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Metformin Cancer Stem Cells

Response Of Breast Cancer Cells And Cancer Stem Cells To Metformin And Hyperthermia Alone Or Combined

Response Of Breast Cancer Cells And Cancer Stem Cells To Metformin And Hyperthermia Alone Or Combined

Response of Breast Cancer Cells and Cancer Stem Cells to Metformin and Hyperthermia Alone or Combined Affiliation Department of Microbiology, College of Medicine, Inha University, Incheon, Korea * E-mail: [email protected] (HJP); [email protected] (CSP) Affiliation Department of Microbiology, College of Medicine, Inha University, Incheon, Korea * E-mail: [email protected] (HJP); [email protected] (CSP) Affiliation Department of Pharmacology, College of Medicine, Inha University, Incheon, Korea Affiliation Department of Microbiology, College of Medicine, Inha University, Incheon, Korea Affiliation Department of Microbiology, College of Medicine, Inha University, Incheon, Korea Affiliation Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America Affiliation Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America Affiliation Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America Continue reading >>

Metformin Targets Gastric Cancer Stem Cells.

Metformin Targets Gastric Cancer Stem Cells.

Eur J Cancer. 2017 Oct;84:193-201. doi: 10.1016/j.ejca.2017.07.020. Epub 2017 Aug 17. Metformin targets gastric cancer stem cells. INSERM, Univ. Bordeaux, UMR1053 Bordeaux Research in Translational Oncology, BaRITOn, F-33000 Bordeaux, France. Institut Europen de Chimie et Biologie, 2 Rue Robert Escarpit, 33607 Pessac, France; INSERM U1218 Unit, Institut Bergoni, 229 Cours de l'Argonne, 33076 Bordeaux, France; University of Bordeaux, 146 rue Lo Saignat, 33076 Bordeaux, France. INSERM, Univ. Bordeaux, UMR1053 Bordeaux Research in Translational Oncology, BaRITOn, F-33000 Bordeaux, France; Animal Facilities, University of Bordeaux, 146 rue Lo Saignat, 33076 Bordeaux, France. INSERM, Univ. Bordeaux, UMR1053 Bordeaux Research in Translational Oncology, BaRITOn, F-33000 Bordeaux, France; CHU de Bordeaux, Laboratoire de bactriologie, Place Amlie Raba Lon, 33076 Bordeaux, France. INSERM, Univ. Bordeaux, UMR1053 Bordeaux Research in Translational Oncology, BaRITOn, F-33000 Bordeaux, France; CHU de Bordeaux, Laboratoire de bactriologie, Place Amlie Raba Lon, 33076 Bordeaux, France. Electronic address: [email protected] Gastric cancer is the third leading cause of cancer-related deaths worldwide and has still a poor prognosis. Therefore, new therapeutic strategies are needed: among them, targeting cancer stem cells (CSCs) could offer new opportunities. The aim of our study was to evaluate the anti-tumoural effect of metformin on gastric cancer invitro and invivoand especially, to determine whether this molecule could target the gastric CSCs. Metformin effects were evaluated on the proliferation and tumourigenic properties of the gastric CSCs from patient-derived primary tumour xenografts (PDXs) and cancer cell lines (MKN45, AGSand MKN74) invitro in conventional 2 dimen Continue reading >>

Metformin Suppresses Triple-negative Breast Cancer Stem Cells By Targeting Klf5 For Degradation

Metformin Suppresses Triple-negative Breast Cancer Stem Cells By Targeting Klf5 For Degradation

