Improved Chemosensitivity in Metastatic Castration-Resistant Prostate Cancer: The Synergistic Effects of S-Adenosylmethionine and Cabazitaxel.

Abstract

<p>Metastatic castration-resistant prostate cancer (mCRPC) is the most aggressive kind of prostate cancer (PCa). Because the traditional taxane-based therapy is ineffective, cabazitaxel (CBZ), a second-generation, semisynthetic taxane, has been developed. Despite it demonstrating efficacy in patients resistant to docetaxel and paclitaxel, two commonly used taxanes, and representing one of the second-line therapeutic options for patients with mCRPC, CBZ has limitations, including considerable side issues and reduced drug susceptibility that gradually emerge and constitute the primary cause of therapeutic failure. For the purposes of this study, the application of nature-derived adjuvants in chemotherapy is emerging as a promising area of research. S-Adenosyl-L-methionine (AdoMet) is a naturally occurring sulfur-containing nucleoside that serves as the major methyl donor for numerous methyltransferases, which is a key metabolite in the cell, participating in a broad range of essential biochemical processes. In the current research, we bring attention to the effectiveness of the combination of AdoMet and CBZ during treatment of mCRPC cells. Using mCRPC cell lines DU 145 and PC-3, we found that the combination of CBZ and AdoMet worked better than either agent alone in suppressing cancer cell growth. This synergistic effect may be mediated by increased production of reactive oxygen species (ROS) and a weakening of the cancer cells' antioxidant defenses, including reductions in glutathione, GPX4, and catalase. The resulting oxidative stress caused DNA damage and interference with mitotic spindle assembly, which induces cell cycle arrest and programmed cell death. These data indicate that AdoMet is capable of intensifying CBZ responsiveness in mCRPC cells, making the treatment more effective.</p>