/15/2018] [Indexed: 02/06/2023] Open
Abstract
Cancer is a widespread worldwide chronic disease. In most cases, the high mortality rate from cancer correlates with a lack of clear symptoms, which results in late diagnosis for patients, and consequently, advanced tumor disease with poor probabilities for cure, since many patients will show chemo- and radio-resistance. Several mechanisms have been studied to explain chemo- and radio-resistance to anti-tumor therapies, including cell signaling pathways, anti-apoptotic mechanisms, stemness, metabolism, and cellular phenotypes. Interestingly, the presence of cancer stem cells (CSCs), which are a subset of cells within the tumors, has been related to therapy resistance. In this review, we focus on evaluating the presence of CSCs in different tumors such as breast cancer, gastric cancer, lung cancer, and hematological neoplasias, highlighting studies where CSCs were identified in patient samples. It is evident that there has been a great drive to identify the cell surface phenotypes of CSCs so that they can be used as a tool for anti-tumor therapy treatment design. We also review the potential effect of nanoparticles, drugs, natural compounds, aldehyde dehydrogenase inhibitors, cell signaling inhibitors, and antibodies to treat CSCs from specific tumors. Taken together, we present an overview of the role of CSCs in tumorigenesis and how research is advancing to target these highly tumorigenic cells to improve oncology patient outcomes.
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Affiliation(s)
- Mariel E Toledo-Guzmán
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Mexico City 14080, Mexico
| | | | - Miguel Ibáñez Hernández
- Departamento de Bioquímica, Laboratorio de Terapia Génica, Escuela Nacional de Ciencias Biológicas, Posgrado de Biomedicina y Biotecnología Molecular, Instituto Politécnico Nacional, Mexico City 11340, Mexico
| | - Elizabeth Ortiz-Sánchez
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Mexico City 14080, Mexico.
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Kwon YS, Chun SY, Nan HY, Nam KS, Lee C, Kim S. Metformin selectively targets 4T1 tumorspheres and enhances the antitumor effects of doxorubicin by downregulating the AKT and STAT3 signaling pathways. Oncol Lett 2018; 17:2523-2530. [PMID: 30675314 DOI: 10.3892/ol.2018.9827] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 11/14/2018] [Indexed: 02/06/2023] Open
Abstract
Recent studies have reported that metformin (Met), the first-line medication for the treatment of type 2 diabetes, exhibited anticancer and chemoprotective effects in diverse cancer cells. In this study, we investigated the effects of Met on the drug-resistance of 4T1 murine breast cancer tumorspheres (TS) and the mechanism responsible for its drug-resistance. 4T1 TS exhibited accumulations of cells at the G0/G1 phase compared with cells in monolayer culture, which suggested the majority of cells in TS were quiescent. Furthermore, it was identified that activations of the signal transducer and activator of transcription 3 (STAT3) and protein kinase B (AKT) signaling pathways in 4T1 TS conferred drug-resistance to doxorubicin (Dox) and lapatinib (Lapa). However, Met selectively targeted TS rather than cells in monolayer culture and increased the cytotoxic effect of Dox on TS by inhibiting activations of the STAT3 and AKT signaling pathways. These observations suggested that inhibitions of STAT3 and AKT underlie the selective cytotoxic effects of Met on TS. In addition, Met exhibited synergistic antitumor effects with Dox on 4T1 tumor-bearing BALB/c mice. Our findings suggest that combinations of Met and cytotoxic anticancer drugs may offer an advantage for treating drug-resistant breast cancer.
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Affiliation(s)
- Yun-Suk Kwon
- Department of Pharmacology and Intractable Disease Research Center, School of Medicine, Dongguk University, Gyeongju, Gyeongsangbuk-do 380660, Republic of Korea
| | - So-Young Chun
- Department of Pharmacology and Intractable Disease Research Center, School of Medicine, Dongguk University, Gyeongju, Gyeongsangbuk-do 380660, Republic of Korea
| | - Hong-Yan Nan
- Department of Biochemistry and Molecular Biology, School of Medicine, Yeungnam University, Daegu 42415, Republic of Korea
| | - Kyung-Soo Nam
- Department of Pharmacology and Intractable Disease Research Center, School of Medicine, Dongguk University, Gyeongju, Gyeongsangbuk-do 380660, Republic of Korea
| | - Chuhee Lee
- Department of Biochemistry and Molecular Biology, School of Medicine, Yeungnam University, Daegu 42415, Republic of Korea
| | - Soyoung Kim
- Department of Pharmacology and Intractable Disease Research Center, School of Medicine, Dongguk University, Gyeongju, Gyeongsangbuk-do 380660, Republic of Korea
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Dittmer J. Breast cancer stem cells: Features, key drivers and treatment options. Semin Cancer Biol 2018; 53:59-74. [PMID: 30059727 DOI: 10.1016/j.semcancer.2018.07.007] [Citation(s) in RCA: 117] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Revised: 07/10/2018] [Accepted: 07/18/2018] [Indexed: 02/06/2023]
Abstract
The current view is that breast cancer is a stem cell disease characterized by the existence of cancer cells with stem-like features and tumor-initiating potential. These cells are made responsible for tumor dissemination and metastasis. Common therapies by chemotherapeutic drugs fail to eradicate these cells and rather increase the pool of cancer stem cells in tumors, an effect that may increase the likelyhood of recurrence. Fifteen years after the first evidence for a small stem-like subpopulation playing a major role in breast cancer initiation has been published a large body of knowledge has been accumulated regarding the signaling cascades and proteins involved in maintaining stemness in breast cancer. Differences in the stem cell pool size and in mechanisms regulating stemness in the different breast cancer subtypes have emerged. Overall, this knowledge offers new approaches to intervene with breast cancer stem cell activity. New options are particularly needed for the treatment of triple-negative breast cancer subtype, which is particularly rich in cancer stem cells and is also the subtype for which specific therapies are still not available.
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Affiliation(s)
- Jürgen Dittmer
- Clinic for Gynecology, Martin Luther University Halle-Wittenberg, Germany.
