Abstract 5253: Oral administration of Withaferin-A effectively suppresses prostate carcinogenesis in PTEN-Knockout mice

Androgen ablation therapy alone or in combination with radiation therapy is the mainstay for prostate cancer (CaP), which is initially effective in de-bulking the tumor volume, however, eventually these patients will progress to a castration-resistant prostate cancer (CRPC), which requires more aggressive chemotherapies. Treating CRPC with second generation androgen -ablation based therapies like enzalutamide and abiraterone exhibit only a short window of therapeutic benefit resulting in chemoresistance. Hence, there is an immediate need for identification of novel targets to eradicate CRPC effectively. We and others have reported targeting AKT activation could efficiently suppress the growth of CRPC cells; in fact a number of clinical trials have shown some promise that AKT could be an attractive target for CRPC. In fact, clinical studies from our lab have suggested that AKT activation predominantly occurs in Gleason stage specific manner suggesting identification of novel drugs to inhibit AKT activation is imperative. Our earlier finding suggests that Withaferin-A (WA), an herbal molecule effectively inhibits the growth of CRPC cells by downregulating AKT activation and its downstream pro-survival events. Present study investigated whether oral administration of WA may inhibit tumor development in Pten conditional knockout mice [(Pten-loxp/loxp:PB-Cre4+) (Pten-KO)] which will be a unique and appropriate preclinical model to study the AKT driven prostate tumor. Oral administration of WA for 45 weeks effectively prevented the tumor growth without any significant signs of toxicity to organs in Pten-KO mice. Vehicle and WA (5mg/kg body weight) were orally given up to 45 weeks. Gross pathological studies suggested a significant inhibition of growth and micro metastasis in WA-treated mice as compared to the vehicle treated mice. On microscopic examination of the prostatic tissue, we found that the WA-treated tumors showed more necrosis than the control group and some of the tumors were more differentiated than the controls in the same group. All the organs were completely submitted for histological evaluation. None of the WA-treated mice organs showed any metastatic lesion on the other hand, we found discrete metastasis to lungs in the control tumors. Our ongoing immunohistochemistry analysis may corroborate our in vitro findings that down regulation of AKT and epithelial-to-mesenchymal transition (EMT) markers such as β-catenin, snail, and vimentin in WA treated tumors as compared to the control mice. Overall, these results provide important scientific evidence in support of AKT signaling as a target to inhibit CRPC as well as metastatic CRPC. Citation Format: Chendil Damodaran, Suman Suman, Trinath P. Das, Houda Alatassi, Murali K. Ankem. Oral administration of Withaferin-A effectively suppresses prostate carcinogenesis in PTEN-Knockout mice. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5253.