Metformin suppresses triple-negative breast cancer stem cells by targeting KLF5 for degradation Cell Discovery volume 3, Articlenumber:17010 (2017) Out of the breast cancer subtypes, triple-negative breast cancer (TNBC) has the poorest prognosis without effective targeted therapies. Metformin, a first-line drug for type 2 diabetes mellitus, was demonstrated to target breast cancer stem cells selectively. However, the efficiency and the mechanism of action of metformin in TNBC are unclear. In this study, we demonstrated that metformin decreased the percentage of TNBC stem cells partially through the downregulation of the expression of the stem cell transcription factor Krppel-like factor 5 (KLF5) and its downstream target genes, such as Nanog and FGF-BP1, in TNBC cell lines. Metformin induced glycogen synthase kinase-3 (GSK3)-mediated KLF5 protein phosphorylation and degradation through the inhibition of protein kinase A (PKA) activity in TNBC cells. Consistently, PKA activators increased the expression levels of KLF5. We observed a positive correlation between p-CREB, p-GSK3, KLF5 and FGF-BP1 protein levels in human TNBC samples. These findings suggest that metformin suppresses TNBC stem cells partially through the PKA-GSK3-KLF5 signaling pathway. Breast cancer is the most common cancer in women in China and the United States. China was estimated to have 268 600 new cases in 2015, and the United States was estimated to have 246 660 new cases in 2016 [ 1 , 2 ]. Triple-negative breast cancer (TNBC; estrogen receptor -, progesterone receptor and HER2-negative) is the subtype of breast cancer with the poorest prognosis due to a lack of targeted therapies [ 3 ]. TNBC can further be divided into different subtypes, including the basal-like and claudin-low subtypes [ 4 ]. Bas Continue reading >>

Metformin Targets Mammary/cancer Stem Cells In Breast Cancer Prevention And Treatment | 22321

Metformin Targets Mammary/cancer Stem Cells In Breast Cancer Prevention And Treatment | 22321

Increasing evidence suggests that targeting cancer stem cells (CSCs)/tumor-initiating cells (TICs) is a promising approachto treat and prevent cancer diseases. Recent advances indicate that use of metformin, a common anti- diabetes drug, isassociated with reduced risk of breast and other types of cancers. However, the mechanisms of metformin mediated anticanceractivities remain unclear. ErbB2/Her2 amplification in breast cancer has been associated with poor prognosis andtherapeutic resistance. It was sought to determine the effect of metformin on CSCs/TICs in ERBB2 tumor models. In vitroresults showed that metformin has potent anti-proliferative effects on trastuzumab-resistant breast cancer cells via inhibitionof erbB2/IGF-1R interactions. Using mammary tumor virus (MMTV)-ErbB2 transgenic mouse model, it was demonstratedthat systemic administration of metformin to these mice during the premalignant risk window selectively inhibited the CD61(high)/CD49f (high) mammary epithelial cells. Cells with this phenotype had been identified as luminal progenitor cellsand may function as TICs during tumor development in MMTV-ErbB2 mice. It was further demonstrated that metforminalso inhibited CD61 (high)/CD49f (high) subpopulation in ErbB2 tumor-derived cells in vitro and tumor development in asyngeneic tumor graft model. Mechanistic studies indicated that metformin inhibited the expression and activation of ErbBfamily members and IGF-1R, AKT/mTOR signaling, and STAT3, c-myc associated activities. In vitro data also showed that lowdoses of metformin inhibited the self-renewal/proliferation of cancer stem cells (CSCs)/TICs in ErbB2-overexpressing breastcancer cells. Results provide fundamental support for developing metformin-mediated preventive strategies targeting ErbB2-associat Continue reading >>

Stem Cell Cancer Therapy | Oasis Of Hope In Tijuana, Mexico

Stem Cell Cancer Therapy | Oasis Of Hope In Tijuana, Mexico

Not yet. Cancer stem cells must be destroyed, or recurrence is nearly certain. While chemo and radiation dont kill them, there are natural therapies that do. Now, some stem-cell therapy are promising for cancer patients. Again, we know there are cancer stem cells, and some researchers believe the key to a cancer cure relates to inhibiting their proliferation. Think about this: if tumors cant sustain growth without cancer stem cells in fact, tumors cannot survive without themthen we should develop target-specific therapies to destroy them. This is the new hope for improving survival and quality of life for cancer patients, especially those with advanced disease. For years some researchers have proposed that the reason for chemos failure, for its inordinate recurrence rate, is that even though it effectively kills the bulk of a tumors malignant cells to the point of remission, chemo/radiation-resistant cancer stem cells go untouched, ready for a new beginning. Whats more, it would be less toxic, and theoretically more effective, to target treatments directly at the small population of cancer stem cells instead of trying to kill all the billions of cells in a tumor. Eliminating the stem cells would ultimately kill the cancer and halt metastasis. Therefore a number of US and European pharmaceutical labs have developed drugs to selectively target cancer stem cells and are in early clinical phase trials. Results are somewhat encouraging but also are mixed, still far from being FDA-approved, and likely to be very expensive. While we wait for wonder drugs, theres an alternative for directly and selectively attacking cancer stem cells. Incredibly, this option comes from observational studies of diabetes, a chronic disease correlated with increased risk of breast and other cance Continue reading >>