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Given JE, Loane M, Garne E, Addor MC, Bakker M, Bertaut-Nativel B, Gatt M, Klungsoyr K, Lelong N, Morgan M, Neville AJ, Pierini A, Rissmann A, Dolk H. Metformin exposure in first trimester of pregnancy and risk of all or specific congenital anomalies: exploratory case-control study. BMJ 2018; 361:k2477. [PMID: 29941493 PMCID: PMC6016021 DOI: 10.1136/bmj.k2477] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE To investigate whether exposure to metformin during the first trimester of pregnancy, for diabetes or other indications, increases the risk of all or specific congenital anomalies. DESIGN Population based exploratory case-control study using malformed controls. Cases of 29 specific subgroups of non-genetic anomalies, and all non-genetic anomalies combined, were compared with controls (all other non-genetic anomalies or genetic syndromes). SETTING 11 EUROmediCAT European congenital anomaly registries surveying 1 892 482 births in Europe between 2006 and 2013. PARTICIPANTS 50 167 babies affected by congenital anomaly (41 242 non-genetic and 8925 genetic) including live births, fetal deaths from 20 weeks' gestation, and terminations of pregnancy for fetal anomaly. MAIN OUTCOME MEASURE Odds ratios adjusted for maternal age, registry, multiple birth, and maternal diabetes status. RESULTS 168 babies affected by congenital anomaly (141 non-genetic and 27 genetic) were exposed to metformin, 3.3 per 1000 births. No evidence was found for a higher proportion of exposure to metformin during the first trimester among babies with all non-genetic anomalies combined compared with genetic controls (adjusted odds ratio 0.84, 95% confidence interval 0.55 to 1.30). The only significant result was for pulmonary valve atresia (adjusted odds ratio 3.54, 1.05 to 12.00, compared with non-genetic controls; 2.86, 0.79 to 10.30, compared with genetic controls). CONCLUSIONS No evidence was found for an increased risk of all non-genetic congenital anomalies combined following exposure to metformin during the first trimester, and the one significant association was no more than would be expected by chance. Further surveillance is needed to increase sample size and follow up the cardiac signal, but these findings are reassuring given the increasing use of metformin in pregnancy.
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Affiliation(s)
- Joanne E Given
- Administrative Data Research Centre Northern Ireland, Ulster University, Belfast BT37 0QB, UK
| | - Maria Loane
- Institute of Nursing and Health Research, Ulster University, Belfast BT37 0QB, UK
| | - Ester Garne
- Paediatric Department, Hospital Lillebaelt, Kolding, DK-6000, Denmark
| | | | - Marian Bakker
- University of Groningen, University Medical Center Groningen, Department of Genetics, Eurocat Northern Netherlands, 9700RB, Netherlands
| | | | - Miriam Gatt
- Directorate for Health Information and Research, Guardamangia, PTA 1313, Malta
| | - Kari Klungsoyr
- Division of Mental and Physical Health, Norwegian Institute of Public Health, Bergen, Norway
- Department of Global Public Health and Primary Care, University of Bergen, N-5018, Norway
| | - Nathalie Lelong
- Inserm UMR 1153, Obstetrical, Perinatal and Pediatric Epidemiology Research Team (Epopé), Center for Epidemiology and Statistics Sorbonne Paris Cité and DHU Risks in pregnancy, Paris Descartes University, Paris, 75014, France
| | - Margery Morgan
- Congenital Anomaly Register and Information Service for Wales, Public Health Wales, Swansea SA2 8QA, UK
| | - Amanda J Neville
- IMER Registry (Emilia Romagna Registry of Birth Defects), University of Ferrara and Azienda Ospedaliero Universitaria di Ferrara, Ferrara, 44100, Italy
| | - Anna Pierini
- Tuscany Registry of Congenital Defects, Institute of Clinical Physiology, National Research Council/Fondazione Toscana Gabriele Monasterio, Pisa, 56126, Italy
| | - Anke Rissmann
- Malformation Monitoring Centre Saxony-Anhalt, Medical Faculty Otto-von-Guericke University Magdeburg, Magdeburg, D-39120, Germany
| | - Helen Dolk
- Institute of Nursing and Health Research, Ulster University, Belfast BT37 0QB, UK
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A pharmacodynamic study of sirolimus and metformin in patients with advanced solid tumors. Cancer Chemother Pharmacol 2018; 82:309-317. [PMID: 29948021 DOI: 10.1007/s00280-018-3619-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 06/04/2018] [Indexed: 01/14/2023]
Abstract
BACKGROUND Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor. Metformin may potentiate mTOR inhibition by sirolimus while mitigating its adverse effects. We conducted a pilot study to test this hypothesis. METHODS Patients with advanced solid tumor were treated with sirolimus for 7 days followed by randomization to either sirolimus with metformin (Arm A) or sirolimus (Arm B) until day 21. From day 22 onwards, all patients received sirolimus and metformin. The primary aim was to compare the change in phospho-p70S6K (pp70S6K) in peripheral blood mononuclear cells (PBMC) from day 8 to day 22 using a two-sample t test. Secondary aims were objective response rate, toxicity, and other serum pharmacodynamic biomarkers (e.g., fasting glucose, triglycerides, insulin, C-peptide, IGF-1, IGF-1R, IGF-BP, and leptin). RESULTS 24 patients were enrolled, with 18 evaluable for the primary endpoint. There was no significant difference in mean change in pp70S6K in arm A vs. arm B (- 0.12 vs. - 0.16; P = 0.64). Similarly, there were no significant differences in other serum pharmacodynamic biomarkers. There were no partial responses. There were no dose-limiting or unexpected toxicities. CONCLUSIONS Adding metformin to sirolimus, although well tolerated, was not associated with significant changes in pp70S6K in PBMC or other serum pharmacodynamic biomarkers. IMPACT Combining metformin with sirolimus did not improve mTOR inhibition.
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Songthaveesin C, Sa-Nongdej W, Limboonreung T, Chongthammakun S. Combination of metformin and 9-cis retinoic acid increases apoptosis in C6 glioma stem-like cells. Heliyon 2018; 4:e00638. [PMID: 29872770 PMCID: PMC5986546 DOI: 10.1016/j.heliyon.2018.e00638] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2018] [Revised: 04/09/2018] [Accepted: 05/25/2018] [Indexed: 12/17/2022] Open
Abstract
Glioblastoma (GBM) is the most commonly diagnosed type of brain cancer and the leading cause of brain cancer-related death. GBM contains a subpopulation of tumor-propagating glioblastoma stem-like cells that are thought to drive cancer progression and recurrence. Although several clinical trials are ongoing to explore new chemotherapeutic agents to treat GBM, the use of metformin (Met), a first-line drug for type 2 diabetes mellitus, in cancer remains controversial. Here, we show that combining Met with 9-cis retinoic acid (9-cis RA) reduced the proliferation rate of C6-GSCs (glioblastoma stem-like cells) in vitro. The results of flow cytometric analysis showed that treatment with 9-cis RA for 24 h induced 4.5% early and 38.0% late apoptosis in C6-GSCs. Twenty-four hours of Met treatment induced 23.6% early and 33.5% late apoptosis in C6-GSCs. Combination of Met and 9-cis RA treatment significantly increased both early and late apoptosis to 30.4% and 55.4%, respectively. The present findings suggest that not only 9-cis RA but also Met has the potential to induce early and late apoptotic GSCs death by affecting the functional cytoplasmic and nuclear organelles. At the protein level, there was increased cleaved caspase-3 but decreased procaspase-3 expression in Met-, 9-cis RA- and Met+9-cis RA-treated C6 GSCs, as detected by western blotting. The ratio of cleaved caspase-3/procaspase-3 was 1.6 times higher in Met+9-cis RA-treated groups compared to control. Ultimately, a combination of Met and 9-cis RA might be a possible therapeutic target for the treatment of GBM.
