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Yao W, Wang Y, Zhang X, Lin Y. B3GNT5 is a novel marker correlated with malignant phenotype and poor outcome in pancreatic cancer. iScience 2024; 27:110889. [PMID: 39319269 PMCID: PMC11421285 DOI: 10.1016/j.isci.2024.110889] [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: 10/19/2023] [Revised: 06/23/2024] [Accepted: 09/03/2024] [Indexed: 09/26/2024] Open
Abstract
Pancreatic cancer (PC) is one of the most lethal malignancies and new therapeutic strategies are urgently needed. β1,3-N-acetylglucosaminyltransferase V (B3GNT5) may be a potential option for cancer treatment, but its role in PC remains unknown. In this study, we first demonstrated through bioinformatics analysis that B3GNT5 was high expression in PC and predicted poor prognosis. We further constructed B3GNT5 overexpression or knockdown cell lines by employing lentivirus packaging techniques and confirmed that B3GNT5 could promote tumor cell viability and autonomous growth using cultured cells and vivo xenograft models. In addition, we found that knockdown of B3GNT5 in PC cells inhibited cell migration, invasion, and angiogenesis, as well as stemness of cancer stem cells and enhanced chemotherapy sensitivity to gemcitabine. Mechanistically, overexpression of the transcription factor STAT5B in PC cells enhanced the transcriptional activity of the B3GNT5 promoter. Our work confirmed a tumor-promotive role of B3GNT5 in PC pathogenesis.
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Affiliation(s)
- Wei Yao
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, P.R. China
| | - Yihui Wang
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, P.R. China
| | - Xin Zhang
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, P.R. China
| | - Yuhe Lin
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, P.R. China
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2
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Wu H, Fu M, Wu M, Cao Z, Zhang Q, Liu Z. Emerging mechanisms and promising approaches in pancreatic cancer metabolism. Cell Death Dis 2024; 15:553. [PMID: 39090116 PMCID: PMC11294586 DOI: 10.1038/s41419-024-06930-0] [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: 04/18/2024] [Revised: 07/17/2024] [Accepted: 07/22/2024] [Indexed: 08/04/2024]
Abstract
Pancreatic cancer is an aggressive cancer with a poor prognosis. Metabolic abnormalities are one of the hallmarks of pancreatic cancer, and pancreatic cancer cells can adapt to biosynthesis, energy intake, and redox needs through metabolic reprogramming to tolerate nutrient deficiency and hypoxic microenvironments. Pancreatic cancer cells can use glucose, amino acids, and lipids as energy to maintain malignant growth. Moreover, they also metabolically interact with cells in the tumour microenvironment to change cell fate, promote tumour progression, and even affect immune responses. Importantly, metabolic changes at the body level deserve more attention. Basic research and clinical trials based on targeted metabolic therapy or in combination with other treatments are in full swing. A more comprehensive and in-depth understanding of the metabolic regulation of pancreatic cancer cells will not only enrich the understanding of the mechanisms of disease progression but also provide inspiration for new diagnostic and therapeutic approaches.
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Affiliation(s)
- Hao Wu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Mengdi Fu
- Department of Clinical Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Mengwei Wu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Zhen Cao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Qiyao Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Ziwen Liu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
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3
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Dixon S, O'connor AT, Brooks-Noreiga C, Clark MA, Levy A, Castejon AM. Role of renin angiotensin system inhibitors and metformin in Glioblastoma Therapy: a review. Cancer Chemother Pharmacol 2024; 94:1-23. [PMID: 38914751 DOI: 10.1007/s00280-024-04686-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 06/13/2024] [Indexed: 06/26/2024]
Abstract
Glioblastoma multiforme (GBM) is a highly aggressive and incurable disease accounting for about 10,000 deaths in the USA each year. Despite the current treatment approach which includes surgery with chemotherapy and radiation therapy, there remains a high prevalence of recurrence. Notable improvements have been observed in persons receiving concurrent antihypertensive drugs such as renin angiotensin inhibitors (RAS) or the antidiabetic drug metformin with standard therapy. Anti-tumoral effects of RAS inhibitors and metformin have been observed in in vitro and in vivo studies. Although clinical trials have shown mixed results, the potential for the use of RAS inhibitors and metformin as adjuvant GBM therapy remains promising. Nevertheless, evidence suggest that these drugs exert multimodal antitumor actions; by particularly targeting several cancer hallmarks. In this review, we highlight the results of clinical studies using multidrug cocktails containing RAS inhibitors and or metformin added to standard therapy for GBM. In addition, we highlight the possible molecular mechanisms by which these repurposed drugs with an excellent safety profile might elicit their anti-tumoral effects. RAS inhibition elicits anti-inflammatory, anti-angiogenic, and immune sensitivity effects in GBM. However, metformin promotes anti-migratory, anti-proliferative and pro-apoptotic effects mainly through the activation of AMP-activated protein kinase. Also, we discussed metformin's potential in targeting both GBM cells as well as GBM associated-stem cells. Finally, we summarize a few drug interactions that may cause an additive or antagonistic effect that may lead to adverse effects and influence treatment outcome.
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Affiliation(s)
- Sashana Dixon
- Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, Ft. Lauderdale, FL, USA.
| | - Ann Tenneil O'connor
- Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, Ft. Lauderdale, FL, USA
| | - Chloe Brooks-Noreiga
- Halmos College of Arts and Sciences, Nova Southeastern University, Ft. Lauderdale, FL, USA
| | - Michelle A Clark
- Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, Ft. Lauderdale, FL, USA
| | - Arkene Levy
- Dr. Kiran C. Patel College of Allopathic Medicine, Nova Southeastern University, Ft. Lauderdale, FL, USA
| | - Ana M Castejon
- Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, Ft. Lauderdale, FL, USA
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Tavares-Valente D, Cannone S, Greco MR, Carvalho TMA, Baltazar F, Queirós O, Agrimi G, Reshkin SJ, Cardone RA. Extracellular Matrix Collagen I Differentially Regulates the Metabolic Plasticity of Pancreatic Ductal Adenocarcinoma Parenchymal Cell and Cancer Stem Cell. Cancers (Basel) 2023; 15:3868. [PMID: 37568684 PMCID: PMC10417137 DOI: 10.3390/cancers15153868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 07/22/2023] [Accepted: 07/24/2023] [Indexed: 08/13/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of less than 10 percent largely due to the intense fibrotic desmoplastic reaction, characterized by high levels of extracellular matrix (ECM) collagen I that constitutes a niche for a subset of cancer cells, the cancer stem cells (CSCs). Cancer cells undergo a complex metabolic adaptation characterized by changes in metabolic pathways and biosynthetic processes. The use of the 3D organotypic model in this study allowed us to manipulate the ECM constituents and mimic the progression of PDAC from an early tumor to an ever more advanced tumor stage. To understand the role of desmoplasia on the metabolism of PDAC parenchymal (CPC) and CSC populations, we studied their basic metabolic parameters in organotypic cultures of increasing collagen content to mimic in vivo conditions. We further measured the ability of the bioenergetic modulators (BMs), 2-deoxyglucose, dichloroacetate and phenformin, to modify their metabolic dependence and the therapeutic activity of paclitaxel albumin nanoparticles (NAB-PTX). While all the BMs decreased cell viability and increased cell death in all ECM types, a distinct, collagen I-dependent profile was observed in CSCs. As ECM collagen I content increased (e.g., more aggressive conditions), the CSCs switched from glucose to mostly glutamine metabolism. All three BMs synergistically potentiated the cytotoxicity of NAB-PTX in both cell lines, which, in CSCs, was collagen I-dependent and the strongest when treated with phenformin + NAB-PTX. Metabolic disruption in PDAC can be useful both as monotherapy or combined with conventional drugs to more efficiently block tumor growth.
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Affiliation(s)
- Diana Tavares-Valente
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal;
- ICVS/3B’s—PT Government Associate Laboratory, 4805-017 Braga, Portugal
- UNIPRO—Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences, CESPU, CRL, 4585-116 Gandra, Portugal;
| | - Stefania Cannone
- Department of Biosciences, Biotechnology and Environment, University of Bari, 70125 Bari, Italy; (S.C.); (M.R.G.); (T.M.A.C.); (G.A.); (R.A.C.)
| | - Maria Raffaella Greco
- Department of Biosciences, Biotechnology and Environment, University of Bari, 70125 Bari, Italy; (S.C.); (M.R.G.); (T.M.A.C.); (G.A.); (R.A.C.)
| | - Tiago Miguel Amaral Carvalho
- Department of Biosciences, Biotechnology and Environment, University of Bari, 70125 Bari, Italy; (S.C.); (M.R.G.); (T.M.A.C.); (G.A.); (R.A.C.)
| | - Fátima Baltazar
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal;
- ICVS/3B’s—PT Government Associate Laboratory, 4805-017 Braga, Portugal
| | - Odília Queirós
- UNIPRO—Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences, CESPU, CRL, 4585-116 Gandra, Portugal;
| | - Gennaro Agrimi
- Department of Biosciences, Biotechnology and Environment, University of Bari, 70125 Bari, Italy; (S.C.); (M.R.G.); (T.M.A.C.); (G.A.); (R.A.C.)
| | - Stephan J. Reshkin
- Department of Biosciences, Biotechnology and Environment, University of Bari, 70125 Bari, Italy; (S.C.); (M.R.G.); (T.M.A.C.); (G.A.); (R.A.C.)
| | - Rosa Angela Cardone
- Department of Biosciences, Biotechnology and Environment, University of Bari, 70125 Bari, Italy; (S.C.); (M.R.G.); (T.M.A.C.); (G.A.); (R.A.C.)
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Pospieszna J, Dams-Kozlowska H, Udomsak W, Murias M, Kucinska M. Unmasking the Deceptive Nature of Cancer Stem Cells: The Role of CD133 in Revealing Their Secrets. Int J Mol Sci 2023; 24:10910. [PMID: 37446085 DOI: 10.3390/ijms241310910] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 06/27/2023] [Accepted: 06/28/2023] [Indexed: 07/15/2023] Open
Abstract
Cancer remains a leading cause of death globally, and its complexity poses a significant challenge to effective treatment. Cancer stem cells and their markers have become key players in tumor growth and progression. CD133, a marker in various cancer types, is an active research area as a potential therapeutic target. This article explores the role of CD133 in cancer treatment, beginning with an overview of cancer statistics and an explanation of cancer stem cells and their markers. The rise of CD133 is discussed, including its structure, functions, and occurrence in different cancer types. Furthermore, the article covers CD133 as a therapeutic target, focusing on gene therapy, immunotherapy, and approaches to affect CD133 expression. Nanoparticles such as gold nanoparticles and nanoliposomes are also discussed in the context of CD133-targeted therapy. In conclusion, CD133 is a promising therapeutic target for cancer treatment. As research in this area progresses, it is hoped that CD133-targeted therapies will offer new and effective treatment options for cancer patients in the future.
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Affiliation(s)
- Julia Pospieszna
- Department of Toxicology, Poznan University of Medical Sciences, 30 Dojazd Street, 10 Uniwersytetu Poznanskiego Street, 60-631 Poznan, Poland
| | - Hanna Dams-Kozlowska
- Department of Cancer Immunology, Poznan University of Medical Sciences, 15 Garbary Street, 61-866 Poznan, Poland
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 15 Garbary Street, 61-866 Poznan, Poland
| | - Wachirawit Udomsak
- Department of Toxicology, Poznan University of Medical Sciences, 30 Dojazd Street, 10 Uniwersytetu Poznanskiego Street, 60-631 Poznan, Poland
| | - Marek Murias
- Department of Toxicology, Poznan University of Medical Sciences, 30 Dojazd Street, 10 Uniwersytetu Poznanskiego Street, 60-631 Poznan, Poland
- Center for Advanced Technology, Adam Mickiewicz University in Poznan, Uniwersytetu Poznanskiego 10 Street, 61-614 Poznan, Poland
| | - Malgorzata Kucinska
- Department of Toxicology, Poznan University of Medical Sciences, 30 Dojazd Street, 10 Uniwersytetu Poznanskiego Street, 60-631 Poznan, Poland
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Mahalingam D, Hanni S, Serritella AV, Fountzilas C, Michalek J, Hernandez B, Sarantopoulos J, Datta P, Romero O, Pillai SMA, Kuhn J, Pollak M, Thompson IM. Utilizing metformin to prevent metabolic syndrome due to androgen deprivation therapy (ADT): a randomized phase II study of metformin in non-diabetic men initiating ADT for advanced prostate cancer. Oncotarget 2023; 14:622-636. [PMID: 37335291 PMCID: PMC10278660 DOI: 10.18632/oncotarget.28458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 06/01/2023] [Indexed: 06/21/2023] Open
Abstract
BACKGROUND Androgen deprivation therapy (ADT) can lead to metabolic syndrome (MS) and is implicated in ADT-resistance. Metformin showed antineoplastic activity through mTOR inhibition secondary AMPK-activation. MATERIALS AND METHODS To investigate whether metformin mitigated ADT-related MS, we conducted a randomized double-blind phase II trial of metformin 500 mg TID or placebo in non-diabetic patients with biochemically-relapsed or advanced PC due for ADT. Fasting serum glucose, insulin, PSA, metformin, weight and waist circumference (WC) were measured at baseline, week 12 and 28. The primary endpoint was a group of MS metrics. Secondary endpoints include PSA response, safety, serum metformin concentrations and analysis of downstream an mTOR target, phospho-S6-kinase. RESULTS 36 men were randomized to either metformin or placebo. Mean age was 68.4. Mean weight, WC and insulin levels increased in both arms. At week 12 and 28, no statistical differences in weight, WC or insulin were observed in either arm. No significant difference in percentage of patients with PSA <0.2 at week 28 between metformin (45.5%) vs. placebo (46.7%). Analysis in the metformin-arm showed variable down-regulation of phospho-S6 kinase. CONCLUSIONS In our small study, metformin added to ADT did not show a reduced risk of ADT-related MS or differences in PSA response.
