Chinnapaka Somaiah, Bakthavachalam Velavan, Dasari Subramanyam, Kannan Jhishnuraj, Sapkota Sworaj, Kumar Raj, Munirathinam Gnanasekar
Department of Biomedical Sciences, University of Illinois College of Medicine, Rockford, Illinois, USA.
School of Medicine, Indiana University, Bloomington, Indiana, USA.
Biofactors. 2025 Jan-Feb;51(1):e2117. doi: 10.1002/biof.2117. Epub 2024 Sep 3.
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.
前列腺癌（PCa）是癌症相关死亡的第二大关键原因，在美国非裔美国人的死亡率更高。死亡率较高的主要原因是种族差异、对前列腺癌生物学及可负担治疗方法缺乏了解，以及非裔美国男性获取最有效和安全治疗的经济负担。包括维生素K在内的微量营养素对各种癌细胞系的影响已得到广泛研究，但维生素K3类似物甲萘醌亚硫酸氢钠（VK3 - OCH3）对非裔美国前列腺癌的潜在抗癌作用尚未得到评估。在本研究中，我们比较了VK3 - OCH3对源自非裔美国人的前列腺癌细胞系RC77 - T和MDA - PCa - 2b的抗癌作用。我们的结果表明，VK3 - OCH3显著抑制RC77 - T和MDA - PCa - 2b这两种非裔美国前列腺癌细胞的增殖并促进细胞凋亡，且两种细胞系中细胞死亡的潜在机制似乎相似。值得注意的是，VK3 - OCH3抑制非裔美国前列腺癌细胞的集落形成能力，并通过在G0期阻断细胞周期诱导细胞凋亡。VK3 - OCH3还通过抑制非裔美国前列腺癌细胞转移特性的迁移能力而发挥抗转移作用。VK3 - OCH3介导的非裔美国前列腺癌细胞死亡与自由基的产生有关，如细胞内和线粒体活性氧（ROS）。有趣的是，抗氧化剂如N - 乙酰半胱氨酸（NAC）和谷胱甘肽（GSH）有效地消除了VK3 - OCH3对源自非裔美国患者的前列腺癌细胞系诱导的氧化应激。值得注意的是，VK3 - OCH3降低了这些前列腺癌细胞中雄激素受体和前列腺特异性抗原的表达。此外，分子动力学研究重申VK3 - OCH3与雄激素受体强烈结合，表明雄激素受体是VK3 - OCH3的潜在分子靶点。另外，蛋白质印迹分析表明，在MDA - PCa - 2b转移性前列腺癌细胞模型中，VK3 - OCH3降低了雄激素受体、TRX2以及抗凋亡信号分子如Bcl - 2和TCTP的表达。总之，我们的结果表明VK3 - OCH3是一种有前景的抗癌药物，可能会降低非裔美国前列腺癌患者的死亡率，值得进一步进行临床前和转化研究。