Metformin Against Cancer Stem Cells Through The Modulation Of Energy Metabolism: Special Considerations On Ovarian Cancer

Metformin Against Cancer Stem Cells Through The Modulation Of Energy Metabolism: Special Considerations On Ovarian Cancer

Metformin against Cancer Stem Cells through the Modulation of Energy Metabolism: Special Considerations on Ovarian Cancer 1Department of Obstetrics and Gynecology, Korean Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea 2Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seongnam 463-707, Republic of Korea 3Biomedical Science Project, Brain Korea 21 Program for Leading Universities & Students, Seoul National University, Seoul 110-799, Republic of Korea 4Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul 110-744, Republic of Korea 5Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea 6Major in Biomodulation, World Class University, Seoul National University, Seoul 151-921, Republic of Korea Received 28 February 2014; Accepted 29 May 2014; Published 24 June 2014 Copyright 2014 Tae Hun Kim et al. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Ovarian cancer is the most lethal gynecologic malignancy among women worldwide and is presumed to result from the presence of ovarian cancer stem cells. To overcome the limitation of current anticancer agents, another anticancer strategy is necessary to effectively target cancer stem cells in ovarian cancer. In many types of malignancies, including ovarian cancer, metformin, one of the most popular antidiabetic drugs, has been demonstrated to exhibit chemopreventive and anticancer efficacy with respect to incidence and overall survival rates. Thus, the metabolic reprogramming of Continue reading >>

Metformin And Cancer Stem Cells.

Metformin And Cancer Stem Cells.

You are here: Home 2016 August Metformin and Cancer STEM cells. Dr. Weeks Comment: I applaud the authors of this article demonstrating that the common oral diabetes drug Metformin targets CSCs in breast cancer, pancreatic cancer, glioblastoma and colon cancer. It does so by lowering circulating blood sugar but also by disruptingoxidative phosphorylation and reducing ATP production at the level of the mitochondria. This creates an energy crisis for the cancer process. So this is a cheap andrelatively safe remedy for cancer STEM cells. One I have recommended for almost a decade now. But Iobject to this unscientific statement that advanced prostate cancer is more difficult to treat and if metastatic, is incurable. Incurable? That statement defies true scientific assessment. No null hypothesis can betested. It is therefore either a non-scientific statement squatting in the middle of a peer-reviewed scientific article or it is a statement of a non-scientist. So all youpeople with prostatecancer out there, discount that care- less, throw away unscientific comment and recall what one of the great doctors in history Paracelsus taught: There are no incurableillness. There are just incurable people. Also, send a penny and read the classic survival text for cancer patients Love Medicine andMiracles by Dr. Bernie Siegel MD Yale CancerSurgeon turned inspired healer. Finally, it would have been nice for the author to point out the common herbal remedy Berberine is equally as beneficial as Metformin and cheaper. Prostate Cancer and Prostatic Diseases18, 303-309 (December 2015) | doi :10.1038/pcan.2015.35 Metformin and prostate cancer stem cells: a novel therapeutic target Prostate cancer is the second most frequently diagnosed cancer in the world. Localized disease can be effectively Continue reading >>

Downregulation Of Rab27a Contributes To Metformininduced Suppression Of Breast Cancer Stem Cells

Downregulation Of Rab27a Contributes To Metformininduced Suppression Of Breast Cancer Stem Cells

