Concurrent HDAC and mTORC1 inhibition attenuate androgen receptor and hypoxia signaling associated with alterations in microRNA expression

• Published in: PloS one 2011-11, Vol.6 (11), p.e27178
• Main Authors: Ellis, Leigh, Lehet, Kristin, Ramakrishnan, Swathi, Adelaiye, Remi, Miles, Kiersten M, Wang, Dan, Liu, Song, Atadja, Peter, Carducci, Michael A, Pili, Roberto
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Androgen receptors; Androgens; Angiogenesis; Animals; Anticancer properties; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antitumor activity; Antitumor agents; Apoptosis; Augmentation; Bioinformatics; Biology; c-Myc protein; Cancer; Cancer therapies; Cell cycle; Cell growth; Cell Line, Tumor; Cell Proliferation - drug effects; Chemotherapy; Clinical trials; Consortia; Cytokines; Cytotoxicity; Deregulation; DNA binding proteins; Drug dosages; Drug Synergism; Epigenetics; Everolimus; Genes, myc; Genetic engineering; Health aspects; Histone deacetylase; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylase Inhibitors - therapeutic use; Hydroxamic Acids - pharmacology; Hydroxamic Acids - therapeutic use; Hypoxia; Hypoxia - metabolism; Indoles; Inhibitors; Kinases; Localization; Male; Mediation; Medicine; Metastases; Metastasis; Mice; Mice, Transgenic; MicroRNA; MicroRNAs; MicroRNAs - genetics; miRNA; Myc protein; Panobinostat; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - pathology; Proteins; Rapamycin; Receptors, Androgen - metabolism; Ribonucleic acid; RNA; Signal Transduction - drug effects; Signaling; Sirolimus - analogs & derivatives; Sirolimus - pharmacology; Sirolimus - therapeutic use; TOR protein; TOR Serine-Threonine Kinases - antagonists & inhibitors; Transcription (Genetics); Transcription factors; Transgenic mice; Treatment Outcome; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0027178

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.