Prostate cancer (PCa) progression to androgen independence is the main cause of death. Although all metastatic patients initially responded to anti-androgen therapy, most failed hormonal treatments in less than 2 years. Tramadol is an opioid agonist with the central effect of treating pain. Ketamine is a flexible medication that has a wide range of clinical uses. This in vitro study evaluated the repurposing of tramadol and/or ketamine as potential anticancer drugs. Moreover, the impact of these drugs on cell death pathways was assessed.

PC-3 and DU145 cell lines were treated with tramadol and/or ketamine. Apoptosis, autophagy, necroptosis, parthanatos, endoplasmic reticulum stress, the Raf/MEK/ERK pathway, and epithelial-mesenchymal transition-related genes were determined by real-time PCR.

Current data showed upregulation of most gene expression in PC-3 cells treated with TRA and/or KET compared to untreated cancer cells, except for N-cadherin, which was insignificantly downregulated by KET. On the other hand, gene expressions in DU145 showed an insignificant difference in all treated cells compared to each other or untreated cancer cells, except for significant up-regulation of ATG3, Beclin1, and ATF6 by KET (P = 0.047, 0.035, and 0.042, respectively), IRE1 by TRA (P = 0.023) and N-cadherin by the combined drug (P = 0.014) compared to untreated cells. PC-3 cells were significantly more susceptible to tramadol and/or ketamine than DU145 cells.

ROS-induced cell death pathways could be the mechanism by which tramadol and ketamine exert their anticancer effects against metastatic PCa. Targeting cell death pathways is an ideal strategy for developing new anticancer therapies.