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Affiliation(s)
- Devalingam Mahalingam
- Division of Hematology and Oncology, University of Texas Health Science Center, San Antonio, TX 77030, USA
- Robert H Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL 60611, USA
| | - Salih Hanni
- Division of Hematology and Oncology, University of Texas Health Science Center, San Antonio, TX 77030, USA
| | - Anthony V. Serritella
- Robert H Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL 60611, USA
| | - Christos Fountzilas
- Division of Hematology and Oncology, University of Texas Health Science Center, San Antonio, TX 77030, USA
- Roswell Park Cancer Institute, Buffalo, NY 14263, USA
| | - Joel Michalek
- Division of Hematology and Oncology, University of Texas Health Science Center, San Antonio, TX 77030, USA
| | - Brian Hernandez
- Division of Hematology and Oncology, University of Texas Health Science Center, San Antonio, TX 77030, USA
| | - John Sarantopoulos
- Institute for Drug Development, Mays Cancer Center at University of Texas Health, San Antonio, TX 78229, USA
| | | | - Ofelia Romero
- Division of Hematology and Oncology, University of Texas Health Science Center, San Antonio, TX 77030, USA
| | | | - John Kuhn
- Division of Hematology and Oncology, University of Texas Health Science Center, San Antonio, TX 77030, USA
| | - Michael Pollak
- Division of Experimental Medicine, Lady Davis Institute of Medical Research, Jewish General Hospital, McGill University, Montreal, Canada
| | - Ian M. Thompson
- Division of Hematology and Oncology, University of Texas Health Science Center, San Antonio, TX 77030, USA
- Christus Health, San Antonio, TX 78229, USA
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7
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Dong Y, Qi Y, Jiang H, Mi T, Zhang Y, Peng C, Li W, Zhang Y, Zhou Y, Zang Y, Li J. The development and benefits of metformin in various diseases. Front Med 2023; 17:388-431. [PMID: 37402952 DOI: 10.1007/s11684-023-0998-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 04/01/2023] [Indexed: 07/06/2023]
Abstract
Metformin has been used for the treatment of type II diabetes mellitus for decades due to its safety, low cost, and outstanding hypoglycemic effect clinically. The mechanisms underlying these benefits are complex and still not fully understood. Inhibition of mitochondrial respiratory-chain complex I is the most described downstream mechanism of metformin, leading to reduced ATP production and activation of AMP-activated protein kinase (AMPK). Meanwhile, many novel targets of metformin have been gradually discovered. In recent years, multiple pre-clinical and clinical studies are committed to extend the indications of metformin in addition to diabetes. Herein, we summarized the benefits of metformin in four types of diseases, including metabolic associated diseases, cancer, aging and age-related diseases, neurological disorders. We comprehensively discussed the pharmacokinetic properties and the mechanisms of action, treatment strategies, the clinical application, the potential risk of metformin in various diseases. This review provides a brief summary of the benefits and concerns of metformin, aiming to interest scientists to consider and explore the common and specific mechanisms and guiding for the further research. Although there have been countless studies of metformin, longitudinal research in each field is still much warranted.
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Affiliation(s)
- Ying Dong
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Yingbei Qi
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China
| | - Haowen Jiang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Tian Mi
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Yunkai Zhang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Chang Peng
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Wanchen Li
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yongmei Zhang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China
| | - Yubo Zhou
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China.
| | - Yi Zang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- Lingang Laboratory, Shanghai, 201203, China.
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
| | - Jia Li
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao, 266237, China.
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
- Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, China.
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Svolacchia F, Brongo S, Catalano A, Ceccarini A, Svolacchia L, Santarsiere A, Scieuzo C, Salvia R, Finelli F, Milella L, Saturnino C, Sinicropi MS, Fabrizio T, Giuzio F. Natural Products for the Prevention, Treatment and Progression of Breast Cancer. Cancers (Basel) 2023; 15:cancers15112981. [PMID: 37296944 DOI: 10.3390/cancers15112981] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 05/23/2023] [Accepted: 05/26/2023] [Indexed: 06/12/2023] Open
Abstract
In this review, we summarize the most used natural products as useful adjuvants in BC by clarifying how these products may play a critical role in the prevention, treatment and progression of this disease. BC is the leading cancer, in terms of incidence, that affects women. The epidemiology and pathophysiology of BC were widely reported. Inflammation and cancer are known to influence each other in several tumors. In the case of BC, the inflammatory component precedes the development of the neoplasm through a slowly increasing and prolonged inflammation that also favors its growth. BC therapy involves a multidisciplinary approach comprising surgery, radiotherapy and chemotherapy. There are numerous observations that showed that the effects of some natural substances, which, in integration with the classic protocols, can be used not only for prevention or integration in order to prevent recurrences and induce a state of chemoquiescence but also as chemo- and radiosensitizers during classic therapy.
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Affiliation(s)
- Fabiano Svolacchia
- Department of Medical-Surgical Sciences and Biotechnologies, La Sapienza University, 00118 Rome, Italy
- Department of Medical Sciences, Policlinic Foundation Tor Vergata University, 00133 Rome, Italy
| | - Sergio Brongo
- Department of Plastic Surgery, University of Salerno, 84131 Campania, Italy
| | - Alessia Catalano
- Department of Pharmacy-Drug Sciences, University of Bari "Aldo Moro", 70126 Bari, Italy
| | - Agostino Ceccarini
- U.O.C. Primary Care and Territorial Health, Social and Health Department, State Hospital, 47893 San Marino, San Marino
| | - Lorenzo Svolacchia
- Department of Medical-Surgical Sciences and Biotechnologies, La Sapienza University, 00118 Rome, Italy
| | - Alessandro Santarsiere
- Department of Science, University of Basilicata, 85100 Potenza, Italy
- CNRS, UMR 7042-LIMA, ECPM, Université de Strasbourg, Université de Haute-Alsace, 67000 Strasbourg, France
| | - Carmen Scieuzo
- Department of Science, University of Basilicata, 85100 Potenza, Italy
- Spinoff XFlies s.r.l., University of Basilicata, 85100 Potenza, Italy
| | - Rosanna Salvia
- Department of Science, University of Basilicata, 85100 Potenza, Italy
- Spinoff XFlies s.r.l., University of Basilicata, 85100 Potenza, Italy
| | | | - Luigi Milella
- Department of Science, University of Basilicata, 85100 Potenza, Italy
| | - Carmela Saturnino
- Department of Science, University of Basilicata, 85100 Potenza, Italy
| | - Maria Stefania Sinicropi
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende, Italy
| | - Tommaso Fabrizio
- Department of Plastic Surgery, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, Italy
| | - Federica Giuzio
- U.O.C. Primary Care and Territorial Health, Social and Health Department, State Hospital, 47893 San Marino, San Marino
- Department of Science, University of Basilicata, 85100 Potenza, Italy
- Spinoff TNcKILLERS s.r.l., University of Basilicata, 85100 Potenza, Italy
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9
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Kumar N, Rachagani S, Natarajan G, Crook A, Gopal T, Rajamanickam V, Kaushal JB, Nagabhishek SN, Powers R, Batra SK, Saraswathi V. Histidine Enhances the Anticancer Effect of Gemcitabine against Pancreatic Cancer via Disruption of Amino Acid Homeostasis and Oxidant-Antioxidant Balance. Cancers (Basel) 2023; 15:cancers15092593. [PMID: 37174059 PMCID: PMC10177467 DOI: 10.3390/cancers15092593] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 04/20/2023] [Accepted: 04/26/2023] [Indexed: 05/15/2023] Open
Abstract
Due to the severe toxicity posed by chemotherapeutic drugs, adjuvant nutritional intervention has gained increased attention in the treatment of pancreatic cancer (PC). Amino acid (AA) metabolism is aberrantly regulated in PC and circulating histidine (His) levels are low in PC patients. We hypothesized that His uptake and/or metabolism is dysregulated in PC and that combining His with gemcitabine (Gem), a drug used in the treatment of PC, will enhance the anti-cancer effects of Gem. We performed in vitro and in vivo studies to determine the anticancer effect of the combination of His and Gem against lethal PC. We demonstrate that circulating His levels are low in both human subjects and genetically engineered mice exhibiting pancreatic tumors. Interestingly, the expression of histidine ammonia lyase, an enzyme involved in His catabolism, is higher in PC compared to normal subjects. His + Gem exerts a more potent cytotoxic effect in PC cells compared to individual treatments. His treatment results in a profound increase in His accumulation, accompanied by a depletion of a number of AAs, promoting cancer cell survival and/or glutathione (GSH) synthesis. His but not Gem increases hydrogen peroxide and depletes cellular GSH. Supplementation with GSH protects cells against His + Gem-induced cytotoxicity. Further, our in vivo studies demonstrate that His + Gem potently reduced tumor mass and improved mouse survival. Taken together, our data suggest that PC cells exhibit an aberrant His uptake/accumulation which, in turn, leads to oxidative stress and depletion of AA pool, thereby enhancing the anticancer effect of Gem.
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Affiliation(s)
- Narendra Kumar
- The Department of Internal Medicine, Division of Diabetes, Endocrinology and Metabolism, University of Nebraska Medical Center, Omaha, NE 68198, USA
- The VA Nebraska Western Iowa Health Care System, Omaha, NE 68105, USA
| | - Satyanarayana Rachagani
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Gopalakrishnan Natarajan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Alexandra Crook
- The Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588, USA
| | - Thiyagarajan Gopal
- The Department of Internal Medicine, Division of Diabetes, Endocrinology and Metabolism, University of Nebraska Medical Center, Omaha, NE 68198, USA
- The VA Nebraska Western Iowa Health Care System, Omaha, NE 68105, USA
| | - Vinothkumar Rajamanickam
- The Department of Internal Medicine, Division of Diabetes, Endocrinology and Metabolism, University of Nebraska Medical Center, Omaha, NE 68198, USA
- The VA Nebraska Western Iowa Health Care System, Omaha, NE 68105, USA
| | - Jyoti B Kaushal
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Sirpu N Nagabhishek
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Robert Powers
- The Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588, USA
- Nebraska Center for Integrated Biomolecular Communication, University of Nebraska-Lincoln, Lincoln, NE 68588, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Viswanathan Saraswathi
- The Department of Internal Medicine, Division of Diabetes, Endocrinology and Metabolism, University of Nebraska Medical Center, Omaha, NE 68198, USA
- The VA Nebraska Western Iowa Health Care System, Omaha, NE 68105, USA
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10
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Dual-drug loaded nanomedicine hydrogel as a therapeutic platform to target both residual glioblastoma and glioma stem cells. Int J Pharm 2022; 628:122341. [DOI: 10.1016/j.ijpharm.2022.122341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 10/19/2022] [Accepted: 10/22/2022] [Indexed: 11/06/2022]
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11
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Moss DY, McCann C, Kerr EM. Rerouting the drug response: Overcoming metabolic adaptation in KRAS-mutant cancers. Sci Signal 2022; 15:eabj3490. [PMID: 36256706 DOI: 10.1126/scisignal.abj3490] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Mutations in guanosine triphosphatase KRAS are common in lung, colorectal, and pancreatic cancers. The constitutive activity of mutant KRAS and its downstream signaling pathways induces metabolic rewiring in tumor cells that can promote resistance to existing therapeutics. In this review, we discuss the metabolic pathways that are altered in response to treatment and those that can, in turn, alter treatment efficacy, as well as the role of metabolism in the tumor microenvironment (TME) in dictating the therapeutic response in KRAS-driven cancers. We highlight metabolic targets that may provide clinical opportunities to overcome therapeutic resistance and improve survival in patients with these aggressive cancers.
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Affiliation(s)
- Deborah Y Moss
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, BT9 7AE Northern Ireland, UK
| | - Christopher McCann
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, BT9 7AE Northern Ireland, UK
| | - Emma M Kerr
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, BT9 7AE Northern Ireland, UK
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12
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Jin P, Jiang J, Zhou L, Huang Z, Nice EC, Huang C, Fu L. Mitochondrial adaptation in cancer drug resistance: prevalence, mechanisms, and management. J Hematol Oncol 2022; 15:97. [PMID: 35851420 PMCID: PMC9290242 DOI: 10.1186/s13045-022-01313-4] [Citation(s) in RCA: 104] [Impact Index Per Article: 34.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 06/29/2022] [Indexed: 02/08/2023] Open
Abstract
Drug resistance represents a major obstacle in cancer management, and the mechanisms underlying stress adaptation of cancer cells in response to therapy-induced hostile environment are largely unknown. As the central organelle for cellular energy supply, mitochondria can rapidly undergo dynamic changes and integrate cellular signaling pathways to provide bioenergetic and biosynthetic flexibility for cancer cells, which contributes to multiple aspects of tumor characteristics, including drug resistance. Therefore, targeting mitochondria for cancer therapy and overcoming drug resistance has attracted increasing attention for various types of cancer. Multiple mitochondrial adaptation processes, including mitochondrial dynamics, mitochondrial metabolism, and mitochondrial apoptotic regulatory machinery, have been demonstrated to be potential targets. However, recent increasing insights into mitochondria have revealed the complexity of mitochondrial structure and functions, the elusive functions of mitochondria in tumor biology, and the targeting inaccessibility of mitochondria, which have posed challenges for the clinical application of mitochondrial-based cancer therapeutic strategies. Therefore, discovery of both novel mitochondria-targeting agents and innovative mitochondria-targeting approaches is urgently required. Here, we review the most recent literature to summarize the molecular mechanisms underlying mitochondrial stress adaptation and their intricate connection with cancer drug resistance. In addition, an overview of the emerging strategies to target mitochondria for effectively overcoming chemoresistance is highlighted, with an emphasis on drug repositioning and mitochondrial drug delivery approaches, which may accelerate the application of mitochondria-targeting compounds for cancer therapy.
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Affiliation(s)
- Ping Jin
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, People's Republic of China
| | - Jingwen Jiang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, People's Republic of China
| | - Li Zhou
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, People's Republic of China
| | - Zhao Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, People's Republic of China
| | - Edouard C Nice
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3800, Australia
| | - Canhua Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, People's Republic of China.
| | - Li Fu
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and International Cancer Center, Shenzhen University Health Science Center, Shenzhen, 518060, Guangdong, People's Republic of China.
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13
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García-Garrido E, Cordani M, Somoza Á. Modified Gold Nanoparticles to Overcome the Chemoresistance to Gemcitabine in Mutant p53 Cancer Cells. Pharmaceutics 2021; 13:2067. [PMID: 34959348 PMCID: PMC8703659 DOI: 10.3390/pharmaceutics13122067] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 11/27/2021] [Accepted: 11/28/2021] [Indexed: 12/29/2022] Open
Abstract
Mutant p53 proteins result from missense mutations in the TP53 gene, the most mutated in human cancer, and have been described to contribute to cancer initiation and progression. Therapeutic strategies for targeting mutant p53 proteins in cancer cells are limited and have proved unsuitable for clinical application due to problems related to drug delivery and toxicity to healthy tissues. Therefore, the discovery of efficient and safe therapeutic strategies that specifically target mutant p53 remains challenging. In this study, we generated gold nanoparticles (AuNPs) chemically modified with low molecular branched polyethylenimine (bPEI) for the efficient delivery of gapmers targeting p53 mutant protein. The AuNPs formulation consists of a combination of polymeric mixed layer of polyethylene glycol (PEG) and PEI, and layer-by-layer assembly of bPEI through a sensitive linker. These nanoparticles can bind oligonucleotides through electrostatic interactions and release them in the presence of a reducing agent as glutathione. The nanostructures generated here provide a non-toxic and powerful system for the delivery of gapmers in cancer cells, which significantly downregulated mutant p53 proteins and altered molecular markers related to cell growth and apoptosis, thus overcoming chemoresistance to gemcitabine.
