@article {Chengjpet.119.261040, author = {Jiongjia Cheng and Stephanie Moore and Jorge Gomez-Galeno and Dong-Hoon Lee and Karl J Okolotowicz and John R Cashman}, title = {A novel small molecule inhibits tumor growth and synergizes effects of enzalutamide on prostate cancer}, elocation-id = {jpet.119.261040}, year = {2019}, doi = {10.1124/jpet.119.261040}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Prostate cancer (PCa) is the second leading cause of cancer-related death for men in the United States. About 35\% of PCa recurs and is often transformed to castrate-resistant PCa (CRPCa), the most deadly and aggressive form of PCa. However, the standard-of-care treatment for CRPCa (e.g., enzalutamide with abiraterone) usually has limited efficacy. Herein, we report a novel molecule (i.e., PAWI-2) that inhibits cellular proliferation of androgen-sensitive (i.e., LNCaP) and androgen-insensitive (i.e., PC-3) cells. In vivo studies in a PC-3 xenograft model showed that PAWI-2 (20 mg/kg/day, 21 days, i.p.) inhibited tumor growth by 49\% compared to vehicle-treated mice. PAWI-2 synergized currently clinically used enzalutamide in in vitro inhibition of PCa cell viability and re-sensitized inhibition of in vivo PC-3 tumor growth. Compared to vehicle-treated mice, PC-3 xenograft studies also showed that PAWI-2 (20 mg/kg/day, 21 days, i.p.) and enzalutamide (5 mg/kg/day, 21 days, i.p.) inhibited tumor growth by 63\%. Synergism was mainly controlled by the imbalance of pro-survival factors (i.e., Bcl-2, Bcl-xL, Mcl-1) and anti-survival factors (i.e., Bax, Bak) induced by affecting mitochondrial membrane potential/mitochondria dynamics. Thus, PAWI-2 utilizes a distinct mechanism of action to inhibit PCa growth independently of androgen receptor signaling overcomes enzalutamide-resistant CRPCa.SIGNIFICANCE STATEMENT CRPCa is the most aggressive human PCa but standard chemotherapies for CRPCa are largely ineffective. PAWI-2 potently inhibits PCa proliferation in vitro and in vivo regardless of AR status and uses a distinct mechanism of action. PAWI-2 has greater utility in treating CRPCa than standard of care therapy. PAWI-2 possesses promising therapeutic potency in low-dose combination therapy with a clinically used drug (i.e., enzalutamide). This study describes a new approach to address the overarching challenge in clinical treatment of CRPCa.}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/early/2019/10/03/jpet.119.261040}, eprint = {https://jpet.aspetjournals.org/content/early/2019/10/03/jpet.119.261040.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }