Synergistic antitumor interaction of valproic acid and simvastatin sensitizes prostate cancer to docetaxel by targeting CSCs compartment via YAP inhibition

Journal of Experimental & Clinical Cancer Research

Rita Mancini¹  Angela Sorice²  Laura Grumetti²  Alessandra Leone²  Alfredo Budillon²  Tania Moccia²  Federica Iannelli²  Maria Rita Milone²  Rita Lombardi²  Chiara Ciardiello²  Maria Serena Roca²  Biagio Pucci²  Elena Di Gennaro²  Susan Costantini²  Simona De Rienzo²  Carlo Vitagliano²  Francesca Bruzzese³  Gennaro Ciliberto⁴ 

[1] Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy;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;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;Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione G. Pascale” – IRCCS, Via Ammiraglio Bianco, 83013, Mercogliano, AV, Italy;IRCCS “Regina Elena” National Cancer Institute, Rome, Italy;

关键词: Valproic acid;    Statin;    Mevalonate pathway;    YAP;    Prostate cancer;    Cancer stem cells;   

DOI  :  10.1186/s13046-020-01723-7

来源: Springer

【 摘 要 】

BackgroundDespite 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.MethodsSynergistic 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.ResultsWe demonstrated the capacity of the combined approach to target CSC compartment by a novel molecular mechanism based on the inhibition of YAP oncogene via concurrent modulation of mevalonate pathway and AMPK. Because both CSCs and YAP activation have been associated with chemo-resistance, we tested if the combined approach can potentiate docetaxel, a standard of care in mCRCP treatment. Indeed, we demonstrated, both in vitro and in vivo models, the ability of valproic acid/simvastatin combination to sensitize mCRPC cells to docetaxel and to revert docetaxel-resistance, by mevalonate pathway/YAP axis modulation.ConclusionOverall, mCRPC progression and therapeutic resistance driven by CSCs via YAP, can be tackled by the combined repurposing of two generic and safe drugs, an approach that warrants further clinical development in this disease.

【 授权许可】

CC BY