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Affiliation(s)
- Chanchai Songthaveesin
- Center for Neuroscience, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand
| | - Wanna Sa-Nongdej
- School of Nursing, Ramathibodi Hospital, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand
| | - Tanapol Limboonreung
- Department of Anatomy and Center for Neuroscience, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
| | - Sukumal Chongthammakun
- Department of Anatomy and Center for Neuroscience, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
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36
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Li L, Wang Y, Peng T, Zhang K, Lin C, Han R, Lu C, He Y. Metformin restores crizotinib sensitivity in crizotinib-resistant human lung cancer cells through inhibition of IGF1-R signaling pathway. Oncotarget 2018; 7:34442-52. [PMID: 27144340 PMCID: PMC5085167 DOI: 10.18632/oncotarget.9120] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2015] [Accepted: 03/31/2016] [Indexed: 01/27/2023] Open
Abstract
Aim Despite the impressive efficacy of crizotinib for the treatment of ALK-positive non-small cell lung cancer, patients invariably develop therapeutic resistance. Suppression of the IGF-1R signaling pathway may abrogate this acquired mechanism of drug resistance to crizotinib. Metformin, a widely used antidiabetic agent, may reverse crizotinib resistance through inhibition of IGF-1R signaling. Results The present study revealed that metformin effectively increased the sensitivity of both crizotinib-sensitive and -resistant non-small cell lung cancer cells to crizotinib, as evidenced by decreased proliferation and invasion and enhanced apoptosis. Metformin reduced IGF-1R signaling activation in crizotinib-resistant cells. Furthermore, the addition of IGF-1 to crizotinib-sensitive H2228 cells induced crizotinib resistance, which was overcome by metformin. Experimental design The effects of metformin to reverse crizotinib resistance were examined in vitro by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT), invasion assay, ki67 incorporation assay, flow cytometry analysis, Western blot analysis, and colony-forming assay. Conclusions Metformin may be used in combination with crizotinib in ALK+ NSCLC patients to overcome crizotinib resistance and prolong survival.
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Affiliation(s)
- Li Li
- Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Yubo Wang
- Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Tao Peng
- Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Kejun Zhang
- Department of Clinical Labratory, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Caiyu Lin
- Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Rui Han
- Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Conghua Lu
- 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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Zi F, Zi H, Li Y, He J, Shi Q, Cai Z. Metformin and cancer: An existing drug for cancer prevention and therapy. Oncol Lett 2018; 15:683-690. [PMID: 29422962 PMCID: PMC5772929 DOI: 10.3892/ol.2017.7412] [Citation(s) in RCA: 84] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2016] [Accepted: 09/22/2017] [Indexed: 12/17/2022] Open
Abstract
Metformin is a standard clinical drug used to treat type 2 diabetes mellitus (T2DM) and polycystic ovary syndrome. Recently, epidemiological studies and meta-analyses have revealed that patients with T2DM have a lower incidence of tumor development than healthy controls and that patients diagnosed with cancer have a lower risk of mortality when treated with metformin, demonstrating an association between metformin and tumorigenesis. In vivo and in vitro studies have revealed that metformin has a direct antitumor effect, which may depress tumor proliferation and induce the apoptosis, autophagy and cell cycle arrest of tumor cells. The mechanism underpinning the antitumor effect of metformin has not been well established. Studies have demonstrated that reducing insulin and insulin-like growth factor levels in the peripheral blood circulation may lead to the inhibition of phosphoinositide 3-kinase/Akt/mechanistic target of rapamycin (mTOR) signaling or activation of AMP-activated protein kinase, which inhibits mTOR signaling, a process that may be associated with the antitumor effect of metformin. The present review primarily focuses on the recent progress in understanding the function of metformin in tumor development.
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Affiliation(s)
- Fuming Zi
- Department of Hematology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330008, P.R. China
| | - Huapu Zi
- Department of Oncology, Rizhao Traditional Chinese Medicine Hospital of Shandong Traditional Chinese Medicine University, Rizhao, Shandong 276800, P.R. China
| | - Yi Li
- Bone Marrow Transplantation Center, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
| | - Jingsong He
- Bone Marrow Transplantation Center, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
| | - Qingzhi Shi
- Department of Hematology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330008, P.R. China
| | - Zhen Cai
- Bone Marrow Transplantation Center, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
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38
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Di Costanzo GG, Tortora R, Morisco F, Addario L, Guarino M, Cordone G, Falco L, Caporaso N. Impact of Diabetes on Outcomes of Sorafenib Therapy for Hepatocellular Carcinoma. Target Oncol 2017; 12:61-67. [PMID: 27503006 DOI: 10.1007/s11523-016-0454-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Patients with diabetes are at increased risk of developing hepatocellular carcinoma (HCC) and have a poorer prognosis as compared to non-diabetics when HCC occurs. Diabetics with non-HCC cancers are at higher risk of toxicity related to systemic therapy, but data on HCC are lacking. OBJECTIVE The aim of this study was to evaluate safety and effectiveness of sorafenib in HCC patients according to the presence/absence of diabetes. PATIENTS AND METHODS From October 2008 to June 2014, 313 patients with HCC treated with sorafenib were enrolled. The patients were staged according to the BCLC system. Treatment response was evaluated according to the mRECIST criteria. The main evaluated outcomes were the overall survival and the safety in the two groups. RESULTS Patients were divided in two groups: 80 diabetics (DIAB) and 233 nondiabetics (nDIAB). The median treatment duration was 4 months in DIAB and 3 months in nDIAB. Main adverse events occurred with comparable frequency in both groups, with the exception of rash, that was more frequent among DIAB than in nDIAB: 27.5 % vs 17.6 % (P = .047). The median overall survival was 9 months in nDIAB and 10 months in DIAB group (P = .535). Median time-to-progression (TTP) was longer the in DIAB than the nDIAB group (P = .038). CONCLUSIONS Sorafenib was as safe as effective in DIAB and in nDIAB patients. The longer TTP observed among DIAB than in nDIAB patients might suggest a better anticancer effect of sorafenib in patients with diabetes.
