Cyclooxygenase-2 (COX-2) is known to play a role in carcinogenesis and tumor progression. An increased expression of COX-2 has been observed in various cancers including prostate cancer. Although the specific COX-2 inhibitor celecoxib has a chemopreventive effect on cancer, its molecular mechanisms remain unclear. It is important to develop chemotherapeutic strategy that simultaneously targets COX-2 and other related key molecules in cancer therapy. In our previous work, to discover new COX-2 inhibitors, a structure-based virtual screening was carried out using the DOCK program to screen the SPECS small-molecule database. Through the computational screening approach, J13016 was identified as a selective COX-2 inhibitor (IC50 = 1.3 μM), with less inhibition on COX-1 (IC50 = 34.4 μM). Furthermore, the lead compound J13016 was also shown to induce apoptosis as in the case of celecoxib. We used LNcaP (wild-type p53), DU145 (mutant-type p53), and PC-3 (p53 deficient) human prostate cancer cells to gain further insights into the mechanism of J13016-induced apoptosis. Treatment of prostate cell lines with J13016 reduced their proliferation in a dose-dependent and time-dependent manner. The effect manifested as an increasing population of apoptotic cells and the changes of the amount of the pro-apoptotic and anti-apoptotic proteins under J13016 treatment. Taken together, the anti-proliferative activity of J13016 through apoptosis in prostate cancer cells suggests that J13016 is a potential compound for further COX-2 inhibitor design and lead optimization. In addition, the works which focus on the unveiled interaction between COX-2 and other key signaling pathways that coordinately regulate prostate cancer growth are ongoing. Understanding the mechanisms and interplays will facilitate the development of more effective chemopreventive and therapeutic strategies.
- American Association for Cancer Research