Novel α-Trifluoromethyl Chalcone Exerts Antitumor Effects Against Prostate Cancer Cells

Abstract

Background/Aim: Despite treating advanced prostate cancer (PCa) with androgen deprivation therapy, it eventually progresses to castration-resistant PCa. Subsequently, taxanes are administered, but when PCa becomes resistant to taxanes, another treatment is needed, which has not yet been established. We previously synthesized a novel α-trifluoromethyl chalcone, YS71, and reported its antitumor effects against PCa cells. In this study, we confirmed its efficacy against androgen-sensitive, androgen-independent, and taxane-resistant PCa cells. Materials and Methods: The PCa cell lines used were LNCaP, DU145,, , DU145-TxR, and DU145-TxR/CxR. The antiproliferative effects of YS71 were evaluated using proliferation assay. The reverse transcriptase transcriptionpolymerase chain reaction and western blot were performed to determine the expression level of androgen receptor (AR), whereas luciferase assay was performed to determine the AR activity. Furthermore, TUNEL assay and western blot were performed to investigate the mechanism of the antiproliferative effect. Results: YS71 exerted a dose-dependent antitumor effect, inhibited AR activity, and induced apoptosis in all PCa cells in a dose-dependent manner. Western blot showed that YS71 increased the levels of apoptosis-related proteins, cleaved caspase-3, and cleaved PARP, and decreased the levels of the antiapoptotic proteins, Bcl-xL and Bcl-2. In addition, microarray analysis revealed that YS71 decreased several cancer-related genes. Conclusion: YS71 exhibits antitumor activity by inducing apoptosis in PCa cells, including taxaneresistant cells. It could be a potential future therapeutic option for hormone-and chemotherapy-resistant PCa.Prostate cancer (PCa) is the most frequently diagnosed cancer among men and the second leading cause of cancer-related mortality in the United States (1). Most untreated PCas progress in an androgen-dependent manner; therefore androgen deprivation therapy (ADT) is effective for PCas (2). However, PCas gradually become resistant to ADT and eventually progress to castration-resistant prostate cancer (CRPC). Novel androgen receptor axis target (ARAT) agents, such as abiraterone, enzalutamide, apalutamide, and darolutamide, are used to treat CRPC (3-6). However, even ARAT agents eventually fail to provide therapeutic benefits, and patients with CRPC who relapse following the administration of ARAT agents are subsequently treated with docetaxel (7). Furthermore, if CRPC becomes resistant to docetaxel, it is treated with cabazitaxel (8). Recently, the combination of docetaxel and hormone therapy has proven to be an effective initial treatment for metastatic PCa (CHAARTED trial) (9). At present, there is no clear treatment option for cabazitaxelresistant CRPC. Thus, therapeutic agents for cabazitaxelresistant CRPC need to be urgently developed.