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Affiliation(s)
- Eduardo García-Garrido
- Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA Nanociencia), Faraday 9, 28049 Madrid, Spain
| | - Marco Cordani
- Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA Nanociencia), Faraday 9, 28049 Madrid, Spain
| | - Álvaro Somoza
- Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA Nanociencia), Faraday 9, 28049 Madrid, Spain
- Unidad Asociada al Centro Nacional de Biotecnología (CSIC), Darwin 3, 28049 Madrid, Spain
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14
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Chuang HW, Wei IH, Li CT, Huang CC. Decreased efficacy of the ketamine and scopolamine-induced sustained antidepressant-like effects in rats receiving metformin. Pharmacol Rep 2021; 74:340-352. [PMID: 34850372 DOI: 10.1007/s43440-021-00342-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Revised: 11/18/2021] [Accepted: 11/20/2021] [Indexed: 11/26/2022]
Abstract
BACKGROUND Metformin is the most widely used drug for treating type 2 diabetes mellitus (DM), which frequently co-occurs with depressive disorders. Thus, patients with depression are likely to receive metformin. Metformin activates AMP-activated kinase (AMPK), which inhibits mechanistic target of rapamycin complex 1 (mTORC1) signaling. mTORC1 activation is essential for the antidepressant effects of ketamine and scopolamine. Thus, we hypothesized that metformin may attenuate ketamine- or scopolamine-induced antidepressant efficacies by blocking their mTORC1 activation. METHODS We assessed the acute and sustained antidepressant-like actions of ketamine and scopolamine in male Sprague-Dawley rats subjected to the forced swim test with or without metformin pretreatment. The expressions of AMPK, mTORC1, and brain-derived neurotrophic factor (BDNF) in their prefrontal cortex were assessed. RESULTS Metformin (50 mg/kg) attenuated the sustained, but not acute, antidepressant-like effects of ketamine (10 mg/kg) and scopolamine (25 μg/kg). Although metformin reduced mTORC1 downstream activated P70S6K, it did not significantly alter mTORser2448 activation and even increased BDNF expression. Notably, ketamine, scopolamine, and metformin all exerted significant antidepressant-like actions, as evidenced by increased AMPK phosphorylation and BDNF expression. CONCLUSIONS Metformin-induced attenuation of sustained antidepressant-like effects are not directly dependent on AMPK-deactivated mTORC1. Our results indicate the complexity of interactions between AMPK, BDNF, and mTORC1. Further research, including mechanistic studies, is warranted to comprehensively evaluate the application of metformin in patients receiving mTORC1-based antidepressants.
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Affiliation(s)
- Han-Wen Chuang
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
| | - I-Hua Wei
- Department of Anatomy, China Medical University, No.91, Hsueh-Shih Road, Taichung, 404333, Taiwan.
| | - Chun-Te Li
- Department of Medicine, China Medical University, Taichung, Taiwan
| | - Chih-Chia Huang
- Tsaotun Psychiatric Center, Ministry of Health and Welfare, No. 161, Yu-Pin Road Tsaotun Township, Nantou, 54249, Taiwan.
- Department of Psychiatry, China Medical University, Taichung, Taiwan.
- Department of Psychiatry, China Medical University Hospital, Taichung, Taiwan.
- Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan.
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15
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Fan Y, Ren X, Wang Y, Xu E, Wang S, Ge R, Liu Y. Metformin inhibits the proliferation of canine mammary gland tumor cells through the AMPK/AKT/mTOR signaling pathway in vitro. Oncol Lett 2021; 22:852. [PMID: 34733370 PMCID: PMC8561621 DOI: 10.3892/ol.2021.13113] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 06/14/2021] [Indexed: 11/25/2022] Open
Abstract
As an anti-diabetic drug, metformin has been demonstrated to exhibit antitumor effects. However, the mechanisms involved in decreasing tumor formation, including canine mammary gland tumors (CMGTs), are not well elucidated. The aim of the present study was to evaluate the ability of metformin to induce apoptosis and cell cycle arrest in CMGT cells, as well as identifying the pathways underlying these effects. Cell viability was assessed by Cell Counting Kit-8 analysis following treating with metformin. Subsequently, apoptosis and cell cycle progression were assessed by flow cytometry, and the expression of associated proteins was examined. Expression levels of classical AMP-activated protein kinase (AMPK), protein kinase B (AKT), mechanistic target of rapamycin (mTOR) and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) were then investigated using western blot analysis. Metformin inhibited the proliferation of CHMm cells in a concentration-dependent manner. Specifically, metformin induced cell cycle arrest in the G0/G1 phases, accompanied by increased expression of p21 and p27, and decreased expression of cyclin D1 and cyclin-dependent kinase 4. Marked levels of apoptosis were observed in CHMm cells alongside the activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase. Also, the level of Bcl-2 was decreased, and that of Bax was increased. The expression of associated signaling molecules revealed that metformin markedly increased the phosphorylation of AMPK in CHMm cells, and decreased the levels of phosphorylated (p-)AKT, p-mTOR and p-4E-BP1, while Compound C reversed these changes. These findings demonstrated that metformin may be a potential therapeutic agent for CMGTs, acting via the AMPK/AKT/mTOR signaling pathway.
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Affiliation(s)
- Yuying Fan
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang 150000, P.R. China
| | - Xiaoli Ren
- College of Veterinary Medicine, Henan University of Animal Husbandry and Economy, Zhengzhou, Henan 450046, P.R. China
| | - Yingxue Wang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang 150000, P.R. China
| | - Enshuang Xu
- College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163000, P.R. China
| | - Shuang Wang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang 150000, P.R. China
| | - Ruidong Ge
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang 150000, P.R. China
| | - Yun Liu
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang 150000, P.R. China
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16
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Ezzeldeen Y, Swidan S, ElMeshad A, Sebak A. Green Synthesized Honokiol Transfersomes Relieve the Immunosuppressive and Stem-Like Cell Characteristics of the Aggressive B16F10 Melanoma. Int J Nanomedicine 2021; 16:5693-5712. [PMID: 34465990 PMCID: PMC8402984 DOI: 10.2147/ijn.s314472] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 06/17/2021] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Honokiol (HK) is a natural bioactive compound with proven antineoplastic properties against melanoma. However, it shows very low bioavailability when administered orally. Alternatively, topical administration may offer a promising route. The objective of the current study was to fabricate HK transfersomes (HKTs) for topical treatment of melanoma. As an ultradeformable carrier system, transfersomes can overcome the physiological barriers to topical treatment of melanoma: the stratum corneum and the anomalous tumor microenvironment. Moreover, the immunomodulatory and stemness-regulation roles of HKTs were the main interest of this study. METHODS TFs were prepared using the modified scalable heating method. A three-factor, three-level Box-Behnken design was utilized for the optimization of the process and formulation variables. Intracellular uptake and cytotoxicity of HKTs were evaluated in nonactivated and stromal cell-activated B16F10 melanoma cells to investigate the influence of the complex tumor microenvironment on the efficacy of HK. Finally, ELISA and Western blot were performed to evaluate the expression levels of TGF-β and clusters of differentiation (CD47 and CD133, respectively). RESULTS The optimized formula exhibited a mean size of 190 nm, highly negative surface charge, high entrapment efficiency, and sustained release profile. HKTs showed potential to alleviate the immunosuppressive characteristics of B16F10 melanoma in vitro via downregulation of TGF-β signaling. In addition, HKTs reduced expression of the "do not eat me" signal - CD47. Moreover, HKTs possessed additional interesting potential to reduce the expression of the stem-like cell marker CD133. These outcomes were boosted upon combination with metformin, an antihyperglycemic drug recently reported to possess different functions in cancer, while combination with collagenase, an extracellular matrix-depleting enzyme, produced detrimental effects. CONCLUSION HKTs represent a promising scalable formulation for treatment of the aggressive B16F10 melanoma, which is jam-packed with immunosuppressive and stem-like cell markers.
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Affiliation(s)
- Yasmeen Ezzeldeen
- Department of Pharmaceutics, Faculty of Pharmacy, The British University in Egypt (BUE), El-Sherouk City, Cairo, 11837, Egypt
| | - Shady Swidan
- Department of Pharmaceutics, Faculty of Pharmacy, The British University in Egypt (BUE), El-Sherouk City, Cairo, 11837, Egypt
- The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo, 11837, Egypt
| | - Aliaa ElMeshad
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt
- Department of Bio Nano, Faculty of Nanotechnology for Postgraduate Studies, Cairo University, El-Sheikh Zayed, Giza, 12588, Egypt
| | - Aya Sebak
- Department of Pharmaceutical Technology, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), Cairo, Egypt
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17
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Djamgoz MBA, Jentzsch V. Integrative Management of Pancreatic Cancer (PDAC): Emerging Complementary Agents and Modalities. Nutr Cancer 2021; 74:1139-1162. [PMID: 34085871 DOI: 10.1080/01635581.2021.1934043] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 04/19/2021] [Accepted: 05/10/2021] [Indexed: 02/07/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease. The standard first-line treatment for PDAC is gemcitabine chemotherapy which, unfortunately, offers only limited chance of a lasting cure. This review further evaluates the hypothesis that the effectiveness of gemcitabine can be improved by combining it with evidence-based complementary measures. Previously, supported by clinical trial data, we suggested that a number of dietary factors and nutraceuticals can be integrated with gemcitabine therapy. Here, we evaluate a further 10 agents for which no clinical trials have (yet) been carried out but there are promising data from in vivo and/or in vitro studies including experiments involving combined treatments with gemcitabine. Two groups of complementary agents are considered: Dietary factors (resveratrol, epigallocatechin gallate, vitamin B9, capsaicin, quercetin and sulforaphane) and nutraceutical agents (artemisinin, garcinol, thymoquinone and emodin). In addition, we identified seven promising agents for which there is currently only basic (mostly in vitro) data. Finally, as a special case of combination therapy, we highlighted synergistic drug combinations involving gemcitabine with "repurposed" aspirin or metformin. We conclude overall that integrated management of PDAC currently is likely to produce the best outcome for patients and for this a wide range of complementary measures is available.
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Affiliation(s)
- Mustafa B A Djamgoz
- Department of Life Sciences, Imperial College London, London, UK
- Biotechnology Research Centre, Cyprus International University, Nicosia, Cyprus
| | - Valerie Jentzsch
- Department of Life Sciences, Imperial College London, London, UK
- Department of Health Policy, London School of Economics and Political Science, London, UK
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18
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Paramanantham A, Jung EJ, Go SIL, Jeong BK, Jung JM, Hong SC, Kim GS, Lee WS. Activated ERK Signaling Is One of the Major Hub Signals Related to the Acquisition of Radiotherapy-Resistant MDA-MB-231 Breast Cancer Cells. Int J Mol Sci 2021; 22:ijms22094940. [PMID: 34066541 PMCID: PMC8124562 DOI: 10.3390/ijms22094940] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 04/19/2021] [Accepted: 04/30/2021] [Indexed: 02/07/2023] Open
Abstract
Breast cancer is one of the major causes of deaths due to cancer, especially in women. The crucial barrier for breast cancer treatment is resistance to radiation therapy, one of the important local regional therapies. We previously established and characterized radio-resistant MDA-MB-231 breast cancer cells (RT-R-MDA-MB-231 cells) that harbor a high expression of cancer stem cells (CSCs) and the EMT phenotype. In this study, we performed antibody array analysis to identify the hub signaling mechanism for the radiation resistance of RT-R-MDA-MB-231 cells by comparing parental MDA-MB-231 (p-MDA-MB-231) and RT-R-MDA-MB-231 cells. Antibody array analysis unveiled that the MAPK1 protein was the most upregulated protein in RT-R-MDA-MB-231 cells compared to in p-MDA-MB-231 cells. The pathway enrichment analysis also revealed the presence of MAPK1 in almost all enriched pathways. Thus, we used an MEK/ERK inhibitor, PD98059, to block the MEK/ERK pathway and to identify the role of MAPK1 in the radio-resistance of RT-R-MDA-MB-231 cells. MEK/ERK inhibition induced cell death in both p-MDA-MB-231 and RT-R-MDA-MB-231 cells, but the death mechanism for each cell was different; p-MDA-MB-231 cells underwent apoptosis, showing cell shrinkage and PARP-1 cleavage, while RT-R-MDA-MB-231 cells underwent necroptosis, showing mitochondrial dissipation, nuclear swelling, and an increase in the expressions of CypA and AIF. In addition, MEK/ERK inhibition reversed the radio-resistance of RT-R-MDA-MB-231 cells and suppressed the increased expression of CSC markers (CD44 and OCT3/4) and the EMT phenotype (β-catenin and N-cadherin/E-cadherin). Taken together, this study suggests that activated ERK signaling is one of the major hub signals related to the radio-resistance of MDA-MB-231 breast cancer cells.
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Affiliation(s)
- Anjugam Paramanantham
- Departments of Internal Medicine, Institute of Health Sciences and Gyeongsang National University Hospital, Gyeongsang National University College of Medicine, 90 Chilam-dong, Jinju 660-702, Korea; (A.P.); (E.J.J.); (S.-I.G.)
- School of Veterinary and Institute of Life Science, Gyeongsang National University, 900 Gajwadong, Jinju 660-701, Korea
| | - Eun Joo Jung
- Departments of Internal Medicine, Institute of Health Sciences and Gyeongsang National University Hospital, Gyeongsang National University College of Medicine, 90 Chilam-dong, Jinju 660-702, Korea; (A.P.); (E.J.J.); (S.-I.G.)
| | - Se-IL Go
- Departments of Internal Medicine, Institute of Health Sciences and Gyeongsang National University Hospital, Gyeongsang National University College of Medicine, 90 Chilam-dong, Jinju 660-702, Korea; (A.P.); (E.J.J.); (S.-I.G.)
| | - Bae Kwon Jeong
- Departments of Radiation Oncology, Institute of Health Sciences and Gyeongsang National University Hospital, Gyeongsang National University College of Medicine, 90 Chilam-dong, Jinju 660-702, Korea;
| | - Jin-Myung Jung
- Departments of Neurosurgery, Institute of Health Sciences and Gyeongsang National University Hospital, Gyeongsang National University College of Medicine, 90 Chilam-dong, Jinju 660-702, Korea;
| | - Soon Chan Hong
- Departments of Surgery, Institute of Health Sciences and Gyeongsang National University Hospital, Gyeongsang National University College of Medicine, 90 Chilam-dong, Jinju 660-702, Korea;
| | - Gon Sup Kim
- School of Veterinary and Institute of Life Science, Gyeongsang National University, 900 Gajwadong, Jinju 660-701, Korea
- Correspondence: (G.S.K.); (W.S.L.); Tel.: +82-55-772-2356 (G.S.K.); +82-55-750-8733 (W.S.L.); Fax: +82-55-758-9122 (W.S.L.)
| | - Won Sup Lee
- Departments of Internal Medicine, Institute of Health Sciences and Gyeongsang National University Hospital, Gyeongsang National University College of Medicine, 90 Chilam-dong, Jinju 660-702, Korea; (A.P.); (E.J.J.); (S.-I.G.)
- Correspondence: (G.S.K.); (W.S.L.); Tel.: +82-55-772-2356 (G.S.K.); +82-55-750-8733 (W.S.L.); Fax: +82-55-758-9122 (W.S.L.)
