Combination of doxorubicin and myo-inositol induces apoptosis in MCF7 cells associated with altered total p38 MAPK levels

Abstract Natural compounds are attracting increasing attention in cancer treatment due to their ability to regulate key pathways associated with cell proliferation, apoptosis, and chemotherapy resistance. Myo-inositol, a naturally occurring carbocyclic sugar, has demonstrated its potential in hormone-sensitive cancers, including breast cancer. This study investigates the synergistic effect of combining doxorubicin with myo-inositol on MCF7 breast cancer cells (ER+), and the possible involvement of the p38 MAPK signaling pathway. We hypothesized that myo-inositol enhances doxorubicin-induced cytotoxicity and promotes apoptosis in MCF7 cells, potentially by modulating stress-responsive Total p38 MAPK levels. Cell viability was assessed using the MTS assay, while apoptosis, p38 MAPK levels, and ROS were assessed by flow cytometry. ADME predictions, KEGG pathway analysis, and subcellular compartment analysis were performed to explore potential mechanistic links. The combination treatment significantly reduced MCF7 cell proliferation in a dose- and time-dependent manner, with minimal effect on normal MCF 10 A cells, suggesting selective cytotoxicity. The combined treatment induced 25.12% apoptotic cell death. Interestingly, Phospho-p38-MAPK levels were lower in the combination group (58.82%) compared to doxorubicin (90.17%) and myo-inositol (72.51%) alone, indicating a 1.53-fold ( p < 0.01) and 1.23-fold ( p < 0.05) reduction, respectively. These findings suggest that the combination of myo-inositol and doxorubicin enhances apoptotic cell death in MCF7 cells, potentially through modulation of Total p38 MAPK, with computational analyses supporting a mechanistic basis.