Elucidating the anticancer properties of posaconazole in triple-negative breast cancer through in-silico and in-vitro analysis.

The present study focused on repurposing antifungal drugs for cancer treatment. Repurposing refers to the evaluation of an existing drug that has been used to treat a specific disease and to identify its potential to be used for other therapeutic purposes due to similarities in targets. Posaconazole is a second-generation lipophilic antifungal agent that exhibits broad-spectrum activity against various fungal infections associated with several fungal species. Posaconazole was chosen as the target drug for proteins screened through Swiss Pred to inhibit triple-negative breast cancer. The selected targets were allowed to develop a PPI network using a string database to identify bottleneck proteins. These target proteins were used for molecular docking and molecular dynamics simulations. In-silico analysis was further validated by cell viability assay in which posaconazole exhibited notable decrease in cell viability with an IC value of 7.2 μM in MDA-MB-231 triple negative breast cancer cell lines (TNBC). Furthermore, the migration potential of MDA-MB-231 cells following posaconazole treatment was investigated using a wound healing assay. Additionally, Posaconazole caused a notable decrease in sphere and colony formation ability. The mechanism of cell death was further analyzed using intracellular reactive oxygen species generation, mitochondrial depolarization, and cell cycle analysis. The results demonstrated that all tested variables including cell viability, migration colony formation, cell cycle analysis, ROS generation, mitochondrial depolarization and apoptosis showed statistically significant changes (p < 0.01) against the untreated control groups. The potent anticancer potential of posaconazole has opened new avenues for repurposing antifungal drugs to treat cancer.