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Affiliation(s)
| | - Raffaella Tortora
- Department of Transplantation - Liver Unit, Cardarelli Hospital, Via A. Cardarelli 9, 80131, Naples, Italy
| | - Filomena Morisco
- Department of Clinical Medicine and Surgery - Gastroenterology Unit, University of Naples "Federico II", Naples, Italy
| | - Luigi Addario
- Department of Transplantation - Liver Unit, Cardarelli Hospital, Via A. Cardarelli 9, 80131, Naples, Italy
| | - Maria Guarino
- Department of Clinical Medicine and Surgery - Gastroenterology Unit, University of Naples "Federico II", Naples, Italy
| | - Gabriella Cordone
- Department of Transplantation - Liver Unit, Cardarelli Hospital, Via A. Cardarelli 9, 80131, Naples, Italy
| | - Luigia Falco
- Department of Transplantation - Liver Unit, Cardarelli Hospital, Via A. Cardarelli 9, 80131, Naples, Italy
| | - Nicola Caporaso
- Department of Clinical Medicine and Surgery - Gastroenterology Unit, University of Naples "Federico II", Naples, Italy
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Gong J, Kelekar G, Shen J, Shen J, Kaur S, Mita M. The expanding role of metformin in cancer: an update on antitumor mechanisms and clinical development. Target Oncol 2017; 11:447-67. [PMID: 26864078 DOI: 10.1007/s11523-016-0423-z] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Metformin has been used for nearly a century to treat type 2 diabetes mellitus. Epidemiologic studies first identified the association between metformin and reduced risk of several cancers. The anticancer mechanisms of metformin involve both indirect or insulin-dependent pathways and direct or insulin-independent pathways. Preclinical studies have demonstrated metformin's broad anticancer activity across a spectrum of malignancies. Prospective clinical trials involving metformin in the chemoprevention and treatment of cancer now number in the hundreds. We provide an update on the anticancer mechanisms of metformin and review the results thus far available from prospective clinical trials investigating metformin's efficacy in cancer.
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Affiliation(s)
- Jun Gong
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Gauri Kelekar
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - James Shen
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - John Shen
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Sukhpreet Kaur
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Monica Mita
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. .,Experimental Therapeutics Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, SCCT Mezzanine MS 35, Los Angeles, CA, 90048, USA.
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Kim EH, Lee JH, Oh Y, Koh I, Shim JK, Park J, Choi J, Yun M, Jeon JY, Huh YM, Chang JH, Kim SH, Kim KS, Cheong JH, Kim P, Kang SG. Inhibition of glioblastoma tumorspheres by combined treatment with 2-deoxyglucose and metformin. Neuro Oncol 2017; 19:197-207. [PMID: 27571886 DOI: 10.1093/neuonc/now174] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Background Deprivation of tumor bioenergetics by inhibition of multiple energy pathways has been suggested as an effective therapeutic approach for various human tumors. However, this idea has not been evaluated in glioblastoma (GBM). We hypothesized that dual inhibition of glycolysis and oxidative phosphorylation could effectively suppress GBM tumorspheres (TS). Methods Effects of 2-deoxyglucose (2DG) and metformin, alone and in combination, on GBM-TS were evaluated. Viability, cellular energy metabolism status, stemness, invasive properties, and GBM-TS transcriptomes were examined. In vivo efficacy was tested in a mouse orthotopic xenograft model. Results GBM-TS viability was decreased by the combination of 2DG and metformin. ATP assay and PET showed that cellular energy metabolism was also decreased by this combination. Sphere formation, expression of stemness-related proteins, and invasive capacity of GBM-TS were also significantly suppressed by combined treatment with 2DG and metformin. A transcriptome analysis showed that the expression levels of stemness- and epithelial mesenchymal transition-related genes were also significantly downregulated by combination of 2DG and metformin. Combination treatment also prolonged survival of tumor-bearing mice and decreased invasiveness of GBM-TS. Conclusion The combination of 2DG and metformin effectively decreased the stemness and invasive properties of GBM-TS and showed a potential survival benefit in a mouse orthotopic xenograft model. Our findings suggest that targeting TS-forming cells by this dual inhibition of cellular bioenergetics warrants expedited clinical evaluation for the treatment of GBM.
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Affiliation(s)
- Eui Hyun Kim
- Departments of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Ji-Hyun Lee
- Departments of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yoonjee Oh
- Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - Ilkyoo Koh
- Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - Jin-Kyoung Shim
- Departments of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Junseong Park
- Departments of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Junjeong Choi
- Departments of Pharmacy, Yonsei University College of Pharmacy, Songdo, Incheon, Republic of Korea
| | - Mijin Yun
- Departments of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jeong Yong Jeon
- Departments of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yong Min Huh
- Departments of Radiology, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jong Hee Chang
- Departments of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sun Ho Kim
- Departments of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Kyung-Sup Kim
- Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jae-Ho Cheong
- Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Pilnam Kim
- Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - Seok-Gu Kang
- Departments of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
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Dasgupta A, Trucco M, Rainusso N, Bernardi RJ, Shuck R, Kurenbekova L, Loeb DM, Yustein JT. Metabolic modulation of Ewing sarcoma cells inhibits tumor growth and stem cell properties. Oncotarget 2017; 8:77292-77308. [PMID: 29100387 PMCID: PMC5652780 DOI: 10.18632/oncotarget.20467] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Accepted: 07/20/2017] [Indexed: 12/11/2022] Open
Abstract
Ewing sarcoma (EWS) is a highly aggressive and metabolically active malignant tumor. Metabolic activity can broadly be characterized by features of glycolytic activity and oxidative phosphorylation. We have further characterized metabolic features of EWS cells to identify potential therapeutic targets. EWS cells had significantly more glycolytic activity compared to their non-malignant counterparts. Thus, metabolic inhibitors of glycolysis such as 2-deoxy-D-glucose (2DG) and of the mitochondrial respiratory pathway, such as metformin, were evaluated as potential therapeutic agents against a panel of EWS cell lines in vitro. Results indicate that 2DG alone or in combination with metformin was effective at inducing cell death in EWS cell lines. The predominant mechanism of cell death appears to be through stimulating apoptosis leading into necrosis with concomitant activation of AMPK-α. Furthermore, we demonstrate that the use of metabolic modulators can target putative EWS stem cells, both in vitro and in vivo, and potentially overcome chemotherapeutic resistance in EWS. Based on these data, clinical strategies using drugs targeting tumor cell metabolism present a viable therapeutic modality against EWS.