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19
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Barman S, Fatima I, Singh AB, Dhawan P. Pancreatic Cancer and Therapy: Role and Regulation of Cancer Stem Cells. Int J Mol Sci 2021; 22:ijms22094765. [PMID: 33946266 PMCID: PMC8124621 DOI: 10.3390/ijms22094765] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 04/20/2021] [Accepted: 04/20/2021] [Indexed: 12/21/2022] Open
Abstract
Despite significant improvements in clinical management, pancreatic cancer (PC) remains one of the deadliest cancer types, as it is prone to late detection with extreme metastatic properties. The recent findings that pancreatic cancer stem cells (PaCSCs) contribute to the tumorigenesis, progression, and chemoresistance have offered significant insight into the cancer malignancy and development of precise therapies. However, the heterogeneity of cancer and signaling pathways that regulate PC have posed limitations in the effective targeting of the PaCSCs. In this regard, the role for K-RAS, TP53, Transforming Growth Factor-β, hedgehog, Wnt and Notch and other signaling pathways in PC progression is well documented. In this review, we discuss the role of PaCSCs, the underlying molecular and signaling pathways that help promote pancreatic cancer development and metastasis with a specific focus on the regulation of PaCSCs. We also discuss the therapeutic approaches that target different PaCSCs, intricate mechanisms, and therapeutic opportunities to eliminate heterogeneous PaCSCs populations in pancreatic cancer.
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Affiliation(s)
- Susmita Barman
- Department of Biochemistry and Molecular Biology, Omaha, NE 68198, USA; (S.B.); (I.F.); (A.B.S.)
| | - Iram Fatima
- Department of Biochemistry and Molecular Biology, Omaha, NE 68198, USA; (S.B.); (I.F.); (A.B.S.)
| | - Amar B. Singh
- Department of Biochemistry and Molecular Biology, Omaha, NE 68198, USA; (S.B.); (I.F.); (A.B.S.)
- VA Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68105, USA
| | - Punita Dhawan
- Department of Biochemistry and Molecular Biology, Omaha, NE 68198, USA; (S.B.); (I.F.); (A.B.S.)
- VA Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68105, USA
- Correspondence:
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20
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Tang Z, Tang N, Jiang S, Bai Y, Guan C, Zhang W, Fan S, Huang Y, Lin H, Ying Y. The Chemosensitizing Role of Metformin in Anti-Cancer Therapy. Anticancer Agents Med Chem 2021; 21:949-962. [PMID: 32951587 DOI: 10.2174/1871520620666200918102642] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 07/23/2020] [Accepted: 08/08/2020] [Indexed: 11/22/2022]
Abstract
Chemoresistance, which leads to the failure of chemotherapy and further tumor recurrence, presents the largest hurdle for the success of anti-cancer therapy. In recent years, metformin, a widely used first-line antidiabetic drug, has attracted increasing attention for its anti-cancer effects. A growing body of evidence indicates that metformin can sensitize tumor responses to different chemotherapeutic drugs, such as hormone modulating drugs, anti-metabolite drugs, antibiotics, and DNA-damaging drugs via selective targeting of Cancer Stem Cells (CSCs), improving the hypoxic microenvironment, and by suppressing tumor metastasis and inflammation. In addition, metformin may regulate metabolic programming, induce apoptosis, reverse Epithelial to Mesenchymal Transition (EMT), and Multidrug Resistance (MDR). In this review, we summarize the chemosensitization effects of metformin and focus primarily on its molecular mechanisms in enhancing the sensitivity of multiple chemotherapeutic drugs, through targeting of mTOR, ERK/P70S6K, NF-κB/HIF-1 α, and Mitogen- Activated Protein Kinase (MAPK) signaling pathways, as well as by down-regulating the expression of CSC genes and Pyruvate Kinase isoenzyme M2 (PKM2). Through a comprehensive understanding of the molecular mechanisms of chemosensitization provided in this review, the rationale for the use of metformin in clinical combination medications can be more systematically and thoroughly explored for wider adoption against numerous cancer types.>.
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Affiliation(s)
- Zhimin Tang
- Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology and Department of Pathophysiology, Schools of Basic Medical Sciences, Nanchang University, Nanchang 330006, China
| | - Nan Tang
- Nanchang Joint Program, Queen Mary School, Nanchang University, Nanchang 330006, China
| | - Shanshan Jiang
- Institute of Hematological Research, Shanxi Provincial People's Hospital, Xian 710000, China
| | - Yangjinming Bai
- Nanchang Joint Program, Queen Mary School, Nanchang University, Nanchang 330006, China
| | - Chenxi Guan
- Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology and Department of Pathophysiology, Schools of Basic Medical Sciences, Nanchang University, Nanchang 330006, China
| | - Wansi Zhang
- Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology and Department of Pathophysiology, Schools of Basic Medical Sciences, Nanchang University, Nanchang 330006, China
| | - Shipan Fan
- Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GRMH-GDL), Guangzhou 510005, China
| | - Yonghong Huang
- Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology and Department of Pathophysiology, Schools of Basic Medical Sciences, Nanchang University, Nanchang 330006, China
| | - Hui Lin
- Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology and Department of Pathophysiology, Schools of Basic Medical Sciences, Nanchang University, Nanchang 330006, China
| | - Ying Ying
- Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology and Department of Pathophysiology, Schools of Basic Medical Sciences, Nanchang University, Nanchang 330006, China
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21
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Cioce M, Pulito C, Strano S, Blandino G, Fazio VM. Metformin: Metabolic Rewiring Faces Tumor Heterogeneity. Cells 2020; 9:E2439. [PMID: 33182253 PMCID: PMC7695274 DOI: 10.3390/cells9112439] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Revised: 10/13/2020] [Accepted: 11/03/2020] [Indexed: 02/07/2023] Open
Abstract
Tumor heterogeneity impinges on all the aspects of tumor history, from onset to metastasis and relapse. It is growingly recognized as a propelling force for tumor adaptation to environmental and micro-environmental cues. Metabolic heterogeneity perfectly falls into this process. It strongly contributes to the metabolic plasticity which characterizes cancer cell subpopulations-capable of adaptive switching under stress conditions, between aerobic glycolysis and oxidative phosphorylation-in both a convergent and divergent modality. The mitochondria appear at center-stage in this adaptive process and thus, targeting mitochondria in cancer may prove of therapeutic value. Metformin is the oldest and most used anti-diabetic medication and its relationship with cancer has witnessed rises and falls in the last 30 years. We believe it is useful to revisit the main mechanisms of action of metformin in light of the emerging views on tumor heterogeneity. We first analyze the most consolidated view of its mitochondrial mechanism of action and then we frame the latter in the context of tumor adaptive strategies, cancer stem cell selection, metabolic zonation of tumors and the tumor microenvironment. This may provide a more critical point of view and, to some extent, may help to shed light on some of the controversial evidence for metformin's anticancer action.
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Affiliation(s)
- Mario Cioce
- Department of Medicine, R.U. in Molecular Medicine and Biotechnology, University Campus Bio-Medico of Rome, 00128 Rome, Italy;
| | - Claudio Pulito
- Oncogenomic and Epigenetic Unit, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; (C.P.); (G.B.)
| | - Sabrina Strano
- SAFU Unit, Department of Research, Diagnosis and Innovative Technologies, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy;
| | - Giovanni Blandino
- Oncogenomic and Epigenetic Unit, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; (C.P.); (G.B.)
| | - Vito Michele Fazio
- Department of Medicine, R.U. in Molecular Medicine and Biotechnology, University Campus Bio-Medico of Rome, 00128 Rome, Italy;
- Institute of Translation Pharmacology, National Research Council of Italy (CNR), 00133 Rome, Italy
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22
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Gu Y, Zhang B, Gu G, Yang X, Qian Z. Metformin Increases the Chemosensitivity of Pancreatic Cancer Cells to Gemcitabine by Reversing EMT Through Regulation DNA Methylation of miR-663. Onco Targets Ther 2020; 13:10417-10429. [PMID: 33116621 PMCID: PMC7569251 DOI: 10.2147/ott.s261570] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 09/06/2020] [Indexed: 12/12/2022] Open
Abstract
Background Pancreatic cancer is a devastating malignancy with poor prognosis. Metformin, a classic anti-diabetes drug, seems to improve survival of pancreatic cancer patients in some studies. Methods Cell counting kit-8 assay was used to detect the BxPC-3 and MIAPaCa-2 cell viability after treatment with gemcitabine only or with different concentrations of metformin. The methylation state and expression level of miR-663 were detected by methylation analysis and RT-PCR. Dual-luciferase reporter gene analysis, Western blot and RT-PCR were used to confirm the target of miR-663. Moreover, xenograft experiment was also performed to validate the role of metformin in chemosensitivity in vivo. Results We found that metformin increased the chemosensitivity of pancreatic cancer cells to gemcitabine, and epithelial-mesenchymal transition (EMT) progress caused by gemcitabine was suppressed by metformin. We further explored the possible molecular mechanisms and it was demonstrated that CpG islands of miR-663 were hypomethylated and relative expression level of miR-663 was up-regulated after treatment of metformin. miR-663, an important cancer suppressor miRNA, was confirmed to increase the chemosensitivity of pancreatic cancer cells by reversing EMT directly targeted TGF-β1. Moreover, we identified that metformin increased the chemosensitivity through up-regulating expression of miR-663. Conclusion We demonstrated that metformin increased the chemosensitivity of pancreatic cancer cells to gemcitabine by reversing EMT through regulation DNA methylation of miR-663.
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Affiliation(s)
- Yuqing Gu
- Pancreas Center, The Second Affiliated Hospital to Nanjing Medical University, Nanjing 210003, People's Republic of China
| | - Bin Zhang
- Pancreas Center, The Second Affiliated Hospital to Nanjing Medical University, Nanjing 210003, People's Republic of China
| | - Guangliang Gu
- Pancreas Center, The Second Affiliated Hospital to Nanjing Medical University, Nanjing 210003, People's Republic of China
| | - Xiaojun Yang
- Pancreas Center, The Second Affiliated Hospital to Nanjing Medical University, Nanjing 210003, People's Republic of China
| | - Zhuyin Qian
- Pancreas Center, The Second Affiliated Hospital to Nanjing Medical University, Nanjing 210003, People's Republic of China
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23
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Cao N, Lu Y, Liu J, Cai F, Xu H, Chen J, Zhang X, Hua ZC, Zhuang H. Metformin Synergistically Enhanced the Antitumor Activity of Celecoxib in Human Non-Small Cell Lung Cancer Cells. Front Pharmacol 2020; 11:1094. [PMID: 32792943 PMCID: PMC7387512 DOI: 10.3389/fphar.2020.01094] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Accepted: 07/06/2020] [Indexed: 12/25/2022] Open
Abstract
Celecoxib has potential as an effective antineoplastic agent, but it may exhibit side effects. Given the glucose-addicted properties of tumor cells, metformin is recognized for its inhibitory effect on oxidative phosphorylation. In the present study, we aimed to combine low dose of celecoxib with metformin to alleviate the side effects of nonsteroidal anti-inflammatory drugs (NSAIDs) and overcome potential drug resistance. We found that celecoxib combined with metformin obviously suppressed cell migration and proliferation and induced cell apoptosis. Most importantly, in vivo experiments revealed the superior antitumor efficacy of combination treatment with a low dosage of celecoxib (25 mg/kg/day) without apparent toxicity. Further study of the underlying mechanism revealed that the two drugs in combination caused ROS aggregation in NSCLC cells, leading to DNA double-strand breaks and increased expression of the tumor suppressor factor p53. Elevated p53 subsequently caused cell cycle arrest and cell proliferation inhibition. The presence of metformin also sensitized NSCLC cells to celecoxib-induced apoptosis by activating caspase-9, -8, -3, and -7, upregulating the pro-apoptotic proteins Bad and Bax, and downregulating the antiapoptotic proteins Bcl-xl and Bcl-2. Moreover, the superior anticancer effect of combined therapy was also due to suppression of Raf-MEK-ERK cascades and PI3K-AKT signaling, which is conducive to overcoming drug resistance. In addition, either celecoxib alone or in combination with metformin suppressed NSCLC cell migration and invasion by inhibiting FAK, N-cadherin, and matrix metalloproteinase-9 activities. Together, our study provided a rational combination strategy with a low dosage of celecoxib and metformin for preclinical cancer application.
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Affiliation(s)
- Nini Cao
- The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China
| | - Yanyan Lu
- The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China
| | - Jia Liu
- The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China
| | - Fangfang Cai
- The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China
| | - Huangru Xu
- The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China
| | - Jia Chen
- The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China
| | - Xiangyu Zhang
- The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China
| | - Zi-Chun Hua
- The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China.,Changzhou High-Tech Research Institute of Nanjing University and Jiangsu TargetPharma Laboratories Inc., Changzhou, China
| | - Hongqin Zhuang
- The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China
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24
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Chen ZX, Liu MD, Guo DK, Zou MZ, Wang SB, Cheng H, Zhong Z, Zhang XZ. A MSN-based tumor-targeted nanoplatform to interfere with lactate metabolism to induce tumor cell acidosis for tumor suppression and anti-metastasis. NANOSCALE 2020; 12:2966-2972. [PMID: 31971210 DOI: 10.1039/c9nr10344a] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Lactate, the main contributor to the acidic tumor microenvironment, not only promotes the proliferation of tumor cells, but also closely relates to tumor invasion and metastasis. Here, a tumor targeting nanoplatform, designated as Me&Flu@MSN@MnO2-FA, was fabricated for effective tumor suppression and anti-metastasis by interfering with lactate metabolism of tumor cells. Metformin (Me) and fluvastatin sodium (Flu) were incorporated into MnO2-coated mesoporous silicon nanoparticles (MSNs), the synergism between Me and Flu can modulate the pyruvate metabolic pathway to produce more lactate, and concurrently inhibit lactate efflux to induce intracellular acidosis to kill tumor cells. As a result of the restricted lactate efflux, the extracellular lactate concentration is reduced, and the ability of the tumor cells to migrate is also weakened. This ingenious strategy based on Me&Flu@MSN@MnO2-FA showed an obvious inhibitory effect on tumor growth and resistance to metastasis.
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Affiliation(s)
- Zhao-Xia Chen
- Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, P. R. China.
| | - Miao-Deng Liu
- Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, P. R. China.
| | - Deng-Ke Guo
- Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, P. R. China.
| | - Mei-Zhen Zou
- Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, P. R. China.
| | - Shi-Bo Wang
- Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, P. R. China.
| | - Han Cheng
- Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, P. R. China.
| | - Zhenlin Zhong
- Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, P. R. China.
| | - Xian-Zheng Zhang
- Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, P. R. China.
