Vitamin K3 derivative inhibits androgen receptor signaling in targeting aggressive prostate cancer cells

Abstract Prostate cancer (PCa) is the second critical cause of cancer‐related deaths, with African Americans dying at higher rates in the U.S. The main reasons for the higher mortality rate are ethnic differences and lack of understanding of prostate cancer biology and affordable treatments, as well as the financial burden of African American men to obtain the most effective and safe treatments. The effect of micronutrients, including Vitamin K, on various cancer cell lines has been widely studied, but the potential anticancer effect of VK3‐OCH3, an analog of vitamin K3 (Menadione), on African American prostate cancer has not been evaluated. In this study, we compared the anticancer effect of VK3‐OCH3 on targeting African American derived PCa cell lines namely RC77‐T and MDA‐PCa‐2b. Our results show that VK3‐OCH3 significantly inhibits the proliferation of both RC77‐T and MDA‐PCa‐2b African American PCa cells and promotes apoptosis, and the underlying mechanism of cell death appears to be similar in both the cell lines. Notably, VK3‐OCH3 inhibits colony‐forming ability and induces apoptosis by blocking the cell cycle at G0 in African American PCa cells. VK3‐OCH3 also acts as an anti‐metastatic agent by inhibiting the migration ability of the metastatic properties of African American PCa cells. The cell death of African American PCa cells mediated by VK3‐OCH3 is associated with the production of free radicals, such as intracellular and mitochondrial reactive oxygen species (ROS). Interestingly, antioxidants such as N‐Acetylcysteine (NAC) and Glutathione (GSH) effectively negated the oxidative stress induced by VK3‐OCH3 on PCa cell lines derived from African American patients. Of note, VK3‐OCH3 reduces androgen receptor and prostate‐specific antigen expression in these PCa cells. Furthermore, molecular dynamic studies reiterated that VK3‐OCH3 strongly binds to the androgen receptor, suggesting that the androgen receptor is the potential molecular target of VK3‐OCH3. In addition, Western blot analysis showed that VK3‐OCH3 reduces the expression of androgen receptor, TRX2, and anti‐apoptotic signaling molecules such as Bcl‐2 and TCTP in the MDA‐PCa‐2b metastatic PCa cellular model. In conclusion, our results suggested that VK3‐OCH3 is a promising anticancer agent that could potentially reduce the mortality rates of African American PCa patients, warranting further preclinical and translational studies.