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Aim: The aim of our study is to the evaluation of melatonin (MLT) and Momordica charantia (MC) combination on PC-3 and HT-29 cancer lines and to address the question of where or not MLT increases MC antitumor effect in the PC-3 and HT-29 cancer lines. Material and Method: The PC-3 and HT-29 cell lines were grown in a manufacturer-specified culture medium. Cisplatin, MLT, increasing concentrations of MC, 40 μg/ml MLT + increasing concentrations MC were applied to PC-3 and HT-29 cell lines for 72 hours. 3-(4,5-Dimethylthiazol-2-Yl)-2,5-Diphenyltetrazolium Bromide (MTT) cell viability, Total Antioxidant Capacity (TAC), Total Oxidant Status (TOS), Cellular Migration (Wound Healing test), and Lactate Dehydrogenase (LDH) tests were done 72 hours after drug administration. Results: The combination of MLT 40 μg/ml + MC 100 µg/ml reduced cell viability in both PC-3 and HT-29 cells. Besides, TAC and TOS levels showed a correlation with LDH and MTT assays and were found to be statistically significant (P