Inhibition of Prostate Cancer Cell Growth Using Antagonists of the Adenosine A3 Receptors

Introduction: The A3 adenosine receptors (A3ARs) play a significant role in cancer. However, very little is known about their function in prostate cancer (PCa). Objective: The A3AR antagonists AR 292 and AR 357 were investigated on PCa cell lines to validate their potential therapeutic effects. Materials & Methods: LNCaP, DU-145 and PC3 cell lines were treated with AR 292 and AR 357 compounds. The cytotoxic effect of these compounds was determined using viability assays, flow cytometry and western blot analyses. Moreover, the drug transporter gene profile was evaluated by RT-PCR in untreated and A3AR antagonists-treated PCa cells. Results: The SRB assay showed the antiproliferative effect of both compounds. Our results also demonstrated that A3AR antagonists induce significant cell cycle arrest, with AR 292 blocking the cycle in the G2-M phase and AR 357 in the G1 phase. The observed increase in ROS production and DNA damage also support our findings that these antagonists induce significant cell viability impairment. Moreover, both compounds induce apoptotic cell death in DU-145 cells and reduce HIF1α protein levels in DU-145 and PC3. Finally, AR 357 modulates drug transporter genes involved in chemoresistance more than AR 292. Conclusion: Based on these findings, A3AR ligands exert different anti-cancer effects on PCa cell lines through the activation of multiple pathways.