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Affiliation(s)
- Atreyi Dasgupta
- The Faris D. Virani Ewing Sarcoma Center at The Texas Children's Cancer and Hematology Centers, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Matteo Trucco
- Sylvester Comprehensive Cancer Center, Department of Pediatrics, Hematology-Oncology, University of Miami-Miller School of Medicine, Miami, FL 33136, USA
| | - Nino Rainusso
- The Faris D. Virani Ewing Sarcoma Center at The Texas Children's Cancer and Hematology Centers, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Ronald J Bernardi
- The Faris D. Virani Ewing Sarcoma Center at The Texas Children's Cancer and Hematology Centers, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Ryan Shuck
- The Faris D. Virani Ewing Sarcoma Center at The Texas Children's Cancer and Hematology Centers, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Lyazat Kurenbekova
- The Faris D. Virani Ewing Sarcoma Center at The Texas Children's Cancer and Hematology Centers, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - David M Loeb
- Sydney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, MD 21231, USA
| | - Jason T Yustein
- The Faris D. Virani Ewing Sarcoma Center at The Texas Children's Cancer and Hematology Centers, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.,Integrative Molecular and Biological Sciences Program, Baylor College of Medicine, Houston, TX 77030, USA.,Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
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Siddappa G, Kulsum S, Ravindra DR, Kumar VV, Raju N, Raghavan N, Sudheendra HV, Sharma A, Sunny SP, Jacob T, Kuruvilla BT, Benny M, Antony B, Seshadri M, Lakshminarayan P, Hicks W, Suresh A, Kuriakose MA. Curcumin and metformin-mediated chemoprevention of oral cancer is associated with inhibition of cancer stem cells. Mol Carcinog 2017; 56:2446-2460. [DOI: 10.1002/mc.22692] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Revised: 05/23/2017] [Accepted: 06/13/2017] [Indexed: 01/21/2023]
Affiliation(s)
- Gangotri Siddappa
- Integrated Head and Neck Oncology Research Program, DSRG-5; Mazumdar Shaw Centre for Translational Research; Mazumdar Shaw Medical Centre; Narayana Health; Bangalore Karnataka India
- Head and Neck Oncology; Mazumdar Shaw Medical Centre; Narayana Health; Bangalore Karnataka India
| | - Safeena Kulsum
- Integrated Head and Neck Oncology Research Program, DSRG-5; Mazumdar Shaw Centre for Translational Research; Mazumdar Shaw Medical Centre; Narayana Health; Bangalore Karnataka India
- School of Biosciences and Technology; VIT University; Vellore Tamil Nadu India
| | - Doddathimmasandra Ramanjanappa Ravindra
- Integrated Head and Neck Oncology Research Program, DSRG-5; Mazumdar Shaw Centre for Translational Research; Mazumdar Shaw Medical Centre; Narayana Health; Bangalore Karnataka India
| | - Vinay V. Kumar
- Department of Oral Surgery; Dr. BR Ambedkar Medical College; Bangalore Karnataka India
| | - Nalini Raju
- Department of Histopathology; Mazumdar Shaw Medical Centre; Narayana Health; Bangalore Karnataka India
| | - Nisheena Raghavan
- Department of Histopathology; Mazumdar Shaw Medical Centre; Narayana Health; Bangalore Karnataka India
| | - Holalugunda Vittalamurthy Sudheendra
- Integrated Head and Neck Oncology Research Program, DSRG-5; Mazumdar Shaw Centre for Translational Research; Mazumdar Shaw Medical Centre; Narayana Health; Bangalore Karnataka India
| | - Anupam Sharma
- Stem Cell Research Laboratory; GROW Laboratory; Narayana Nethralaya; Narayana Health; Bangalore Karnataka India
| | - Sumsum P. Sunny
- Integrated Head and Neck Oncology Research Program, DSRG-5; Mazumdar Shaw Centre for Translational Research; Mazumdar Shaw Medical Centre; Narayana Health; Bangalore Karnataka India
- Head and Neck Oncology; Mazumdar Shaw Medical Centre; Narayana Health; Bangalore Karnataka India
| | - Tina Jacob
- Department of Oral Pathology and Microbiology; Bangalore Institute of Dental Sciences; Bangalore Karnataka India
| | | | - Merina Benny
- Arjuna Natural Extracts Ltd.; Alwaye, Kochi Kerala India
| | - Benny Antony
- Arjuna Natural Extracts Ltd.; Alwaye, Kochi Kerala India
| | - Mukund Seshadri
- Department of Pharmacology and Therapeutics; Roswell Park Cancer Institute; Buffalo New York
- Mazumdar Shaw Medical Centre-Roswell Park Collaboration Program; Roswell Park Cancer Institute; Buffalo New York
| | - Padma Lakshminarayan
- Department of Pharmacology; Dr. BR Ambedkar Medical College; Bangalore Karnataka India
| | - Wesley Hicks
- Mazumdar Shaw Medical Centre-Roswell Park Collaboration Program; Roswell Park Cancer Institute; Buffalo New York
- Department of Head and Neck/Plastic & Reconstructive Surgery; Roswell Park Cancer Institute; Buffalo New York
| | - Amritha Suresh
- Integrated Head and Neck Oncology Research Program, DSRG-5; Mazumdar Shaw Centre for Translational Research; Mazumdar Shaw Medical Centre; Narayana Health; Bangalore Karnataka India
- Mazumdar Shaw Medical Centre-Roswell Park Collaboration Program; Roswell Park Cancer Institute; Buffalo New York
| | - Moni A. Kuriakose
- Integrated Head and Neck Oncology Research Program, DSRG-5; Mazumdar Shaw Centre for Translational Research; Mazumdar Shaw Medical Centre; Narayana Health; Bangalore Karnataka India
- Head and Neck Oncology; Mazumdar Shaw Medical Centre; Narayana Health; Bangalore Karnataka India
- Mazumdar Shaw Medical Centre-Roswell Park Collaboration Program; Roswell Park Cancer Institute; Buffalo New York
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Peled Y, Lavee J, Raichlin E, Katz M, Arad M, Kassif Y, Peled A, Asher E, Elian D, Har-Zahav Y, Shlomo N, Freimark D, Goldenberg I, Klempfner R. Metformin therapy reduces the risk of malignancy after heart transplantation. J Heart Lung Transplant 2017; 36:1350-1357. [PMID: 28736111 DOI: 10.1016/j.healun.2017.06.009] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Revised: 06/11/2017] [Accepted: 06/21/2017] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Malignancy and diabetes mellitus (DM) cause significant morbidity and mortality after heart transplantation (HTx). Metformin, one of the most commonly used anti-diabetic drugs worldwide, has also been shown to exhibit anti-tumor activity. We therefore investigated the association between metformin therapy and malignancy after HTx. METHODS The study population comprised 237 patients who underwent HTx between 1991 and 2016 and were prospectively followed-up. Clinical data were recorded on prospectively designed forms. The primary outcome was any cancer recorded during 15 years of follow-up. Treatment with metformin and the development of DM after HTx were assessed as time-dependent factors in the analyses. RESULTS Of the 237 study patients, 85 (36%) had diabetes. Of the DM patients, 48 (56%) were treated with metformin. Kaplan-Meier survival analysis showed that, at 15 years after HTx, malignancy rate was 4% for DM patients treated with metformin, 62% for those who did not receive metformin and 27% for non-DM patients (log-rank test, p < 0.0001). Consistently, multivariate analysis showed that for DM patients, metformin therapy was independently associated with a significant 90% reduction (hazard ratio = 0.10; 95% confidence interval 0.02 to 0.40; p = 0.001) in the risk of the development of a malignancy. DM patients who were treated with metformin had a markedly lower risk (65%; p = 0.001) for the development of a malignancy or death after HTx as compared with non-DM patients. CONCLUSIONS Our findings suggest that metformin therapy is independently associated with a significant reduction in the risk of malignancy after HTx.
