Abstract Cancer remains one of the significant causes of mortality throughout the globe, with treatment often requiring prolonged therapy. Multidrug resistance, primarily mediated by P-glycoprotein (P-gp) transporters, poses a considerable challenge in the long-term treatment of cancer. To overcome this, P-gp inhibitors can be co-administered for improved drug accumulation and therapeutic efficacy. In the present study, a total of 37 phytochemicals were evaluated for their potential P-gp blocking activity using molecular docking and Molecular Mechanics/Generalized Born Surface Area analysis against the P-gp protein (PDB ID: 6FN1) and compared with Verapamil as a reference P-gp inhibitor. Among the screened compounds, Andrographolide demonstrated the most favourable binding interactions and was further subjected to molecular dynamics simulations, confirming its stable interaction with P-gp. Subsequent in vitro cell line studies revealed that Andrographolide, at effective inhibitory concentrations, did not exhibit inherent cytotoxicity but significantly enhanced the cell internalization and cytotoxicity of paclitaxel, a known P-gp substrate. This suggests that Andrographolide plays a role in reversing multidrug resistance through P-gp inhibition, rather than direct cell killing, for effective cancer therapy. These findings indicate that co-administration of phytochemicals, such as Andrographolide, may enhance cell internalization and the efficacy of anticancer drugs, thereby improving chemotherapy outcomes.
Bhat et al. (Wed,) studied this question.