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25
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Zhang X, Liu P, Shang Y, Kerndl H, Kumstel S, Gong P, Vollmar B, Zechner D. Metformin and LW6 impairs pancreatic cancer cells and reduces nuclear localization of YAP1. J Cancer 2020; 11:479-487. [PMID: 31897243 PMCID: PMC6930432 DOI: 10.7150/jca.33029] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Accepted: 08/27/2019] [Indexed: 01/15/2023] Open
Abstract
The poor survival rate of pancreatic cancer is still a major challenge for the clinicians and their patients. In this study, we evaluated the efficacy of metformin, an inhibitor of oxidative phosphorylation, in combination with LW6, which impairs malate dehydrogenase 2 activities, in treating pancreatic cancer cells. We observed that this combinational therapy significantly reduced cell proliferation, migration, and significantly induced cell death when compared to cells treated by each monotherapy or Sham. In addition, we found that the combination of metformin and LW6 increased the phosphorylation of yes-associated protein 1 at serine 127 and attenuated the nuclear localization of this transcription factor. This combinatorial treatment also decreased the level of cellular yes-associated protein 1. This suggests that metformin in combination with LW6 impairs pancreatic cancer cells and reduces nuclear localization of yes-associated protein 1.
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Affiliation(s)
- Xianbin Zhang
- Institute for Experimental Surgery, Rostock University Medical Center, Schillingallee 69a, 18059, Rostock, Germany.,Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jiyan Road 440, 250117, Jinan, China
| | - Peng Liu
- Department of General Surgery, Shenzhen University General Hospital, Xueyuan Road 1098, 518055, Shenzhen, China
| | - Yuru Shang
- Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jiyan Road 440, 250117, Jinan, China.,Molecular Oncology and Immunotherapy, Department of General Surgery, Rostock University Medical Center, Schillingallee 69, 18059, Rostock, Germany
| | - Hagen Kerndl
- Institute for Experimental Surgery, Rostock University Medical Center, Schillingallee 69a, 18059, Rostock, Germany
| | - Simone Kumstel
- Institute for Experimental Surgery, Rostock University Medical Center, Schillingallee 69a, 18059, Rostock, Germany
| | - Peng Gong
- Department of General Surgery, Shenzhen University General Hospital, Xueyuan Road 1098, 518055, Shenzhen, China
| | - Brigitte Vollmar
- Institute for Experimental Surgery, Rostock University Medical Center, Schillingallee 69a, 18059, Rostock, Germany
| | - Dietmar Zechner
- Institute for Experimental Surgery, Rostock University Medical Center, Schillingallee 69a, 18059, Rostock, Germany
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26
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Wu J, Tang Q, Ren X, Zheng F, He C, Chai X, Li L, Hann SS. Reciprocal interaction of HOTAIR and SP1 together enhance the ability of Xiaoji decoction and gefitinib to inhibit EP4 expression. JOURNAL OF ETHNOPHARMACOLOGY 2019; 237:128-140. [PMID: 30910577 DOI: 10.1016/j.jep.2019.03.027] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Revised: 03/09/2019] [Accepted: 03/10/2019] [Indexed: 06/09/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The Chinese herbal prescription Xiaoji decoction (XJD) has long been used for cancer treatment. However, the molecular mechanisms underlying the effects of this medicine, particularly to enhance the efficiency of EGFR-TKI in the treatment of lung cancer have not been well elucidated. MATERIALS AND METHODS Cell viability and cell cycle distribution were detected by MTT assay and flow cytometry, respectively. The phosphorylation of ERK1/2 and protein levels of SP1 and EP4 were determined by Western blot. The expression of the HOX transcript antisense RNA (HOTAIR) was measured by qRT-PCR. Transient transfection experiments were used to overexpress the HOTAIR, SP1 and EP4 genes. The interaction between HOTAIR and SP1 were further examined via RNA immunoprecipitation (RIP) assay. A tumor xenograft model was used to confirm the in vitro findings. RESULTS We showed that XJD inhibited growth and induced cell arrest of human non-small cell lung cancer (NSCLC) cells. We also found that XJD increased the phosphorylation of ERK1/2 and inhibited levels of HOTAIR and SP1, EP4 proteins, which were blocked by inhibitor of MEK/ERK. There was reciprocal interaction between HOTAIR and SP1. Silencing of HOTAIR reduced EP4 protein levels and repressed the growth of NSCLC cells, while overexpression of HOTAIR and SP1 overcame XJD-reduced EP4 protein expression. Additionally, excessive expressed EP4 reversed the effect of XJD on cell growth. Importantly, there was synergy of XJD with another cancer treatment drug, EGFR-TKI gefitinib, in this process. We also found that XJD inhibited tumor growth in a xenograft nude mice model. CONCLUSIONS Our results show that XJD inhibits NSCLC cell growth via ERK1/2-mediated reciprocal repression of HOTAIR and SP1 protein expression, followed by reduced EP4 gene expression. XJD and gefitinib exhibit synergy in this process. The in vitro and in vivo study provides a novel mechanism by which XJD enhances the growth inhibitory effect of gefitinib in gefitinib-resistant NSCLC cells.
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MESH Headings
- Animals
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/therapeutic use
- Carcinoma, Non-Small-Cell Lung/drug therapy
- Carcinoma, Non-Small-Cell Lung/genetics
- Carcinoma, Non-Small-Cell Lung/metabolism
- Cell Line, Tumor
- Drug Synergism
- Drugs, Chinese Herbal/pharmacology
- Drugs, Chinese Herbal/therapeutic use
- Female
- Gefitinib/pharmacology
- Gefitinib/therapeutic use
- Humans
- Lung Neoplasms/drug therapy
- Lung Neoplasms/genetics
- Lung Neoplasms/metabolism
- MAP Kinase Signaling System/drug effects
- Mice, Nude
- Protein Kinase Inhibitors/pharmacology
- Protein Kinase Inhibitors/therapeutic use
- RNA, Long Noncoding/physiology
- Receptors, Prostaglandin E, EP4 Subtype/physiology
- Sp1 Transcription Factor/physiology
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Affiliation(s)
- Jingjing Wu
- Laboratory of Tumor Biology, The Second Clinical Collage of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, 510120, China
| | - Qing Tang
- Laboratory of Tumor Biology, The Second Clinical Collage of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, 510120, China
| | - Xiaolin Ren
- Laboratory of Tumor Biology, The Second Clinical Collage of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, 510120, China
| | - Fang Zheng
- Laboratory of Tumor Biology, The Second Clinical Collage of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, 510120, China
| | - ChunXia He
- Department of Medical Oncology, Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical Collage of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, 510120, China
| | - XiaoSu Chai
- Department of Medical Oncology, Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical Collage of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, 510120, China
| | - Liuning Li
- Department of Medical Oncology, Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical Collage of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, 510120, China.
| | - Swei Sunny Hann
- Laboratory of Tumor Biology, The Second Clinical Collage of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, 510120, China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, The Second Clinical Collage of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, 510120, China.
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27
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Maehara O, Ohnishi S, Asano A, Suda G, Natsuizaka M, Nakagawa K, Kobayashi M, Sakamoto N, Takeda H. Metformin Regulates the Expression of CD133 Through the AMPK-CEBPβ Pathway in Hepatocellular Carcinoma Cell Lines. Neoplasia 2019; 21:545-556. [PMID: 31042624 PMCID: PMC6488768 DOI: 10.1016/j.neo.2019.03.007] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 03/14/2019] [Accepted: 03/15/2019] [Indexed: 02/07/2023]
Abstract
CD133 is a cellular surface protein, which has been reported to be a cancer stem cell marker, and thus is considered a potential target for cancer treatment. Metformin, one of the biguanides used for the treatment of diabetes, is also known to reduce the risk of cancer development and cancer stem-like cells (CSCs), including the expression of CD133. However, the mechanism underlying the reduction of the expression of CD133 by metformin is not yet understood. This study shows that metformin suppressed CD133 expression mainly by affecting the CD133 P1 promoter via adenosine monophosphate (AMP)-activated protein kinase (AMPK) signaling but not the mammalian target of rapamycin (mTOR). AMPK inhibition rescued the reduction of CD133 by metformin. Further experiments demonstrated that CCAAT/enhancer-binding protein beta (CEBPβ) was upregulated by metformin and that two isoforms of CEBPβ reciprocally regulated the expression of CD133. Specifically, the liver-enriched activator protein (LAP) isoform increased the expression of CD133 by directly binding to the P1 promoter region, whereas the liver-enriched inhibitory protein (LIP) isoform suppressed the expression of CD133. Consistent with these findings, a three dimensional (3D) culture assay and drug sensitivity assay demonstrated that LAP-overexpressing cells formed large spheroids and were more resistant to 5-fluorouracil (5-FU) treatment, whereas LIP-overexpressing cells were more sensitive to 5-FU and showed combined effects with metformin. Our results indicated that metformin-AMPK-CEBPβ signaling plays a crucial role in regulating the gene expression of CD133. Additionally, regulating the ratio of LAP/LIP may be a novel strategy for targeting CSCs for the treatment of cancer.
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Key Words
- acc, acetyl-coa-carboxylase
- ampk, amp-activated protein kinase
- csc, cancer stem-like cells
- cebpβ, ccaat/enhancer-binding protein beta
- dmem, dulbecco's modified eagle's medium
- facs, fluorescence activated cell sorting
- h&e, hematoxylin and eosin
- lap, liver-enriched activator protein
- lip, liver-enriched inhibitory protein
- sds, sodium dodecyl sulfate
- tbs, tris-buffered saline
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Affiliation(s)
- Osamu Maehara
- Department of Pathophysiology and Therapeutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
| | - Shunsuke Ohnishi
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
| | - Ayaka Asano
- Department of Pathophysiology and Therapeutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
| | - Goki Suda
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Mitsuteru Natsuizaka
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Koji Nakagawa
- Department of Pathophysiology and Therapeutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
| | - Masanobu Kobayashi
- Department of Nursing, Health Sciences University of Hokkaido, Tobetsu, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Hiroshi Takeda
- Department of Pathophysiology and Therapeutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
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Di R, Yang Z, Xu P, Xu Y. Silencing PDK1 limits hypoxia-induced pulmonary arterial hypertension in mice via the Akt/p70S6K signaling pathway. Exp Ther Med 2019; 18:699-704. [PMID: 31281449 DOI: 10.3892/etm.2019.7627] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2017] [Accepted: 06/15/2018] [Indexed: 12/16/2022] Open
Abstract
The present study aimed to investigate the effect of phosphoinositide-dependent protein kinase-1 (PDK1) on hypoxia-induced pulmonary arterial hypertension (PAH). A mouse model of hypoxia-induced PAH was generated using normal or PDK1-knockout mice. Histological analysis and hemodynamic evaluations were performed to identify the progression of PAH. The expression and phosphorylation of PDK1/protein kinase B (Akt) signaling pathway associated proteins were detected by western blot analysis. Increased lung vessel thickness, right ventricular (RV) systolic pressure (RVSP), RV hypertrophy index (RVHI) values [the RV weight-to-left ventricular (LV) plus septum (S) weight ratio] and PDK1 expression were observed in the hypoxia-induced PAH model compared with the normal control. The phosphorylation of AktT308, proline-rich Akt1 substrate 1 (PRAS40) and S6KT229 was also notably increased in the PAH model compared with the control. The changes of proteins were not observed in the hypoxia treated PDK1flox/+ : Tie2-Cre mice. Similarly, the RVSP and RVHI values, and PDK1 expression were reduced in the hypoxia treated PDK1flox/+: Tie2-Cre mice to a level comparable with those in the control, suggesting that PDK1 partial knockout significantly limited hypoxia-induced PAH. The results of the present study indicate that PDK1 is essential for hypoxia-induced PAH through the PDK1/Akt/S6K signaling cascades.
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Affiliation(s)
- Ruomin Di
- Department of Cardiology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, P.R. China
| | - Zhongzhou Yang
- MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, Jiangsu 210061, P.R. China
| | - Peng Xu
- Department of Cardiology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, P.R. China
| | - Yingjia Xu
- Department of Cardiology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, P.R. China
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29
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Yi Y, Zhang W, Yi J, Xiao ZX. Role of p53 Family Proteins in Metformin Anti-Cancer Activities. J Cancer 2019; 10:2434-2442. [PMID: 31258748 PMCID: PMC6584340 DOI: 10.7150/jca.30659] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Accepted: 04/23/2019] [Indexed: 12/13/2022] Open
Abstract
Metformin has been used as therapy for type 2 diabetes for many years. Clinical and basic evidence as indicated that metformin has anti-cancer activities. It has been well-established that metformin activates AMP-activated protein kinase (AMPK), which in turn regulates energy homeostasis. However, the mechanistic aspects of metformin anti-cancer activity remain elusive. p53 family proteins, including p53, p63 and p73, have diverse biological functions, including regulation of cell growth, survival, development, senescence and aging. In this review, we highlight the evidence and mechanisms by which metformin inhibits cancer cell survival and tumor growth. We also aimed to discuss the role of p53 family proteins in metformin-mediated suppression of cancer growth and survival.
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30
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Salaroglio IC, Mungo E, Gazzano E, Kopecka J, Riganti C. ERK is a Pivotal Player of Chemo-Immune-Resistance in Cancer. Int J Mol Sci 2019; 20:ijms20102505. [PMID: 31117237 PMCID: PMC6566596 DOI: 10.3390/ijms20102505] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Revised: 05/08/2019] [Accepted: 05/18/2019] [Indexed: 12/16/2022] Open
Abstract
The extracellular signal-related kinases (ERKs) act as pleiotropic molecules in tumors, where they activate pro-survival pathways leading to cell proliferation and migration, as well as modulate apoptosis, differentiation, and senescence. Given its central role as sensor of extracellular signals, ERK transduction system is widely exploited by cancer cells subjected to environmental stresses, such as chemotherapy and anti-tumor activity of the host immune system. Aggressive tumors have a tremendous ability to adapt and survive in stressing and unfavorable conditions. The simultaneous resistance to chemotherapy and immune system responses is common, and ERK signaling plays a key role in both types of resistance. In this review, we dissect the main ERK-dependent mechanisms and feedback circuitries that simultaneously determine chemoresistance and immune-resistance/immune-escape in cancer cells. We discuss the pros and cons of targeting ERK signaling to induce chemo-immune-sensitization in refractory tumors.
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Affiliation(s)
- Iris C Salaroglio
- Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy.
| | - Eleonora Mungo
- Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy.
| | - Elena Gazzano
- Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy.
| | - Joanna Kopecka
- Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy.
| | - Chiara Riganti
- Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy.