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Affiliation(s)
- Yael Peled
- The Olga and Lev Leviev Heart Center, Sheba Medical Center, Ramat Gan, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
| | - Jacob Lavee
- The Olga and Lev Leviev Heart Center, Sheba Medical Center, Ramat Gan, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Eugenia Raichlin
- Cardiology Department, Loyola University Medical Center, Maywood, Illinois, USA
| | - Moshe Katz
- The Olga and Lev Leviev Heart Center, Sheba Medical Center, Ramat Gan, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Michael Arad
- The Olga and Lev Leviev Heart Center, Sheba Medical Center, Ramat Gan, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Yigal Kassif
- The Olga and Lev Leviev Heart Center, Sheba Medical Center, Ramat Gan, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Amir Peled
- Clalit Health Services, Central Region, Israel
| | - Elad Asher
- The Olga and Lev Leviev Heart Center, Sheba Medical Center, Ramat Gan, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Dan Elian
- The Olga and Lev Leviev Heart Center, Sheba Medical Center, Ramat Gan, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Yedael Har-Zahav
- The Olga and Lev Leviev Heart Center, Sheba Medical Center, Ramat Gan, Israel
| | - Nir Shlomo
- Israeli Association for Cardiovascular Trials, The Olga and Lev Leviev Heart Center, Sheba Medical Center, Ramat Gan, Israel
| | - Dov Freimark
- The Olga and Lev Leviev Heart Center, Sheba Medical Center, Ramat Gan, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ilan Goldenberg
- The Olga and Lev Leviev Heart Center, Sheba Medical Center, Ramat Gan, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; Israeli Association for Cardiovascular Trials, The Olga and Lev Leviev Heart Center, Sheba Medical Center, Ramat Gan, Israel
| | - Robert Klempfner
- The Olga and Lev Leviev Heart Center, Sheba Medical Center, Ramat Gan, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
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44
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Zhu RC, Rattanakorn K, Pham S, Mallam D, McIntyre T, Salifu MO, Youssef I, McFarlane SI, Vignesh S. Survival benefits in colorectal adenocarcinoma with the use of metformin among a black diabetic inner city population. COLORECTAL CANCER 2017; 6:33-41. [PMID: 29308089 DOI: 10.2217/crc-2017-0001] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
We assessed the association of metformin use with survival in colorectal cancer in a population consists mostly of African-American and Afro-Caribbean patients. We identified 585 colorectal cancer patients, 167 (28.6%) and 418 (71.5%) were as diabetic (DM) and nondiabetic, respectively. The diagnosis of diabetes did not impact cancer survival or extent of disease. Overall, DMs with metformin use (D+M+) have better overall survival than both DMs without metformin use (D+M∼) and nondiabetics (D∼M∼), with a mean survival of 109.9 months compared with 95.7 and 106.1 months, respectively (log-rank p < 0.05). The use of metformin shows significant reduction of risk of mortality compared with nonusers (hazard ratio: 0.34; 95% CI: 0.15-0.81; p = 0.01). Use of insulin and status of diabetes did not have a significant impact on overall cancer survival.
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Affiliation(s)
- Roger C Zhu
- Department of Medicine, Divisions of Gastroenterology & Endocrinology, State University of New York, Downstate Medical Center & Kings County Hospital, Brooklyn, NY 11203, USA
| | - Kirk Rattanakorn
- Department of Medicine, Divisions of Gastroenterology & Endocrinology, State University of New York, Downstate Medical Center & Kings County Hospital, Brooklyn, NY 11203, USA
| | - Steven Pham
- Department of Medicine, Divisions of Gastroenterology & Endocrinology, State University of New York, Downstate Medical Center & Kings County Hospital, Brooklyn, NY 11203, USA
| | - Divya Mallam
- Department of Medicine, Divisions of Gastroenterology & Endocrinology, State University of New York, Downstate Medical Center & Kings County Hospital, Brooklyn, NY 11203, USA
| | - Thomas McIntyre
- Department of Medicine, Divisions of Gastroenterology & Endocrinology, State University of New York, Downstate Medical Center & Kings County Hospital, Brooklyn, NY 11203, USA
| | - Moro O Salifu
- Department of Medicine, Divisions of Gastroenterology & Endocrinology, State University of New York, Downstate Medical Center & Kings County Hospital, Brooklyn, NY 11203, USA
| | - Irini Youssef
- Department of Medicine, Divisions of Gastroenterology & Endocrinology, State University of New York, Downstate Medical Center & Kings County Hospital, Brooklyn, NY 11203, USA
| | - Samy I McFarlane
- Department of Medicine, Divisions of Gastroenterology & Endocrinology, State University of New York, Downstate Medical Center & Kings County Hospital, Brooklyn, NY 11203, USA
| | - Shivakumar Vignesh
- Department of Medicine, Divisions of Gastroenterology & Endocrinology, State University of New York, Downstate Medical Center & Kings County Hospital, Brooklyn, NY 11203, USA
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45
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El-Ashmawy NE, Khedr NF, El-Bahrawy HA, Abo Mansour HE. Metformin augments doxorubicin cytotoxicity in mammary carcinoma through activation of adenosine monophosphate protein kinase pathway. Tumour Biol 2017; 39:1010428317692235. [PMID: 28459206 DOI: 10.1177/1010428317692235] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Since the incidence of breast cancer increases dramatically all over the world, the search for effective treatment is an urgent need. Metformin has demonstrated anti-tumorigenic effect both in vivo and in vitro in different cancer types. This work was designed to examine on molecular level the mode of action of metformin in mice bearing solid Ehrlich carcinoma and to evaluate the use of metformin in conjunction with doxorubicin as a combined therapy against solid Ehrlich carcinoma. Ehrlich ascites carcinoma cells were inoculated in 60 female mice as a model of breast cancer. The mice were divided into four equal groups: Control tumor, metformin, doxorubicin, and co-treatment. Metformin (15 mg/kg) and doxorubicin (4 mg/kg) were given intraperitoneally (i.p.) for four cycles every 5 days starting on day 12 of inoculation. The anti-tumorigenic effect of metformin was mediated by enhancement of adenosine monophosphate protein kinase activity and elevation of P53 protein as well as the suppression of nuclear factor-kappa B, DNA contents, and cyclin D1 gene expression. Metformin and doxorubicin mono-treatments exhibited opposing action regarding cyclin D1 gene expression, phosphorylated adenosine monophosphate protein kinase, and nuclear factor-kappa B levels. Co-treatment markedly decreased tumor volume, increased survival rate, and improved other parameters compared to doxorubicin group. In parallel, the histopathological findings demonstrated enhanced apoptosis and absence of necrosis in tumor tissue of co-treatment group. Metformin proved chemotherapeutic effect which could be mediated by the activation of adenosine monophosphate protein kinase and related pathways. Combining metformin and doxorubicin, which exhibited different mechanisms of action, produced greater efficacy as anticancer therapeutic regimen.