Downregulation of Rab27A contributes to metformininduced suppression of breast cancer stem cells Affiliations: Department of Clinical Laboratory, The Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, Shaanxi 712000, P.R. China, Department of Clinical Laboratory, The XianYang Central Hospital, Xianyang, Shaanxi 712000, P.R. China, Department of Pharmacogenomics, The School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China Published online on: July 8, 2017 Copyright: Feng et al. This is an open access article distributed under the terms of Creative Commons Attribution License. Metrics: HTML 0 views | PDF 0 views Cited By (CrossRef): 0 citations Cancer stem cells (CSCs) are associated with tumor initiation, therapeutic resistance, relapse and metastasis. However, the underlying mechanisms CSCs use to preserve stemness are not yet fully understood. The present study demonstrated that the expression of RAB27A, member RAS oncogene family (Rab27a), which was reported to promote tumor progression by upregulating exocytosis of extracellular vesicles, was higher in mammosphere cells than in adherent MDAMB231 breast cancer cells. Downregulation of Rab27A inhibited mammosphere formation by decreasing the proportion of CD44+CD24/low cells of the MDAMB231 cell line. Furthermore, Rab27A overexpression redistributed the cell cycle of breast (b) CSCs. The present study revealed that downregulation of Rab27A enhanced the capacity of metformin, the most widely used oral hypoglycemic drug for the treatment of type II diabetes, to inhibit mammosphere growth. Metformin reduced the expression of Rab27A dosedependently. These data suggested that Rab27A acts as a mediator of human bCSCs by promoting the growth of mammospheres and that syn Continue reading >>

Evaluation Of Metformin, Targeting Cancer Stem Cells For Prevention Of Relapse In Gynecologic Patients

Evaluation Of Metformin, Targeting Cancer Stem Cells For Prevention Of Relapse In Gynecologic Patients

You have reached the maximum number of saved studies (100). Please remove one or more studies before adding more. Evaluation of Metformin, Targeting Cancer Stem Cells for Prevention of Relapse in Gynecologic Patients The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. ClinicalTrials.gov Identifier: NCT01579812 Information provided by (Responsible Party): Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information The primary objective of this study is to determine if metformin administered in combination with chemotherapy to women with advanced ovarian, primary peritoneal or fallopian tube cancer will improve recurrence-free survival at 18 months compared to controls. Ovarian, Fallopian Tube, and Primary Peritoneal Cancer Despite 70% remission rates with surgery and chemotherapy, the majority of patients with stage III/IV ovarian cancer will relapse and die of their disease. This is consistent with a cancer stem cell (CSC) model in which a few residual treatment resistant stem cells persist and initiate disease recurrence. Laboratory studies indicate therapies targeting CSC will greatly improve cancer outcomes. We have recently characterized a population of CSC in ovarian cancer. Importantly, similar to that observed in breast cancer, we have found that the diabetes drug metformin can restrict ovarian CSC growth and proliferation. In addition metformin increases tumor cell sensitivity to chemotherapy. Consistent with this, epidemiologic studies demonstrate that diabetic patients with ovarian cancer taking metformi Continue reading >>

Metformin And Ampk Link Cancer Stem Cell Elimination With The Potential Eradication Of Hiv

Metformin And Ampk Link Cancer Stem Cell Elimination With The Potential Eradication Of Hiv

Metformin and AMPK link cancer stem cell elimination with the potential eradication of HIV Cancer stem cells (CSCs) are cancer cells that exhibit several stem cell-like qualities that are characteristic of embryonic or adult stem cells, including self-renewal, differentiation, and the ability to initiate tumorigenesis. CSCs, similar to adult stem cells (ASCs), may also undergo quiescence, a state or period of inactivity or dormancy that contributes to the resistance of CSCs to radiation and/or chemotherapy, potentially allowing CSCs to re-seed tumors at a later time. Fig. 1. Goldsmith Content Providers: CDC/ C. Goldsmith, P. Feorino, E. L. Palmer, W. R. McManus [Public domain], via Wikimedia Commons; By Christaras A (Created myself from anonymized patient MR) [GFDL (CC BY 2.5 (via Wikimedia Commons. Intriguingly, HIV-1 has been shown to establish durable and long-stating latency, similar to CSC quiescence, in central CD4+ memory T cells as well as in T memory stem cells, T cell subsets that also display stem-cell like qualities including self renewal and differentiation. Latency establishment by HIV-1 in these T cell subsets prevents immune system detection and virus destruction or virus-induced cell death, analogous to CSC quiescence. Because the use of AMPK activators, including metformin, bryostain-1, JQ1, and resveratrol as single agents or in a combinatorial fashion reactivates latent HIV-1 (facilitating virus detection and destruction) and induces CSC differentiation and/or apoptosis, this paper proposes the novel observation that AMPK activation links the reactivation of latent HIV-1 (known as the shock and kill approach in HIV-1 cure research) with the activation, differentiation, and/or apoptosis of CSCs (which may also be labeled as a shock and kill approach) Continue reading >>

