Synergistic antitumor interaction of valproic acid and simvastatin sensitizes prostate cancer to docetaxel by targeting
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RESEARCH
(2020) 39:213
Open Access
Synergistic antitumor interaction of valproic acid and simvastatin sensitizes prostate cancer to docetaxel by targeting CSCs compartment via YAP inhibition Federica Iannelli1, Maria Serena Roca1, Rita Lombardi1, Chiara Ciardiello1, Laura Grumetti1, Simona De Rienzo1, Tania Moccia1, Carlo Vitagliano1, Angela Sorice1, Susan Costantini1, Maria Rita Milone1, Biagio Pucci1, Alessandra Leone1, Elena Di Gennaro1, Rita Mancini2, Gennaro Ciliberto3, Francesca Bruzzese1,4*† and Alfredo Budillon1*†
Abstract Background: Despite the introduction of several novel therapeutic approaches that improved survival, metastatic castration-resistant prostate cancer (mCRPC) remains an incurable disease. Herein we report the synergistic antitumor interaction between two well-known drugs used for years in clinical practice, the antiepileptic agent with histone deacetylase inhibitory activity valproic acid and the cholesterol lowering agent simvastatin, in mCRPC models. Methods: Synergistic anti-tumor effect was assessed on PC3, 22Rv1, DU145, DU145R80, LNCaP prostate cancer cell lines and EPN normal prostate epithelial cells, by calculating combination index (CI), caspase 3/7 activation and colony formation assays as well as on tumor spheroids and microtissues scored with luminescence 3D-cell viability assay. Cancer stem cells (CSC) compartment was studied evaluating specific markers by RT-PCR, western blotting and flow cytometry as well as by limiting dilution assay. Cholesterol content was evaluated by 1H-NMR. Overexpression of wild-type YAP and constitutively active YAP5SA were obtained by lipofectamine-based transfection and evaluated by immunofluorescence, western blotting and RT-PCR. 22Rv1 R_39 docetaxel resistant cells were selected by stepwise exposure to increasing drug concentrations. In vivo experiments were performed on xenograft models of DU145R80, 22Rv1 parental and docetaxel resistant cells, in athymic mice. (Continued on next page)
* Correspondence: [email protected]; [email protected] † Alfredo Budillon and Francesca Bruzzese are contributed equally as co– senior authors of this article. 1 Experimental Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione G. Pascale” – IRCCS, Via M. Semmola, 80131 Naples, Italy Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons
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