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Affiliation(s)
- Nahla E El-Ashmawy
- Department of Biochemistry, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Naglaa F Khedr
- Department of Biochemistry, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Hoda A El-Bahrawy
- Department of Biochemistry, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Hend E Abo Mansour
- Department of Biochemistry, Faculty of Pharmacy, Tanta University, Tanta, Egypt
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46
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Grasso C, Jansen G, Giovannetti E. Drug resistance in pancreatic cancer: Impact of altered energy metabolism. Crit Rev Oncol Hematol 2017; 114:139-152. [PMID: 28477742 DOI: 10.1016/j.critrevonc.2017.03.026] [Citation(s) in RCA: 179] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Accepted: 03/21/2017] [Indexed: 02/07/2023] Open
Abstract
Pancreatic cancer is a highly deadly disease: almost all patients develop metastases and conventional treatments have little impact on survival. Therapeutically, this tumor is poorly responsive, largely due to drug resistance. Accumulating evidence suggest that this chemoresistance is intimately linked to specific metabolic aberrations of pancreatic cancer cells, notably an increased use of glucose and the amino acid glutamine fueling anabolic processes. Altered metabolism contributes also to modulation of apoptosis, angiogenesis and drug targets, conferring a resistant phenotype. As a modality to overcome chemoresistance, a variety of experimental compounds inhibiting key metabolic pathways emerged as a promising approach to potentiate the standard treatments for pancreatic cancer in preclinical studies. These results warrant confirmation in clinical trials. Thus, this review summarizes the impact of metabolic aberrations from the perspective of drug resistance and discusses possible novel applications of metabolic inhibition for the development of more effective drugs against pancreatic cancer.
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Affiliation(s)
- Cristoforo Grasso
- Laboratory Medical Oncology, Department of Medical Oncology VU University Medical Center (VUmc), Amsterdam, The Netherlands
| | - Gerrit Jansen
- Department of Rheumatology, Amsterdam Rheumatology and Immunology Center, VUmc, Amsterdam, The Netherlands
| | - Elisa Giovannetti
- Laboratory Medical Oncology, Department of Medical Oncology VU University Medical Center (VUmc), Amsterdam, The Netherlands; Cancer Pharmacology Lab, AIRC Start-Up Unit, University of Pisa, Pisa, Italy.
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47
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Athreya AP, Kalari KR, Cairns J, Gaglio AJ, Wills QF, Niu N, Weinshilboum R, Iyer RK, Wang L. Model-based unsupervised learning informs metformin-induced cell-migration inhibition through an AMPK-independent mechanism in breast cancer. Oncotarget 2017; 8:27199-27215. [PMID: 28423712 PMCID: PMC5432329 DOI: 10.18632/oncotarget.16109] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Accepted: 02/18/2017] [Indexed: 11/25/2022] Open
Abstract
We demonstrate that model-based unsupervised learning can uniquely discriminate single-cell subpopulations by their gene expression distributions, which in turn allow us to identify specific genes for focused functional studies. This method was applied to MDA-MB-231 breast cancer cells treated with the antidiabetic drug metformin, which is being repurposed for treatment of triple-negative breast cancer. Unsupervised learning identified a cluster of metformin-treated cells characterized by a significant suppression of 230 genes (p-value < 2E-16). This analysis corroborates known studies of metformin action: a) pathway analysis indicated known mechanisms related to metformin action, including the citric acid (TCA) cycle, oxidative phosphorylation, and mitochondrial dysfunction (p-value < 1E-9); b) 70% of these 230 genes were functionally implicated in metformin response; c) among remaining lesser functionally-studied genes for metformin-response was CDC42, down-regulated in breast cancer treated with metformin. However, CDC42's mechanisms in metformin response remained unclear. Our functional studies showed that CDC42 was involved in metformin-induced inhibition of cell proliferation and cell migration mediated through an AMPK-independent mechanism. Our results points to 230 genes that might serve as metformin response signatures, which needs to be tested in patients treated with metformin and, further investigation of CDC42 and AMPK-independence's role in metformin's anticancer mechanisms.
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Affiliation(s)
- Arjun P. Athreya
- Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign, Champaign, IL, USA
| | - Krishna R. Kalari
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Junmei Cairns
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
| | - Alan J. Gaglio
- Department of Mechanical Science and Engineering, University of Illinois at Urbana-Champaign, Champaign, IL, USA
| | - Quin F. Wills
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
- Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
| | - Nifang Niu
- Department of Pathology, University of Chicago, Chicago, IL, USA
| | - Richard Weinshilboum
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
| | - Ravishankar K. Iyer
- Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign, Champaign, IL, USA
| | - Liewei Wang
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
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48
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Metformin inhibits gastric cancer cells metastatic traits through suppression of epithelial-mesenchymal transition in a glucose-independent manner. PLoS One 2017; 12:e0174486. [PMID: 28334027 PMCID: PMC5363973 DOI: 10.1371/journal.pone.0174486] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 03/09/2017] [Indexed: 02/08/2023] Open
Abstract
Epithelial-mesenchymal transition (EMT), which is mainly recognized by upregulation of mesenchymal markers and movement of cells, is a critical stage occurred during embryo development and spreading cancerous cells. Metformin is an antidiabetic drug used in treatment of type 2 diabetes. EMT inhibitory effect of metformin has been studied in several cancers; however, it remains unknown in gastric cancer. The aim of the present study was to investigate the metformin effects on inhibition of EMT-related genes as well as migration and invasion of AGS gastric cancer cell line. Moreover, to study the effect of glucose on metformin-mediated EMT inhibition, all experiments were performed in two glucose levels, similar to non-fasting blood sugar (7.8 mM) and hyperglycemic (17.5 mM) conditions. The results showed reduction of mesenchymal markers, including vimentin and β-catenin, and induction of epithelial marker, E-cadherin, by metformin in both glucose concentrations. Furthermore, wound-healing and invasion assays showed a significant decrease in cell migration and invasion after metformin treatment in both glucose levels. In conclusion, our results indicated that metformin strongly inhibited EMT of gastric cancer cells in conditions mimicking normo and hyperglycemic blood sugar.