Metformin As An Anti-cancer Agent: Actions And Mechanisms Targeting Cancer Stem Cells

Metformin As An Anti-cancer Agent: Actions And Mechanisms Targeting Cancer Stem Cells

Metformin as an anti-cancer agent: actions and mechanisms targeting cancer stem cells Julius L. Chambers Biomedical/Biotechnology Research Institute Department of Biological and Biomedical Sciences Julius L. Chambers Biomedical/Biotechnology Research Institute Department of Biological and Biomedical Sciences Correspondence address. Tel: +1-704-250-5726; Fax: + Acta Biochimica et Biophysica Sinica, Volume 50, Issue 2, 1 February 2018, Pages 133143, Nipun Saini, Xiaohe Yang; Metformin as an anti-cancer agent: actions and mechanisms targeting cancer stem cells, Acta Biochimica et Biophysica Sinica, Volume 50, Issue 2, 1 February 2018, Pages 133143, Metformin, a first line medication for type II diabetes, initially entered the spotlight as a promising anti-cancer agent due to epidemiologic reports that found reduced cancer risk and improved clinical outcomes in diabetic patients taking metformin. To uncover the anti-cancer mechanisms of metformin, preclinical studies determined that metformin impairs cellular metabolism and suppresses oncogenic signaling pathways, including receptor tyrosine kinase, PI3K/Akt, and mTOR pathways. Recently, the anti-cancer potential of metformin has gained increasing interest due to its inhibitory effects on cancer stem cells (CSCs), which are associated with tumor metastasis, drug resistance, and relapse. Studies using various cancer models, including breast, pancreatic, prostate, and colon, have demonstrated the potency of metformin in attenuating CSCs through the targeting of specific pathways involved in cell differentiation, renewal, metastasis, and metabolism. In this review, we provide a comprehensive overview of the anti-cancer actions and mechanisms of metformin, including the regulation of CSCs and related pathways. We also discuss Continue reading >>

Oncotarget | Metformin Increases Chemo-sensitivity Via Gene Downregulation Encoding Dna Replication Proteins In 5-fu Resistant Colorectal Cancer Cells

Oncotarget | Metformin Increases Chemo-sensitivity Via Gene Downregulation Encoding Dna Replication Proteins In 5-fu Resistant Colorectal Cancer Cells

Metformin increases chemo-sensitivity via gene downregulation encoding DNA replication proteins in 5-Fu resistant colorectal cancer cells Metrics: PDF 455 views | HTML 730 views | ? Sung-Hee Kim1, Soon-Chan Kim2 and Ja-Lok Ku1,2 1Laboratory of Cell Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea 2Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea Keywords: colorectal cancer, 5-Fu resistant-cell line, metformin, cancer stem cell (CSC), DNA replication Received: January 17, 2017Accepted: April 27, 2017Published: May 11, 2017 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-B 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 resis Continue reading >>

Metformin As An Anti-cancer Agent: Actions And Mechanisms Targeting Cancer Stem Cells.

Metformin As An Anti-cancer Agent: Actions And Mechanisms Targeting Cancer Stem Cells.