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31
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Bishnu A, Sakpal A, Ghosh N, Choudhury P, Chaudhury K, Ray P. Long term treatment of metformin impedes development of chemoresistance by regulating cancer stem cell differentiation through taurine generation in ovarian cancer cells. Int J Biochem Cell Biol 2018; 107:116-127. [PMID: 30593952 DOI: 10.1016/j.biocel.2018.12.016] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Revised: 12/20/2018] [Accepted: 12/25/2018] [Indexed: 12/16/2022]
Abstract
Development of resistance poses a significant challenge to effective first-line platinum based therapy for epithelial ovarian cancer patients. Cancer Stem Cells are envisaged as a critical underlying factor for therapy resistance. Thus, there is a critical need for developing approaches to diminish the enrichment of cancer stem cells and acquirement of resistance. Administration of metformin, a commonly prescribed drug against Type II diabetes exhibited promising effect in the management of ovarian cancer. However, the effect of long term administration of low dose of metformin as an adjuvant to cisplatin and paclitaxel during acquirement of chemoresistant phenotype has not been investigated so far. Using two isogenic cellular chemoresistant models (A2780 and OAW42) developed in the presence or absence of metformin, we demonstrated the ability of metformin to impede the development of resistance through increased drug sensitivity, increased proliferation, and reduced migratory abilities of the resistant cells. Metformin introduction also decreased the cancer stem cell population, expression of specific biomarkers and pluripotent genes. Further metabolic profiling of these cells using 1H-Nuclear Magnetic Resonance spectroscopy revealed significant modulation in taurine and histidine levels in resistant cells developed in the presence of metformin. Intriguingly, taurine treatment considerably reduced the cancer stem cell population and chemoresistance in resistant cells, indicating a novel role of taurine in differentiation of ovarian cancer stem cells. Altogether this is the first report on the potential role of metformin for targeting the cancer stem cell population via up regulation of taurine, leading to impediment in the acquirement of chemoresistance.
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Affiliation(s)
- Aniketh Bishnu
- Imaging Cell Signaling and Therapeutics Laboratory, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, 410210, India; Homi Bhabha National Institute, Mumbai, Anushakti Nagar, India
| | - Asmita Sakpal
- Imaging Cell Signaling and Therapeutics Laboratory, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, 410210, India; Homi Bhabha National Institute, Mumbai, Anushakti Nagar, India
| | - Nilanjana Ghosh
- Clinical Biomarker Research Laboratory, School of Medical Science and Technology, Indian Institute of Technology Kharagpur, West Bengal, 721302, India
| | - Priyanka Choudhury
- Clinical Biomarker Research Laboratory, School of Medical Science and Technology, Indian Institute of Technology Kharagpur, West Bengal, 721302, India
| | - Koel Chaudhury
- Clinical Biomarker Research Laboratory, School of Medical Science and Technology, Indian Institute of Technology Kharagpur, West Bengal, 721302, India
| | - Pritha Ray
- Imaging Cell Signaling and Therapeutics Laboratory, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, 410210, India; Homi Bhabha National Institute, Mumbai, Anushakti Nagar, India.
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32
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Xin M, Wang Y, Ren Q, Guo Y. Formononetin and metformin act synergistically to inhibit growth of MCF-7 breast cancer cells in vitro. Biomed Pharmacother 2018; 109:2084-2089. [PMID: 30551465 DOI: 10.1016/j.biopha.2018.09.033] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Revised: 09/02/2018] [Accepted: 09/05/2018] [Indexed: 01/29/2023] Open
Abstract
Many breast cancer patients suffer from obvious side effects induced by chemotherapy. Formononetin (FM), one kind ingredient of Chinese herbal medicine, has been suggested to inhibit MCF-7 breast cancer cells. And recently metformin (MET) has gained more attention as a potential anti-cancer drug. The aim of this study was to investigate the synergistic effects of FM and MET on the proliferation of MCF-7 cells and to clarify the possible molecular mechanism involved. MCF-7 cells were treated with various concentrations of FM (40 and 80 μM) or FM (40 and 80 μM) combined with MET (150 μM) for 48 h. Cell proliferation was tested by an methyl tetrazolium (MTT) (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide) assay. The percentage of apoptotic cells was measured by flow cytometry. The expression level of b-cell lymphoma/leukemia-2 (bcl-2) mRNA was examined by RT-PCR, while the expression levels of phosphorylated extracellular signal-regulated kinases (p-ERK1/2) and bcl-2 protein were detected by Western blotting. Compared with untreated cells, 40 μM and 80 μM FM efficiently inhibited proliferation and increased apoptosis in MCF-7 cells. Additionally, 40 μM and 80 μM FM greatly downregulated bcl-2 mRNA expression when compared with untreated cells. Furthermore, the protein expression of bcl-2 and p-ERK1/2 was significantly reduced by 40 μM and 80 μM FM. The cytotoxic effect of FM was more remarkable when 150 μM MET was added. Taken together, the combinational use of FM and MET enhanced cell growth inhibition, and the induction of apoptosis in MCF-7 cells mediated by the ERK1/2 signaling pathway.
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Affiliation(s)
- Min Xin
- Department of Physiology, Guilin Medical University, Guilin 541004, PR China
| | - Yong Wang
- Department of Physiology, Guilin Medical University, Guilin 541004, PR China; Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541004, PR China
| | - Qianyao Ren
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541004, PR China
| | - Yanhong Guo
- Department of Physiology, Guilin Medical University, Guilin 541004, PR China.
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33
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Chan MM, Chen R, Fong D. Targeting cancer stem cells with dietary phytochemical - Repositioned drug combinations. Cancer Lett 2018; 433:53-64. [PMID: 29960048 PMCID: PMC7117025 DOI: 10.1016/j.canlet.2018.06.034] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2018] [Revised: 06/11/2018] [Accepted: 06/25/2018] [Indexed: 12/21/2022]
Abstract
The tumor microenvironment is complex with the cancer stem cell (CSC) as a member within its community. This population possesses the capacity to self-renew and to cause cellular heterogeneity of the tumor. CSCs are resistant to conventional anti-proliferative drugs. In order to be curative, it is imperative that CSCs must be eliminated by cancer therapy. A variety of dietary phytochemicals and repositioned drugs can act synergistically with conventional anti-cancer agents. In this review, we advocate the development of a novel approach, namely combination therapy by incorporating both phytochemicals and repositioned drugs to target CSCs. We cover select dietary phytochemicals (curcumin, resveratrol, EGCG, genistein) and repurposed drugs (metformin, niclosamide, thioridazine, chloroquine). Five of the eight (curcumin, resveratrol, EGCG, genistein, metformin) are listed in "The Halifax Project", that explores "the concept of a low-toxicity 'broad-spectrum' therapeutic approach that could simultaneously target many key pathways and mechanisms" [1]. For these compounds, we discuss their mechanisms of action, in which models their anti-CSC activities were identified, as well as advantages, challenges and potentials of combination therapy.
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Affiliation(s)
- Marion M Chan
- Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, 3400 North Broad Street, Philadelphia, PA, 19140, USA.
| | - Rensa Chen
- Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, 3400 North Broad Street, Philadelphia, PA, 19140, USA; Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, 604 Allison Road, Piscataway, NJ, 08854, USA
| | - Dunne Fong
- Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, 604 Allison Road, Piscataway, NJ, 08854, USA.
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Abstract
Type 2 diabetes mellitus and cancer are correlated with changes in insulin signaling, a pathway that is frequently upregulated in neoplastic tissue but impaired in tissues that are classically targeted by insulin in type 2 diabetes mellitus. Many antidiabetes treatments, particularly metformin, enhance insulin signaling, but this pathway can be inhibited by specific cancer treatments. The modulation of cancer growth by metformin and of insulin sensitivity by anticancer drugs is so common that this phenomenon is being studied in hundreds of clinical trials on cancer. Many meta-analyses have consistently shown a moderate but direct effect of body mass index on the incidence of multiple myeloma and lymphoma and the elevated risk of leukemia in adults. Moreover, new epidemiological and preclinical studies indicate metformin as a therapeutic agent in patients with leukemia, lymphomas, and multiple myeloma. In this article, we review current findings on the anticancer activities of metformin and the underlying mechanisms from preclinical and ongoing studies in hematologic malignancies.
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35
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Feng Y, Guo X, Huang X, Wu M, Li X, Wu S, Luo X. Metformin reverses stem cell‑like HepG2 sphere formation and resistance to sorafenib by attenuating epithelial‑mesenchymal transformation. Mol Med Rep 2018; 18:3866-3872. [PMID: 30106125 PMCID: PMC6131649 DOI: 10.3892/mmr.2018.9348] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Accepted: 07/05/2018] [Indexed: 12/19/2022] Open
Abstract
Cancer stem cells (CSCs) have been reported to be associated with the recurrence and drug resistance of liver cancer. In the present study, stem cell-like HepG2 cell spheres were enriched using stem cell conditioned culture medium. As expected, stem-like HepG2 cell spheres exhibited increased resistance to sorafenib. Metformin, a common drug used to treat type 2 diabetes mellitus, reduced the diameters and numbers of stem-like HepG2 spheres, and increased their sensitivity to sorafenib. Western blotting confirmed that low doses of metformin reversed the epithelial-mesenchymal transformation (EMT) process of HepG2 spheres. These results suggested that metformin enhanced sensitivity to sorafenib, which was probably through reversal of the EMT process of sphere-forming cells and by reducing the formation of CSCs.
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Affiliation(s)
- Yan Feng
- Research Department, Affiliated Cancer Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Xing Guo
- Research Department, Affiliated Cancer Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Xinping Huang
- Research Department, Affiliated Cancer Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Manya Wu
- Research Department, Affiliated Cancer Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Xin Li
- Research Department, Affiliated Cancer Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Shushu Wu
- Research Department, Affiliated Cancer Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Xiaoling Luo
- Research Department, Affiliated Cancer Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
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36
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Lim W, Ham J, Bazer FW, Song G. Carvacrol induces mitochondria-mediated apoptosis via disruption of calcium homeostasis in human choriocarcinoma cells. J Cell Physiol 2018; 234:1803-1815. [PMID: 30070691 DOI: 10.1002/jcp.27054] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Accepted: 06/25/2018] [Indexed: 12/12/2022]
Abstract
Carvacrol is a monoterpenoid phenol present in the oils of various plants including Origanum vulgare (oregano) or Origanum majorana (marjoram). For a long time, it has been used as spice in foods because of its antimicrobial properties. Additionally, it appears to have anticancer effects against some cancer but this has not been well studied. Therefore, we conducted various assays to confirm the effects of carvacrol on choriocarcinoma cell lines (JAR and JEG3). Our results indicate that carvacrol has antiproliferative properties and induces apoptosis, resulting in increased expression of proapoptotic proteins. Additionally, carvacrol disrupted the mitochondrial membrane potential and induced calcium ion overload in the mitochondrial matrix in both JAR and JEG3 cells. Furthermore, carvacrol generated oxidative stress and lipid peroxidation in both JAR and JEG3 cells. Moreover, carvacrol-suppressed phosphoinositide 3-kinase-protein kinase B and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase (MAPK) signal transduction whereas expression of phosphor-P38 and c-Jun N-terminal kinase MAPK was increased. Together, our results indicate that carvacrol may be a possible new therapeutic agent or supplement for the control of human choriocarcinomas.
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Affiliation(s)
- Whasun Lim
- Department of Biomedical Sciences, Catholic Kwandong University, Gangneung, Republic of Korea
| | - Jiyeon Ham
- Department of Biotechnology, Institute of Animal Molecular Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
| | - Fuller W Bazer
- Department of Animal Science, Center for Animal Biotechnology and Genomics, Texas A&M University, College Station, Texas
| | - Gwonhwa Song
- Department of Biotechnology, Institute of Animal Molecular Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
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37
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Subramaniam D, Kaushik G, Dandawate P, Anant S. Targeting Cancer Stem Cells for Chemoprevention of Pancreatic Cancer. Curr Med Chem 2018; 25:2585-2594. [PMID: 28137215 DOI: 10.2174/0929867324666170127095832] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2016] [Revised: 12/17/2016] [Accepted: 12/17/2016] [Indexed: 02/06/2023]
Abstract
Pancreatic ductal adenocarcinoma is one of the deadliest cancers worldwide and the fourth leading cause of cancer-related deaths in United States. Regardless of the advances in molecular pathogenesis and consequential efforts to suppress the disease, this cancer remains a major health problem in United States. By 2030, the projection is that pancreatic cancer will be climb up to be the second leading cause of cancer-related deaths in the United States. Pancreatic cancer is a rapidly invasive and highly metastatic cancer, and does not respond to standard therapies. Emerging evidence supports that the presence of a unique population of cells called cancer stem cells (CSCs) as potential cancer inducing cells and efforts are underway to develop therapeutic strategies targeting these cells. CSCs are rare quiescent cells, and with the capacity to self-renew through asymmetric/symmetric cell division, as well as differentiate into various lineages of cells in the cancer. Studies have been shown that CSCs are highly resistant to standard therapy and also responsible for drug resistance, cancer recurrence and metastasis. To overcome this problem, we need novel preventive agents that target these CSCs. Natural compounds or phytochemicals have ability to target these CSCs and their signaling pathways. Therefore, in the present review article, we summarize our current understanding of pancreatic CSCs and their signaling pathways, and the phytochemicals that target these cells including curcumin, resveratrol, tea polyphenol EGCG (epigallocatechin- 3-gallate), crocetinic acid, sulforaphane, genistein, indole-3-carbinol, vitamin E δ- tocotrienol, Plumbagin, quercetin, triptolide, Licofelene and Quinomycin. These natural compounds or phytochemicals, which inhibit cancer stem cells may prove to be promising agents for the prevention and treatment of pancreatic cancers.