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49
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Leonel C, Borin TF, de Carvalho Ferreira L, Moschetta MG, Bajgelman MC, Viloria-Petit AM, de Campos Zuccari DAP. Inhibition of Epithelial-Mesenchymal Transition and Metastasis by Combined TGFbeta Knockdown and Metformin Treatment in a Canine Mammary Cancer Xenograft Model. J Mammary Gland Biol Neoplasia 2017; 22:27-41. [PMID: 28078601 DOI: 10.1007/s10911-016-9370-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Accepted: 12/19/2016] [Indexed: 12/18/2022] Open
Abstract
Epithelial mesenchymal transition (EMT) is a process by which epithelial cells acquire mesenchymal properties, generating metastases. Transforming growth factor beta (TGF-β) is associated with this malignancy by having the ability to induce EMT. Metformin, has been shown to inhibit EMT in breast cancer cells. Based on this evidence we hypothesize that treatment with metformin and the silencing of TGF-β, inhibits the EMT in cancer cells. Canine metastatic mammary tumor cell line CF41 was stably transduced with a shRNA-lentivirus, reducing expression level of TGF-β1. This was combined with metformin treatment, to look at effects on cell migration and the expression of EMT markers. For in vivo study, unmodified or TGF-β1sh cells were injected in the inguinal region of nude athymic female mice followed by metformin treatment. The mice's lungs were collected and metastatic nodules were subsequently assessed for EMT markers expression. The migration rate was lower in TGF-β1sh cells and when combined with metformin treatment. Metformin treatment reduced N-cadherin and increased E-cadherin expression in both CF41 and TGF-β1sh cells. Was demonstrated that metformin treatment reduced the number of lung metastases in animals bearing TGF-β1sh tumors. This paralleled a decreased N-cadherin and vimentin expression, and increased E-cadherin and claudin-7 expression in lung metastases. This study confirms the benefits of TGF-β1 silencing in addition to metformin as potential therapeutic agents for breast cancer patients, by blocking EMT process. To the best of our knowledge, we are the first to report metformin treatment in cells with TGF-β1 silencing and their effect on EMT.
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Affiliation(s)
- Camila Leonel
- Universidade Estadual Paulista "Julio de Mesquita Filho" (UNESP/IBILCE), PostGraduate Program in Genetics, Cristovao Colombo Street, 2265, Jardim Nazareth, Sao Jose do Rio Preto, SP, Brazil
- Faculdade de Medicina de Sao Jose do Rio Preto (FAMERP), Laboratory of Molecular Investigation of Cancer (LIMC), Brigadeiro Faria Lima Avenue, 5416, Vila São Pedro, Sao Jose do Rio Preto, SP, Brazil
| | - Thaiz Ferraz Borin
- Faculdade de Medicina de Sao Jose do Rio Preto (FAMERP), Laboratory of Molecular Investigation of Cancer (LIMC), Brigadeiro Faria Lima Avenue, 5416, Vila São Pedro, Sao Jose do Rio Preto, SP, Brazil
- Faculdade de Medicina de Sao Jose do Rio Preto (FAMERP), PostGraduate Program in Health Sciences, Brigadeiro Faria Lima Avenue, 5416, Vila São Pedro, Sao Jose do Rio Preto, SP, Brazil
| | - Lívia de Carvalho Ferreira
- Universidade Estadual Paulista "Julio de Mesquita Filho" (UNESP/IBILCE), PostGraduate Program in Genetics, Cristovao Colombo Street, 2265, Jardim Nazareth, Sao Jose do Rio Preto, SP, Brazil
- Faculdade de Medicina de Sao Jose do Rio Preto (FAMERP), Laboratory of Molecular Investigation of Cancer (LIMC), Brigadeiro Faria Lima Avenue, 5416, Vila São Pedro, Sao Jose do Rio Preto, SP, Brazil
| | - Marina Gobbe Moschetta
- Faculdade de Medicina de Sao Jose do Rio Preto (FAMERP), Laboratory of Molecular Investigation of Cancer (LIMC), Brigadeiro Faria Lima Avenue, 5416, Vila São Pedro, Sao Jose do Rio Preto, SP, Brazil
- Faculdade de Medicina de Sao Jose do Rio Preto (FAMERP), PostGraduate Program in Health Sciences, Brigadeiro Faria Lima Avenue, 5416, Vila São Pedro, Sao Jose do Rio Preto, SP, Brazil
| | - Marcio Chaim Bajgelman
- National Center for Research in Energy and Materials - CNPEM, Brazilian Biosciences National Laboratory - LNBio, Giuseppe Máximo Scolfaro Street, Campinas, SP, 10000, Brazil
| | - Alicia M Viloria-Petit
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, 50 Stone Rd E, Guelph, ON, N1G 2W1, Canada
| | - Debora Aparecida Pires de Campos Zuccari
- Universidade Estadual Paulista "Julio de Mesquita Filho" (UNESP/IBILCE), PostGraduate Program in Genetics, Cristovao Colombo Street, 2265, Jardim Nazareth, Sao Jose do Rio Preto, SP, Brazil.
- Faculdade de Medicina de Sao Jose do Rio Preto (FAMERP), Laboratory of Molecular Investigation of Cancer (LIMC), Brigadeiro Faria Lima Avenue, 5416, Vila São Pedro, Sao Jose do Rio Preto, SP, Brazil.
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50
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He M, Sui J, Chen Y, Bian S, Cui Y, Zhou C, Sun Y, Liang J, Fan Y, Zhang X. Localized multidrug co-delivery by injectable self-crosslinking hydrogel for synergistic combinational chemotherapy. J Mater Chem B 2017; 5:4852-4862. [DOI: 10.1039/c7tb01026e] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
The multidrug co-loaded injectable hydrogels against tumor showed superiority and potential application values.
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Affiliation(s)
- Mengmeng He
- National Engineering Research Center for Biomaterials
- Sichuan University
- Chengdu 610064
- China
| | - Junhui Sui
- National Engineering Research Center for Biomaterials
- Sichuan University
- Chengdu 610064
- China
| | - Yafang Chen
- National Engineering Research Center for Biomaterials
- Sichuan University
- Chengdu 610064
- China
| | - Shaoquan Bian
- National Engineering Research Center for Biomaterials
- Sichuan University
- Chengdu 610064
- China
| | - Yani Cui
- National Engineering Research Center for Biomaterials
- Sichuan University
- Chengdu 610064
- China
| | - Changchun Zhou
- National Engineering Research Center for Biomaterials
- Sichuan University
- Chengdu 610064
- China
| | - Yong Sun
- National Engineering Research Center for Biomaterials
- Sichuan University
- Chengdu 610064
- China
| | - Jie Liang
- National Engineering Research Center for Biomaterials
- Sichuan University
- Chengdu 610064
- China
| | - Yujiang Fan
- National Engineering Research Center for Biomaterials
- Sichuan University
- Chengdu 610064
- China
| | - Xingdong Zhang
- National Engineering Research Center for Biomaterials
- Sichuan University
- Chengdu 610064
- China
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