Acta Biochim Biophys Sin (Shanghai). 2018 Feb 1;50(2):133-143. doi: 10.1093/abbs/gmx106. Metformin as an anti-cancer agent: actions and mechanisms targeting cancer stem cells. Julius L. Chambers Biomedical/Biotechnology Research Institute, Department of Biological and Biomedical Sciences, North Carolina Central University, North Carolina Research Campus, Kannapolis, NC 28081, USA. Metformin, a first line medication for type II diabetes, initially entered the spotlight as a promising anti-cancer agent due to epidemiologic reports that found reduced cancer risk and improved clinical outcomes in diabetic patients taking metformin. To uncover the anti-cancer mechanisms of metformin, preclinical studies determined that metformin impairs cellular metabolism and suppresses oncogenic signaling pathways, including receptor tyrosine kinase, PI3K/Akt, and mTOR pathways. Recently, the anti-cancer potential of metformin has gained increasing interest due to its inhibitory effects on cancer stem cells (CSCs), which are associated with tumor metastasis, drug resistance, and relapse. Studies using various cancer models, including breast, pancreatic, prostate, and colon, have demonstrated the potency of metformin in attenuating CSCs through the targeting of specific pathways involved in cell differentiation, renewal, metastasis, and metabolism. In this review, we provide a comprehensive overview of the anti-cancer actions and mechanisms of metformin, including the regulation of CSCs and related pathways. We also discuss the potential anti-cancer applications of metformin as mono- or combination therapies. AMPK/mTOR pathway; anti-cancer drugs; cancer stem cells; cellular metabolism; metformin Continue reading >>

Metformin Selectively Targets Cancer Stem Cells, And Acts Together With Chemotherapy To Block Tumor Growth And Prolong Remission

Metformin Selectively Targets Cancer Stem Cells, And Acts Together With Chemotherapy To Block Tumor Growth And Prolong Remission

Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission 1Dept. Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115 2Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111 3These authors made equal contributions to this work 4To whom correspondence should be addressed at [email protected] The publisher's final edited version of this article is available free at Cancer Res This article has been corrected. See the correction in volume 69 onpage8832. See other articles in PMC that cite the published article. The cancer stem cell hypothesis suggests that, unlike most cancer cells within a tumor, cancer stem cells resist chemotherapeutic drugs and can regenerate the various cell types in the tumor, thereby causing relapse of the disease. Thus, drugs that selectively target cancer stem cells offer great promise for cancer treatment, particularly in combination with chemotherapy. Here, we show that low doses of metformin, a standard drug for diabetes, inhibits cellular transformation and selectively kills cancer stem cells in four genetically different types of breast cancer. The combination of metformin and a well-defined chemotherapeutic agent, doxorubicin, kills both cancer stem cells and non-stem cancer cells in culture. Furthermore, this combinatorial therapy reduces tumor mass and prevents relapse much more effectively than either drug alone in a xenograft mouse model. Mice appear to remain tumor-free for at least two months after combinatorial therapy with metformin and doxorubicin is ended. These results provide further evidence supporting the cancer stem cell hypothesis, and they provide a rationale and experimental basis for using Continue reading >>

Antitumoral Effects Of Metformin On Cancer Stem Cells - Em|consulte

Antitumoral Effects Of Metformin On Cancer Stem Cells - Em|consulte

Rsums des intervenants du 32me Congrs de la SFE Antitumoral effects of metformin on cancer stem cells Epidemiological and preclinical studies suggested that metformin, the first-line drug for type-2 diabetes, exerts direct antitumoral activity. Clinical trials are currently ongoing for several human tumors, although the molecular mechanisms of metformin antiproliferative activity are still not completely identified. Several studies reported the involvement of AMP-activated kinase-dependent pathway, and the downstream effectors (e.g., mTOR) in metformin metabolic activity. Nevertheless, contrasting evidence was obtained on the involvement of this pathway in metformin antitumor effect, and several reports showed AMPK-independent antiproliferative activity. According to the hierarchical theory of tumorigenesis, cancer stem cells (CSC) are considered the real pharmacological target to obtain cancer remission. Here, we show that metformin inhibits proliferation of human glioblastoma cells, selectively acting on CSC viability, through the direct inhibition of chloride intracellular channel-1 (CLIC1). CLIC1 chloride current is specifically induced upon translocation and transient membrane insertion of this channel during cell cycle progression. By means of patch clamp experiments, we show that the antiproliferative effect of metformin correlates with the inhibition of CLIC1 current, causing the arrest of the G1-S transition. Furthermore, point mutation of the putative CLIC1 pore region impairs metformin interaction with the channel, highlighting an inhibitory activity from the extracellular side. This effect is rather specific for CSC, since no cytotoxic effects, using metformin at the same concentration, were observed in human normal stem cells. These findings highlight the Continue reading >>

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