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Vazquez-Martin A, Oliveras-Ferraros C, Del Barco S, et al. The anti-diabetic drug metformin suppresses self-renewal and proliferation of trastuzumab-resistant tumor-initiating breast cancer stem cells

Catalan Institute of Oncology, Girona (ICO-Girona), Dr. Josep Trueta University Hospital, Ctra. França s/n, 17007, Girona, Catalonia, Spain.
Breast Cancer Research and Treatment (Impact Factor: 3.94). 05/2010; 126(2):355-64. DOI: 10.1007/s10549-010-0924-x
Source: PubMed

ABSTRACT

We here demonstrate that the anti-diabetic drug metformin interacts synergistically with the anti-HER2 monoclonal antibody trastuzumab (Tzb; Herceptin™) to eliminate stem/progenitor cell populations in HER2-gene-amplified breast carcinoma cells. When using the mammosphere culture technique, graded concentrations of single-agent metformin (range 50-1,000 μmol/l) were found to dose-dependently reduce the number of mammospheres formed by SKBR3 (a Tzb-naïve model), SKBR3 TzbR (a model of acquired auto-resistance to Tzb) and JIMT-1 (a model of refractoriness to Tzb and other HER2-targeted therapies ab initio) HER2-overexpressing breast cancer cells. Single-agent Tzb likewise reduced mammosphere-forming efficiency (MSFE) in Tzb-naïve SKBR3 cells, but it failed to significantly decrease MSFE in Tzb-resistant SKBR3 TzbR and JIMT-1 cells. Of note, CD44-overexpressing Tzb-refractory SKBR3 TzbR and JIMT-1 cells retained an exquisite sensitivity to single-agent metformin. Concurrent combination of metformin with Tzb synergistically reduced MSFE as well as the size of mammospheres in Tzb-refractory SKBR3 TzbR and JIMT-1 cells. Flow cytometry analyses confirmed that metformin and Tzb functioned synergistically to down-regulate the percentage of Tzb-refractory JIMT-1 cells displaying the CD44(pos)/CD24(neg/low) stem/progenitor immunophenotype. Given that MSFE and mammosphere size are indicators of stem self-renewal and progenitor cell proliferation, respectively, our current findings reveal for the first time that: (a) Tzb refractoriness in HER2 overexpressors can be explained in terms of Tzb-resistant/CD44-overexpressing/tumor-initiating stem cells; (b) metformin synergistically interacts with Tzb to suppress self-renewal and proliferation of cancer stem/progenitor cells in HER2-positive carcinomas.

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    • "For the same purpose, retinoic acid and metformin have been used to block BCSC self-renewal and to inhibit proliferation. Oncolytic virotherapy with herpes simplex virus that blocks the BCSC ability to form tumors, and tranilast, which prevents metastasis, tumor growth, colony and mammosphere formation are promising new approaches (Table 2) (Hirsch et al., 2009; Cufi et al., 2010; Vazquez-Martin et al., 2011; Prud'homme, 2012). Additional strategies have been suggested, like NF-KB, IL-6, IL-8, TGF-, CXCR4, and CXCR1 targeting; this would regulate the BCSC niche interaction and the EMT process (Korkaya et al., 2011; Prud'homme, 2012). "
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    ABSTRACT: Much effort has been made by researchers to elucidate the complex biology of breast cancer stem cells (BCSCs), a small subset of breast tumor cells that display stem cell properties, drive tumor initiation, and growth. In recent years, it has been suggested that BCSCs could be responsible for the process of metastasis and the development of drug resistance. These findings make the need to find the distinguishing blend of markers that can recognize only BCSCs of the utmost importance in order to be able to design new targeted therapies. This review will summarize BCSCs' main features as well as the cell surface markers that are currently used to identify them.
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    • "various cancer stem cells (Janzer et al. 2014; Honjo et al. 2014; Lonardo et al. 2013; Shank et al. 2012; Song et al. 2012; Vazquez-Martin et al. 2011; Hirsch et al. 2009; Viale et al. 2014). Indeed, a number of clinical trials of metformin are ongoing as therapy for a variety of cancers (Pollak 2013). "
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    • "Cells were next incubated for 20 min with FITC-conjugated anti-CD44 antibody (BD Biosciences, Franklin Lakes, NJ) followed by incubation with phycoerythrine-conjugated anti-CD24 antibody (BioLegend, San Diego, CA) for 20 min in the dark at 4°C. After washing with PBS containing 1% (v/v) FCS, CD44high/CD24low cells were identified with flow cytometry [6],[15],[27]–[29],[32], and the % of CD44high/CD24low cells was estimated. The same method was applied to identify CD44high/CD24high cells, which are CSCs of MIA PaCa-2 cells [25]. "
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    ABSTRACT: Metformin, the most widely prescribed drug for treatment of type 2 diabetes, has been shown to exert significant anticancer effects. Hyperthermia has been known to kill cancer cells and enhance the efficacy of various anti-cancer drugs and radiotherapy. We investigated the combined effects of metformin and hyperthermia against MCF-7 and MDA-MB-231 human breast cancer cell, and MIA PaCa-2 human pancreatic cancer cells. Incubation of breast cancer cells with 0.5-10 mM metformin for 48 h caused significant clonogenic cell death. Culturing breast cancer cells with 30 µM metformin, clinically relevant plasma concentration of metformin, significantly reduced the survival of cancer cells. Importantly, metformin was preferentially cytotoxic to CD44(high)/CD24(low) cells of MCF-7 cells and, CD44(high)/CD24(high) cells of MIA PaCa-2 cells, which are known to be cancer stem cells (CSCs) of MCF-7 cells and MIA PaCa-2 cells, respectively. Heating at 42°C for 1 h was slightly toxic to both cancer cells and CSCs, and it markedly enhanced the efficacy of metformin to kill cancer cells and CSCs. Metformin has been reported to activate AMPK, thereby suppressing mTOR, which plays an important role for protein synthesis, cell cycle progression, and cell survival. For the first time, we show that hyperthermia activates AMPK and inactivates mTOR and its downstream effector S6K. Furthermore, hyperthermia potentiated the effect of metformin to activate AMPK and inactivate mTOR and S6K. Cell proliferation was markedly suppressed by metformin or combination of metformin and hyperthermia, which could be attributed to activation of AMPK leading to inactivation of mTOR. It is conclude that the effects of metformin against cancer cells including CSCs can be markedly enhanced by hyperthermia.
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