Vitamin D analog calcitriol for breast cancer therapy; an integrated drug discovery approach.

As breast cancer remains leading cause of cancer death globally, it is essential to develop an affordable breast cancer therapy in underdeveloped countries. Drug repurposing offers potential to address gaps in breast cancer treatment. Molecular networking studies were performed for drug repurposing approach by using heterogeneous data. The PPI networks were built to select the target genes from the EGFR overexpression signaling pathway and its associated family members. The selected genes EGFR, ErbB2, ErbB4 and ErbB3 were allowed to interact with 2637 drugs, leads to PDI network construction of 78, 61, 15 and 19 drugs, respectively. As drugs approved for treating non cancer-related diseases or disorders are clinically safe, effective, and affordable, these drugs were given considerable attention. Calcitriol had shown significant binding affinities with all four receptors than standard neratinib. The RMSD, RMSF, and H-bond analysis of protein-ligand complexes from molecular dynamics simulation (100 ns), confirmed the stable binding of calcitriol with ErbB2 and EGFR receptors. In addition, MMGBSA and MMP BSA also affirmed the docking results. These in-silico results were validated with in-vitro cytotoxicity studies in SK-BR-3 and Vero cells. The IC50 value of calcitriol (43.07 mg/ml) was found to be lower than neratinib (61.50 mg/ml) in SK-BR-3 cells. In Vero cells the IC50 value of calcitriol (431.05 mg/ml) was higher than neratinib (404.95 mg/ml). It demonstrates that calcitriol suggestively downregulated the SK-BR-3 cell viability in a dose-dependent manner. These implications revealed calcitriol has shown better cytotoxicity and decreased the proliferation rate of breast cancer cells than neratinib.Communicated by Ramaswamy H. Sarma.