Abstract
Specific inhibitors towards Histone Deacetylases (HDACs) and Mammalian Target of Rapamycin Complex 1 (mTORC1) have been developed and demonstrate potential as treatments for patients with advanced and/or metastatic and castrate resistant prostate cancer (PCa). Further, deregulation of HDAC expression and mTORC1 activity are documented in PCa and provide rational targets to create new therapeutic strategies to treat PCa. Here we report the use of the c-Myc adenocarcinoma cell line from the c-Myc transgenic mouse with prostate cancer to evaluate the in vitro and in vivo anti-tumor activity of the combination of the HDAC inhibitor panobinostat with the mTORC1 inhibitor everolimus. Panobinostat/everolimus combination treatment resulted in significantly greater antitumor activity in mice bearing androgen sensitive Myc-CaP and castrate resistant Myc-CaP tumors compared to single treatments. We identified that panobinostat/everolimus combination resulted in enhanced anti-tumor activity mediated by decreased tumor growth concurrent with augmentation of p21 and p27 expression and the attenuation of angiogenesis and tumor proliferation via androgen receptor, c-Myc and HIF-1α signaling. Also, we observed altered expression of microRNAs associated with these three transcription factors. Overall, our results demonstrate that low dose concurrent panobinostat/everolimus combination therapy is well tolerated and results in greater anti-tumor activity compared to single treatments in tumor bearing immuno-competent mice. Finally, our results suggest that response of selected miRs could be utilized to monitor panobinostat/everolimus in vivo activity.
Highlights
Treatment for advanced prostate cancer currently involves hormone therapies that lower serum testosterone and antagonize the transcriptional capabilities of the androgen receptor (AR) by targeting its ligand binding domain
We utilize the mouse prostate cancer cell line Myc-CaP generated from the Hi-Myc murine model of PCa [16,17] which drives the expression of human c-Myc by the androgen receptor dependent rat probasin promoter to demonstrate that low dose combination of the histone deacetylases (HDACs) inhibitor panobinostat and the Mammalian Target of Rapamycin Complex 1 (mTORC1) inhibitor everolimus in vitro and in vivo result in greater anti-tumor activity than single agent treatment in a murine model of PCa
Because of HDAC inhibitors ability to affect multiple pathways and genes involved in apoptosis [25], cell cycle arrest [26] and angiogenesis [24,27,28], their greatest potential as targeted therapies maybe to be utilized in novel combinational therapeutic strategies in PCa with already existing chemotherapies such as docetaxel [29], or with other novel targeted chemotherapies including mammalian target of rapamycin (mTOR) inhibitors [19]
Summary
Treatment for advanced prostate cancer currently involves hormone therapies that lower serum testosterone and antagonize the transcriptional capabilities of the androgen receptor (AR) by targeting its ligand binding domain. Effective, these therapies are eventually ‘adapted’ to, enabling the cancer to survive in a low androgen environment. Therapies including the microtubule inhibitors docetaxel and cabazitaxel, and the recently approved abiraterone and the autologous immunotherapy sipuleucel T are available therapies to patients with CRPC. These therapies are life prolonging, additional treatment options are still required. More recently epigenetic changes including deregulation of small non-coding RNAs called microRNA as well as histone deacetylases (HDACs) have been documented in PCa pre-clinical and clinical studies [6,7]
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