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Affiliation(s)
- Dharmalingam Subramaniam
- Department of Surgery, the University of Kansas Medical Center, Kansas City, KS 66160, United States.,The University of Kansas Cancer Center, The University of Kansas Medical Center, Kansas City, KS 66160, United States
| | - Gaurav Kaushik
- Department of Surgery, the University of Kansas Medical Center, Kansas City, KS 66160, United States
| | - Prasad Dandawate
- Department of Surgery, the University of Kansas Medical Center, Kansas City, KS 66160, United States
| | - Shrikant Anant
- Department of Surgery, the University of Kansas Medical Center, Kansas City, KS 66160, United States.,The University of Kansas Cancer Center, The University of Kansas Medical Center, Kansas City, KS 66160, United States
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38
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Lin J, Cao S, Wang Y, Hu Y, Liu H, Li J, Chen J, Li P, Liu J, Wang Q, Zheng L. Long non-coding RNA UBE2CP3 enhances HCC cell secretion of VEGFA and promotes angiogenesis by activating ERK1/2/HIF-1α/VEGFA signalling in hepatocellular carcinoma. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2018; 37:113. [PMID: 29866133 PMCID: PMC5987644 DOI: 10.1186/s13046-018-0727-1] [Citation(s) in RCA: 93] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Accepted: 03/06/2018] [Indexed: 12/19/2022]
Abstract
Background Angiogenesis is considered as an important process in the development of malignancies and is associated with cancer progression and metastasis. Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver and is recognized as a typical angiogenic tumor. Thus, it is of great importance to study the underlying mechanism of angiogenesis in HCC. The long non-coding RNA (lncRNA) ubiquitin conjugating enzyme E2C pseudogene 3 (UBE2CP3) has been reported as an oncogene that promotes tumor metastasis in HCC. However, the role and underlying mechanisms of UBE2CP3 in HCC angiogenesis are still unclear. Methods We measured the expression levels of UBE2CP3 by in situ hybridization (ISH) and quantitative real-time polymerase chain reaction (qRT-PCR) in HCC patient samples. We also concomitantly used CD31/PAS double-staining to measure endothelial vessel (EV) density and used qRT-PCR to measure the CD31 mRNA level. HepG2 and SMMC-7721 cells were transfected with Lv-UBE2CP3 or Sh-UBE2CP3 virus to obtain stably over-expressing or knocking-down UBE2CP3 cell lines. The indirect effects of UBE2CP3 on ECs were studied by establishing a co-culture system using Transwell chambers with a 0.4-μm pore size. HCC cells and ECs in the co-culture system were separated, but the cytokines and growth factors were able to communicate with each other. Following exposed to HCC cells, ECs were collected for functional studies. Finally, we studied the function of UBE2CP3 in vivo by chick embryo chorioallantoic membrane (CAM) angiogenesis assays and nude mouse tumorigenicity assays. Results In this study, we found that UBE2CP3 expression was higher in HCC tissues than in para-tumor tissues and was up-regulated in tissues with high EV density. Functionally, we found that in the co-culture systems, HCC cells overexpressing UBE2CP3 promoted HUVEC proliferation, migration and tube formation via the activation of ERK/HIF-1α/p70S6K/VEGFA signalling, increasing the level of VEGFA in HCC cell supernatant. In addition, the opposite results appeared when the expression of UBE2CP3 in HCC cells was knocked down. Consistent with these results, CAM angiogenesis assays and nude mouse tumorigenicity assays showed that UBE2CP3 expression up-regulated EV density in vivo. Conclusion Our study suggests that UBE2CP3 can enhance the interaction between HCC tumor cells and HUVECs and promote HCC tumorigenicity by facilitating angiogenesis. Electronic supplementary material The online version of this article (10.1186/s13046-018-0727-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Jinduan Lin
- Department of Laboratory Medicine Center, Nanfang Hospital, Southern Medical University/The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China.,Department of Clinical Laboratory, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, Guangdong, China
| | - Shunwang Cao
- Department of Laboratory Medicine Center, Nanfang Hospital, Southern Medical University/The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Yu Wang
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University/The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Yanwei Hu
- Department of Laboratory Medicine Center, Nanfang Hospital, Southern Medical University/The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Hongwei Liu
- Department of Clinical Laboratory, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, Guangdong, China
| | - Jiehua Li
- Department of Clinical Laboratory, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, Guangdong, China
| | - Jing Chen
- Department of Laboratory Medicine Center, Nanfang Hospital, Southern Medical University/The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Pan Li
- Department of Laboratory Medicine Center, Nanfang Hospital, Southern Medical University/The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Jumei Liu
- Department of Laboratory Medicine Center, Nanfang Hospital, Southern Medical University/The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Qian Wang
- Department of Laboratory Medicine Center, Nanfang Hospital, Southern Medical University/The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China.
| | - Lei Zheng
- Department of Laboratory Medicine Center, Nanfang Hospital, Southern Medical University/The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China.
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Liu GM, Zhang YM. Targeting FBPase is an emerging novel approach for cancer therapy. Cancer Cell Int 2018; 18:36. [PMID: 29556139 PMCID: PMC5845355 DOI: 10.1186/s12935-018-0533-z] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Accepted: 03/05/2018] [Indexed: 02/06/2023] Open
Abstract
Cancer is a leading cause of death in both developed and developing countries. Metabolic reprogramming is an emerging hallmark of cancer. Glucose homeostasis is reciprocally controlled by the catabolic glycolysis and anabolic gluconeogenesis pathways. Previous studies have mainly focused on catabolic glycolysis, but recently, FBPase, a rate-limiting enzyme in gluconeogenesis, was found to play critical roles in tumour initiation and progression in several cancer types. Here, we review recent ideas and discoveries that illustrate the clinical significance of FBPase expression in various cancers, the mechanism through which FBPase influences cancer, and the mechanism of FBPase silencing. Furthermore, we summarize some of the drugs targeting FBPase and discuss their potential use in clinical applications and the problems that remain unsolved.
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Affiliation(s)
- Gao-Min Liu
- Department of Hepatobiliary Surgery, Meizhou People's Hospital, No. 38 Huangtang Road, Meizhou, 514000 China
| | - Yao-Ming Zhang
- Department of Hepatobiliary Surgery, Meizhou People's Hospital, No. 38 Huangtang Road, Meizhou, 514000 China
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40
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Yang SH, Li S, Lu G, Xue H, Kim DH, Zhu JJ, Liu Y. Metformin treatment reduces temozolomide resistance of glioblastoma cells. Oncotarget 2018; 7:78787-78803. [PMID: 27791206 PMCID: PMC5346677 DOI: 10.18632/oncotarget.12859] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Accepted: 10/14/2016] [Indexed: 12/12/2022] Open
Abstract
It has been reported that metformin acts synergistically with temozolomide (TMZ) to inhibit proliferation of glioma cells including glioblastoma multiforme (GBM). However, the molecular mechanism underlying how metformin exerts its anti-cancer effects remains elusive. We used a combined experimental and bioinformatics approach to identify genes and complex regulatory/signal transduction networks that are involved in restoring TMZ sensitivity of GBM cells after metformin treatment. First, we established TMZ resistant GBM cell lines and found that the resistant cells regained TMZ sensitivity after metformin treatment. We further identified that metformin down-regulates SOX2 expression in TMZ-resistant glioma cells, reduces neurosphere formation capacity of glioblastoma cells, and inhibits GBM xenograft growth in vivo. Finally, the global gene expression profiling data reveals that multiple pathways are involved in metformin treatment related gene expression changes, including fatty acid metabolism and RNA binding and splicing pathways. Our work provided insight of the mechanisms on potential synergistic effects of TMZ and metformin in the treatment of glioblastoma, which will in turn yield potentially translational value for clinical applications.
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Affiliation(s)
- Seung Ho Yang
- Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA.,Department of Neurosurgery, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, South Korea.,Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Shenglan Li
- Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA.,Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Guangrong Lu
- Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Haipeng Xue
- Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA.,Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Dong H Kim
- Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA.,Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Jay-Jiguang Zhu
- Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Ying Liu
- Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA.,Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA
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41
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Chen L, Xue Y, Zheng J, Liu X, Liu J, Chen J, Li Z, Xi Z, Teng H, Wang P, Liu L, Liu Y. MiR-429 Regulated by Endothelial Monocyte Activating Polypeptide-II (EMAP-II) Influences Blood-Tumor Barrier Permeability by Inhibiting the Expressions of ZO-1, Occludin and Claudin-5. Front Mol Neurosci 2018; 11:35. [PMID: 29467620 PMCID: PMC5808301 DOI: 10.3389/fnmol.2018.00035] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Accepted: 01/25/2018] [Indexed: 11/17/2022] Open
Abstract
The blood-tumor barrier (BTB) hinders delivery of chemotherapeutic drugs to tumors in the brain; previous studies have shown that the BTB can be selectively opened by endothelial monocyte activating polypeptide-II (EMAP-II), but the specific mechanism involved remains elusive. In this study, we found that microRNA-429 (miR-429) expression in glioma vascular endothelial cells (GECs) was far lower than in human brain microvascular endothelial cells (ECs). miR-429 had lower expression in GECs and glioma tissues compared to ECs or normal tissues of the brain. Furthermore, miR-429 had lower expression in high grade glioma (HGG) than in low grade glioma (LGG). In in vitro BTB models, we also found that EMAP-II significantly increased BTB permeability, decreased expression of ZO-1, occludin and claudin-5 in GECs, in a time- and dose-dependent manner. EMAP-II greatly increased miR-429 expression in GECs of the BTB models in vitro. Overexpression of miR-429 in GECs significantly decreased the transepithelial electric resistance (TEER) values in BTB models, and led to enhanced horseradish peroxidase (HRP) flux. Overexpression of miR-429 in GECs significantly decreased the expression of tight junction (TJ)-associated proteins (ZO-1, occludin and claudin-5), and decreased the distribution continuity. Silencing of miR-429 in GECs increased the expression of TJ-associated proteins and the distribution continuity. The dual-luciferase reporter assay revealed that ZO-1 and occludin were target genes of miR-429, and we demonstrated that miR-429 overexpression markedly down-regulated protein expression of p70S6K, as well as its phosphorylation levels. The dual-luciferase reporter assay also showed that p70S6K was a target gene of miR-429; miR-429 overexpression down-regulated expression and phosphorylation levels of p70S6K, and also decreased phosphorylation levels of S6 and increased BTB permeability. Conversely, silencing of miR-429 increased the expression and phosphorylation levels of p70S6K, and increased phosphorylation levels of S6, while decreasing BTB permeability. In conclusion, the results indicated that EMAP-II caused an increase in miR-429 expression that directly targeted TJ-associated proteins, which were negatively regulated; on the other hand, miR-429 down-regulated the expression of TJ-associated proteins by targeting p70S6K, also negatively regulated. As a result, the BTB permeability increased.
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Affiliation(s)
- Liangyu Chen
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, China.,Liaoning Clinical Medical Research Center in Nervous System Disease, Shenyang, China.,Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang, China
| | - Yixue Xue
- Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang, China.,Key Laboratory of Cell Biology, Ministry of Public Health of China, China Medical University, Shenyang, China.,Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang, China
| | - Jian Zheng
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, China.,Liaoning Clinical Medical Research Center in Nervous System Disease, Shenyang, China.,Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang, China
| | - Xiaobai Liu
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, China.,Liaoning Clinical Medical Research Center in Nervous System Disease, Shenyang, China.,Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang, China
| | - Jing Liu
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, China.,Liaoning Clinical Medical Research Center in Nervous System Disease, Shenyang, China.,Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang, China
| | - Jiajia Chen
- Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang, China.,Key Laboratory of Cell Biology, Ministry of Public Health of China, China Medical University, Shenyang, China.,Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang, China
| | - Zhen Li
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, China.,Liaoning Clinical Medical Research Center in Nervous System Disease, Shenyang, China.,Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang, China
| | - Zhuo Xi
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, China.,Liaoning Clinical Medical Research Center in Nervous System Disease, Shenyang, China.,Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang, China
| | - Hao Teng
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, China.,Liaoning Clinical Medical Research Center in Nervous System Disease, Shenyang, China.,Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang, China
| | - Ping Wang
- Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang, China.,Key Laboratory of Cell Biology, Ministry of Public Health of China, China Medical University, Shenyang, China.,Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang, China
| | - Libo Liu
- Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang, China.,Key Laboratory of Cell Biology, Ministry of Public Health of China, China Medical University, Shenyang, China.,Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang, China
| | - Yunhui Liu
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, China.,Liaoning Clinical Medical Research Center in Nervous System Disease, Shenyang, China.,Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang, China
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Duan Q, Zhao H, Zhang Z, Li H, Wu H, Shen Q, Wang C, Yin T. Mechanistic Evaluation and Translational Signature of Gemcitabine-induced Chemoresistance by Quantitative Phosphoproteomics Analysis with iTRAQ Labeling Mass Spectrometry. Sci Rep 2017; 7:12891. [PMID: 29018223 PMCID: PMC5634998 DOI: 10.1038/s41598-017-13330-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 09/21/2017] [Indexed: 12/19/2022] Open
Abstract
One of the main causations of the poor prognosis of pancreatic cancer is the lack of effective chemotherapies. Gemcitabine is a widely used chemotherapeutic drug, but limited therapeutic efficacy is achieved due to chemoresistance. Recent studies demonstrated that the presence of cancer stem cells may lead to the failure of chemotherapy. Moreover, gemcitabine can promote the stemness of pancreatic cancer cells. We detected the alterations in protein phosphorylation and signaling pathways in pancreatic cancer cells after gemcitabine treatment using iTRAQ labeling LC-MS/MS, because it was featured with the advantages of strong separation ability and analysis range. A total of 232 differentially expressed phosphorylated proteins were identified in this study. Gene Ontology analysis revealed that nuclear lumen, nuclear part and organelle lumen were enriched for cell components and protein binding, poly (A) RNA binding and RNA binding were enriched for molecular function. A variety of signaling pathways were enriched based on KEGG analysis. AMPK, mTOR and PI3K/Akt pathways were verified after gemcitabine exposure. Moreover, we found there were complex interactions of phosphorylated proteins in modulating cancer stemness induced by gemcitabine exposure based on PPIs map. Our experiments may identify potential targets and strategies for sensitizing pancreatic cancer cells to gemcitabine.
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Affiliation(s)
- Qingke Duan
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Hengqiang Zhao
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Zhengle Zhang
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Hehe Li
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Heshui Wu
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Qiang Shen
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Chunyou Wang
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Tao Yin
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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43
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Li T, Sun X, Jiang X. UCA1 involved in the metformin-regulated bladder cancer cell proliferation and glycolysis. Tumour Biol 2017. [PMID: 28641488 DOI: 10.1177/1010428317710823] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Despite great scientific advances have been achieved in cancer treatment in recent years, the death rate of bladder cancer has been staying at a high level. Metformin, a widely-used and low-cost diabetes medicine, might have the potential of anticancer. The aim of this study was to evaluate the effects of metformin on bladder cancer cells and to identify potential molecular targets and signaling pathways. Bladder cancer 5637 cells transfected with either pcDNA/UCA1 vector or pcDNA3.1 empty vector were treated with various doses of metformin for different periods of time, and then cell proliferation and glycolysis were assessed. Reverse transcription polymerase chain reaction and Western blotting were applied to examine the expression of long non-coding RNA UCA1 and mammalian target of rapamycin-signal transducer and activator of transcription pathway molecules. We found metformin inhibited bladder cancer cell proliferation in a dose- and time-dependent manner. UCA1-overexpressed 5637 cells showed increased proliferation and glycolysis compared with control cells. Metformin downregulated both endogenous and exogenous UCA1 expression, leading to the inhibition of mammalian target of rapamycin-signal transducer and activator of transcription 3-hexokinase 2 signaling pathway. Our study provided the first evidence that metformin inhibited proliferation and glycolysis in cancer cells through regulation of long non-coding RNA UCA1. The discovery also suggested the important roles of long non-coding RNA in chemoprevention, which is a property of metformin.
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Affiliation(s)
- Tian Li
- 1 Department of Urology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,2 Minimally Invasive Technique and Product Translational Center, Guangzhou Medical University, Guangzhou, China
| | - Xiangzhou Sun
- 3 Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xianhan Jiang
- 1 Department of Urology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,2 Minimally Invasive Technique and Product Translational Center, Guangzhou Medical University, Guangzhou, China
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44
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Zechner D, Albert AC, Bürtin F, Vollmar B. Metformin Inhibits Gemcitabine Induced Apoptosis in Pancreatic Cancer Cell Lines. J Cancer 2017; 8:1744-1749. [PMID: 28819370 PMCID: PMC5556636 DOI: 10.7150/jca.17972] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Accepted: 02/24/2017] [Indexed: 12/17/2022] Open
Abstract
Many preclinical and clinical studies are currently evaluating metformin in combination with classical therapeutic agents as anti-cancer therapy. In this study we used three distinct pancreatic cancer cell lines and evaluated cell death by trypan blue assay and Western Blots using antibodies directed against cleaved caspase 3 and PARP. Surprisingly, we observed that 20mM metformin did not enhance, but rather inhibited gemcitabine induced cell death in murine 7265PDA, 6606PDA and 6606l cells. Microenvironmental aspects such as oxygen supply or the pH value did not influence the inhibition of cancer cell apoptosis by metformin. Glucose concentration in the medium, however, had a major effect on the impact of metformin. Medium with 0.5g/L glucose strongly increased metformin induced apoptosis and also prevented the inhibitory effect of metformin on gemcitabine induced cell apoptosis, when compared with medium containing 4.5g/L glucose. We conclude that the combination of metformin with gemcitabine has inappropriate effects for a successful treatment of pancreatic cancer. Thus, it might be more promising to use metformin in combination with other drugs that reduce the uptake or the metabolism of glucose.
