Multi-omics profiling reveals ortho-topolin riboside and protocatechualdehyde combination exhibits anti-proliferative activity by modulating metabolic pathways in in vitro and in vivo radio-resistant MDA-MB-231 cell models

Triple-negative breast cancer (TNBC) poses a significant therapeutic challenge because of its intrinsic resistance to traditional hormonal and targeted therapies. Radio-resistant TNBC is one of the most serious problems in improving treatment outcomes. Furthermore, anticancer activity induced by co-treatment with ortho-topolin riboside (oTR) and protocatechualdehyde (PA) in radio-resistant TNBC cells has not yet been investigated. This study aimed to investigate the potential anticancer effects of oTR and PA in in vitro and in vivo radio-resistant MDA-MB-231 (MDA-MB-231/RR) cells. Transcriptomic, proteomic, and metabolomic analyses were performed to identify the major altered molecular pathways involved in tumor growth inhibition. Co-treatment with oTR and PA synergistically reduced the viability of MDA-MB-231/RR cells compared to treatment with oTR or PA alone. We identified β-alanine metabolism, hypoxia-inducible factor 1 (HIF-1) signaling, FoxO signaling, and the mitogen-activated protein kinase (MAPK) signaling pathways as altered major metabolic pathways. In xenograft mouse models, a significant reduction in tumor volume was observed in both the single treatment (oTR or PA alone) and co-treatment (low- and high-dose) groups, with no significant alterations in body weight. Our findings demonstrate the potential of co-treatment with oTR and PA as a promising therapeutic strategy for the treatment of radio-resistant TNBC.