Co-treatment with melatonin and ortho-topolin riboside exhibits anti-proliferation activity in radioresistant MDA-MB-231 cells by altering metabolic and transcriptomic profiles

This is the first study to demonstrate that co-treatment with MLT and oTR has a synergistic effect in inhibiting the proliferation of MDA-MB-231/RR cells based on metabolic and transcriptomic analyses. Treatment with either 1 mM MLT or 1 μM oTR was not cytotoxic, while their synergistic activity upon co-treatment was cytotoxic. In our previous study, MDA-MB-231 cells acquired radio resistance as mitochondrial respiration increased; however, co-treatment with MLT and oTR simultaneously inhibited mitochondrial respiration and glycolysis. Furthermore, when integrating the transcriptomic and metabolic profile results, alteration of pyrimidine metabolism (aspartate, uracil, CDA, NME1), steroid hormone biosynthesis (AKR1C1, AKR1C2, AKR1C3), and Wnt/β-catenin signaling (TSNAX-DISC1, CYP1B1) was attributed to the synergistic cytotoxicity by the co-treatment. In future studies, proteomic profiling could be performed to verify the results of the metabolomic and transcriptomic profiling in this study. The results of this study should be validated with in vivo experiment as a prelude to future clinical trials for the treatment of radioresistant TNBC. We expect our findings to provide basic information for the treatment of radioresistant TNBC.