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Affiliation(s)
- Dietmar Zechner
- Institute for Experimental Surgery, Rostock University Medical Center, Schillingallee 69a, 18057 Rostock, Germany
| | - Ann-Christin Albert
- Institute for Experimental Surgery, Rostock University Medical Center, Schillingallee 69a, 18057 Rostock, Germany
| | - Florian Bürtin
- Institute for Experimental Surgery, Rostock University Medical Center, Schillingallee 69a, 18057 Rostock, Germany
| | - Brigitte Vollmar
- Institute for Experimental Surgery, Rostock University Medical Center, Schillingallee 69a, 18057 Rostock, Germany
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45
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Molenaar RJ, Coelen RJS, Khurshed M, Roos E, Caan MWA, van Linde ME, Kouwenhoven M, Bramer JAM, Bovée JVMG, Mathôt RA, Klümpen HJ, van Laarhoven HWM, van Noorden CJF, Vandertop WP, Gelderblom H, van Gulik TM, Wilmink JW. Study protocol of a phase IB/II clinical trial of metformin and chloroquine in patients with IDH1-mutated or IDH2-mutated solid tumours. BMJ Open 2017; 7:e014961. [PMID: 28601826 PMCID: PMC5541450 DOI: 10.1136/bmjopen-2016-014961] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
INTRODUCTION High-grade chondrosarcoma, high-grade glioma and intrahepatic cholangiocarcinoma are aggressive types of cancer with a dismal outcome. This is due to the lack of effective treatment options, emphasising the need for novel therapies. Mutations in the genes IDH1 and IDH2 (isocitrate dehydrogenase 1 and 2) occur in 60% of chondrosarcoma, 80% of WHO grade II-IV glioma and 20% of intrahepatic cholangiocarcinoma. IDH1/2-mutated cancer cells produce the oncometabolite D-2-hydroxyglutarate (D-2HG) and are metabolically vulnerable to treatment with the oral antidiabetic metformin and the oral antimalarial drug chloroquine. METHODS AND ANALYSIS We describe a dose-finding phase Ib/II clinical trial, in which patients with IDH1/2-mutated chondrosarcoma, glioma and intrahepatic cholangiocarcinoma are treated with a combination of metformin and chloroquine. Dose escalation is performed according to a 3+3 dose-escalation scheme. The primary objective is to determine the maximum tolerated dose to establish the recommended dose for a phase II clinical trial. Secondary objectives of the study include (1) determination of pharmacokinetics and toxic effects of the study therapy, for which metformin and chloroquine serum levels will be determined over time; (2) investigation of tumour responses to metformin plus chloroquine in IDH1/2-mutated cancers using CT/MRI scans; and (3) whether tumour responses can be measured by non-invasive D-2HG measurements (mass spectrometry and magnetic resonance spectroscopy) of tumour tissue, serum, urine, and/or bile or next-generation sequencing of circulating tumour DNA (liquid biopsies). This study may open a novel treatment avenue for IDH1/2-mutated high-grade chondrosarcoma, glioma and intrahepatic cholangiocarcinoma by repurposing the combination of two inexpensive drugs that are already approved for other indications. ETHICS AND DISSEMINATION This study has been approved by the medical-ethical review committee of the Academic Medical Center, Amsterdam, The Netherlands. The report will be submitted to a peer-reviewed journal. TRIAL REGISTRATION NUMBER This article was registered at ClinicalTrials.gov identifier (NCT02496741): Pre-results.
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Affiliation(s)
- Remco J Molenaar
- Department of Medical Oncology, University of Amsterdam, Meibergdreef, Amsterdam, The Netherlands
- Department of Medical Biology, University of Amsterdam, Meibergdreef, Amsterdam, The Netherlands
| | - Robert JS Coelen
- Department of Experimental Surgery, University of Amsterdam, Meibergdreef, Amsterdam, The Netherlands
| | - Mohammed Khurshed
- Department of Medical Oncology, University of Amsterdam, Meibergdreef, Amsterdam, The Netherlands
- Department of Medical Biology, University of Amsterdam, Meibergdreef, Amsterdam, The Netherlands
| | - Eva Roos
- Department of Experimental Surgery, University of Amsterdam, Meibergdreef, Amsterdam, The Netherlands
| | - Matthan WA Caan
- Department of Radiology, University of Amsterdam, Meibergdreef, Amsterdam, The Netherlands
| | - Myra E van Linde
- Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands
| | - Mathilde Kouwenhoven
- Department of Neurology, VU University Medical Centre, Amsterdam, The Netherlands
| | - Jos AM Bramer
- Department of Orthopaedic Surgery, University of Amsterdam, Meibergdreef, Amsterdam, The Netherlands
- Department of Neurosurgery, Academic Medical Centre, University of Amsterdam, Meibergdreef, Amsterdam, The Netherlands
| | - Judith VMG Bovée
- Department of Medical Oncology, University of Amsterdam, Meibergdreef, Amsterdam, The Netherlands
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
| | - Ron A Mathôt
- Department of Clinical Pharmacology, University of Amsterdam, Meibergdreef, Amsterdam, The Netherlands
| | - Heinz-Josef Klümpen
- Department of Medical Oncology, University of Amsterdam, Meibergdreef, Amsterdam, The Netherlands
| | - Hanneke WM van Laarhoven
- Department of Medical Oncology, University of Amsterdam, Meibergdreef, Amsterdam, The Netherlands
| | - Cornelis JF van Noorden
- Department of Medical Biology, University of Amsterdam, Meibergdreef, Amsterdam, The Netherlands
| | - W Peter Vandertop
- Department of Neurosurgery, Academic Medical Centre, University of Amsterdam, Meibergdreef, Amsterdam, The Netherlands
- Department of Neurosurgery, VU University Medical Centre, Amsterdam, The Netherlands
| | - Hans Gelderblom
- Department of Medical Oncology, VU University Medical Centre, Amsterdam, The Netherlands
| | - Thomas M van Gulik
- Department of Experimental Surgery, University of Amsterdam, Meibergdreef, Amsterdam, The Netherlands
| | - Johanna W Wilmink
- Department of Medical Oncology, University of Amsterdam, Meibergdreef, Amsterdam, The Netherlands
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Metformin increases chemo-sensitivity via gene downregulation encoding DNA replication proteins in 5-Fu resistant colorectal cancer cells. Oncotarget 2017; 8:56546-56557. [PMID: 28915611 PMCID: PMC5593582 DOI: 10.18632/oncotarget.17798] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 04/27/2017] [Indexed: 12/16/2022] Open
Abstract
Metformin is most widely prescribed for type 2 diabetes. Recently, evidences have shown that metformin has anticancer effects on pancreatic-, colorectal-, ovarian-, and other cancers. Because metformin has less adverse effects and is inexpensive, it could be a useful chemo-therapeutic agent with anticancer effects. In this study, we demonstrated metformin inhibited by cell proliferation, cell migration ability, clonogenic ability, and cancer stem cell population. Metformin also induced cell cycle arrest in parental-(SNU-C5), and 5-Fu resistant-colorectal cancer cell line (SNU-C5_5FuR). Moreover, a treatment that combines 5-Fu and metformin was found to have a synergistic effect on the cell proliferation rate, especially in SNU-C5_5FuR, which was mediated by the activation of AMPK pathway and NF-ƙB pathway, well-known metformin mechanisms. In this study, we suggested novel anticancer mechanism of metformin that inhibited DNA replication machinery, such as the MCM family in SNU-C5_5FuR. In conclusion, we provided that how metformin acts as not only a chemo-sensitizer, but also as a synergistic effector of 5-Fu in the 5-Fu resistant-cell line. We speculate that metformin used for adjuvant therapy is effective on 5-Fu resistant cancer cells.
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47
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Candelaria PV, Rampoldi A, Harbuzariu A, Gonzalez-Perez RR. Leptin signaling and cancer chemoresistance: Perspectives. World J Clin Oncol 2017; 8:106-119. [PMID: 28439492 PMCID: PMC5385432 DOI: 10.5306/wjco.v8.i2.106] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2016] [Revised: 12/20/2016] [Accepted: 03/02/2017] [Indexed: 02/06/2023] Open
Abstract
Obesity is a major health problem and currently is endemic around the world. Obesity is a risk factor for several different types of cancer, significantly promoting cancer incidence, progression, poor prognosis and resistance to anti-cancer therapies. The study of this resistance is critical as development of chemoresistance is a serious drawback for the successful and effective drug-based treatments of cancer. There is increasing evidence that augmented adiposity can impact on chemotherapeutic treatment of cancer and the development of resistance to these treatments, particularly through one of its signature mediators, the adipokine leptin. Leptin is a pro-inflammatory, pro-angiogenic and pro-tumorigenic adipokine that has been implicated in many cancers promoting processes such as angiogenesis, metastasis, tumorigenesis and survival/resistance to apoptosis. Several possible mechanisms that could potentially be developed by cancer cells to elicit drug resistance have been suggested in the literature. Here, we summarize and discuss the current state of the literature on the role of obesity and leptin on chemoresistance, particularly as it relates to breast and pancreatic cancers. We focus on the role of leptin and its significance in possibly driving these proposed chemoresistance mechanisms, and examine its effects on cancer cell survival signals and expansion of the cancer stem cell sub-populations.
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48
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Combination of metformin with chemotherapeutic drugs via different molecular mechanisms. Cancer Treat Rev 2017; 54:24-33. [DOI: 10.1016/j.ctrv.2017.01.005] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Revised: 01/09/2017] [Accepted: 01/11/2017] [Indexed: 12/23/2022]
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49
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Imada K, Shiota M, Kuroiwa K, Sugimoto M, Abe T, Kohashi K, Yokomizo A, Eto M, Naito S, Oda Y. FOXO3a Expression Regulated by ERK Signaling is Inversely Correlated With Y-Box Binding Protein-1 Expression in Prostate Cancer. Prostate 2017; 77:145-153. [PMID: 27699813 DOI: 10.1002/pros.23254] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2016] [Accepted: 08/29/2016] [Indexed: 12/13/2022]
Abstract
BACKGROUND FOXO3a is a member of the forkhead O transcription factors. FOXO3a induces the factors that contribute to cell cycle arrest and is considered a tumor suppressor in several malignant tumors. Y-box binding protein-1 (YB-1) is a multifunctional protein whose high expression is correlated with poor prognoses in various malignant tumors. In the current study, we investigated the relationship between FOXO3a and YB-1 to validate their functional roles in prostate cancer. METHODS Western blotting and cytotoxicity assays were conducted in prostate cancer cells, LNCaP, and 22Rv1 cells. We also evaluated the protein expressions of FOXO3a and YB-1 in human prostate cancer tissues, using radical prostatectomy specimens. Then, we investigated the correlations between protein expressions and clinicopathologic parameters. RESULTS We found that both FOXO3a and YB-1 proteins were phosphorylated by ERK signaling, resulting in FOXO3a inactivation and YB-1 activation in LNCaP and 22Rv1 cells. Inversely, inhibition of MEK or treatment with metformin activated FOXO3a through inactivation of ERK signaling and suppressed the viability of LNCaP and 22Rv1 cells in a dose-dependent manner. In immunohistochemical analysis, FOXO3a nuclear expression was inversely correlated with YB-1 nuclear expression (P < 0.0001). Furthermore, high FOXO3a nuclear expression was inversely correlated with a higher Gleason grade (P < 0.0001) and higher preoperative PSA (P = 0.0437). CONCLUSIONS These results showed that in prostate cancer, FOXO3a, and YB-1 play inverse reciprocal roles as a tumor-suppressor gene and oncogene, respectively, through their master regulator ERK. Prostate 77:145-153, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Kenjiro Imada
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masaki Shiota
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kentaro Kuroiwa
- Department of Urology, Miyazaki Prefectural Miyazaki Hospital, Miyazaki, Japan
| | - Masaaki Sugimoto
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tatsuro Abe
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kenichi Kohashi
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Akira Yokomizo
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masatoshi Eto
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Seiji Naito
- Division of Urology, Harasanshin General Hospital, Fukuoka, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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50
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Zhao YD, Zhang QB, Chen H, Fei XF, Shen YT, Ji XY, Ma JW, Wang AD, Dong J, Lan Q, Huang Q. Research on human glioma stem cells in China. Neural Regen Res 2017; 12:1918-1926. [PMID: 29239340 PMCID: PMC5745848 DOI: 10.4103/1673-5374.219055] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Research on human glioma stem cells began early in the 21st century and since then has become a rapidly growing research field with the number of publications increasing year by year. The research conducted by our diverse group of investigators focused primarily on cell culture techniques, molecular regulation, signaling pathways, cancer treatment, the stem cell microenvironment and the cellular origin and function of glioma stem cells. In particular, we put forward our view that there are inverse or forward transformations among neural stem cells, glial cells and glioma stem cells in glioma tissues under certain conditions. Based on the background of the progress of international research on human glioma stem cells, we aim to share our progress and current findings of human glioma stem cell research in China with colleagues around the world.
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Affiliation(s)
- Yao-Dong Zhao
- Department of Neurosurgery and Brain Tumor Research Laboratory, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province; Shanghai General Hospital, Shanghai, China
| | - Quan-Bin Zhang
- Department of Neurosurgery and Brain Tumor Research Laboratory, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province; Shanghai 10th People's Hospital, Shanghai, China
| | - Hua Chen
- Department of Neurosurgery and Brain Tumor Research Laboratory, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province; Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Xi-Feng Fei
- Department of Neurosurgery and Brain Tumor Research Laboratory, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province; Suzhou Kowloon Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yun-Tian Shen
- Department of Neurosurgery and Brain Tumor Research Laboratory, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Xiao-Yan Ji
- Department of Neurosurgery and Brain Tumor Research Laboratory, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Jia-Wei Ma
- Department of Neurosurgery and Brain Tumor Research Laboratory, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Ai-Dong Wang
- Department of Neurosurgery and Brain Tumor Research Laboratory, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Jun Dong
- Department of Neurosurgery and Brain Tumor Research Laboratory, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Qing Lan
- Department of Neurosurgery and Brain Tumor Research Laboratory, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Qiang Huang
- Department of Neurosurgery and Brain Tumor Research Laboratory, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
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