The anti-diabetic drug metformin suppresses self-renewal and proliferation of trastuzumab-resistant tumor-initiating breast cancer stem cells
- نوع فایل : کتاب
- زبان : انگلیسی
- مؤلف : Alejandro Vazquez-Martin Cristina Oliveras-Ferraros Sonia Del Barco Begon˜a Martin-Castillo Javier A. Menendez
- چاپ و سال / کشور: 2010
Description
We here demonstrate that the anti-diabetic drug metformin interacts synergistically with the anti-HER2 monoclonal antibody trastuzumab (Tzb; HerceptinTM) to eliminate stem/progenitor cell populations in HER2-geneamplified breast carcinoma cells. When using the mammosphere culture technique, graded concentrations of single-agent metformin (range 50–1,000 lmol/l) were found to dose-dependently reduce the number of mammospheres formed by SKBR3 (a Tzb-naı¨ve 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-naı¨ve SKBR3 cells, but it failed to significantly decrease MSFE in Tzb-resistant SKBR3 TzbR and JIMT-1 cells. Of note, CD44-overexpressing Tzbrefractory 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 ofmammospheres 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 CD44pos/CD24neg/low stem/progenitor immunophenotype. Given thatMSFE 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.
Breast Cancer Res Treat (2011) 126:355–364 Received: 22 March 2010 / Accepted: 16 April 2010 / Published online: 11 May 2010 Springer Science+Business Media, LLC. 2010
