Reserpine, a lipophilic indole alkaloid derived from Rauwolfia, targets ABCB1 to overcome docetaxel resistance in prostate cancer

Abstract: Background: Overexpression of ATP-binding cassette subfamily B member 1 (ABCB1) is a major driver of docetaxel resistance in prostate cancer. Thus, identifying effective agents that specifically target ABCB1 is essential for overcoming chemoresistance. Objectives: This study aimed to determine whether reserpine, a lipophilic indole alkaloid derived from Rauwolfia, could reverse docetaxel resistance in prostate cancer by modulating ABCB1. Methods: Network pharmacology analysis was used to identify potential targets of Rauwolfia-derived compounds. Molecular docking, cellular thermal shift assay and molecular dynamics simulation were performed to evaluate the interaction between reserpine and ABCB1. Cytotoxicity and reversal assays were conducted in docetaxel-resistant prostate cancer cells and ABCB1-overexpressing cells. Colony formation, 3D spheroid, doxorubicin accumulation/efflux, ATPase, apoptosis and cell-cycle assays were used to investigate the functional effects and underlying mechanism. Results: Reserpine was identified as a candidate Rauwolfia-derived compound associated with ABCB1. Computational and target-engagement analyses supported direct interaction between reserpine and ABCB1. At minimally cytotoxic concentrations, reserpine significantly restored docetaxel sensitivity in DU145-DTX, LNCaP-DTX and HEK293-ABCB1 cells, while showing little effect in parental control cells. Reserpine did not alter ABCB1 expression or subcellular localization, but increased intracellular accumulation of doxorubicin, inhibited drug efflux and stimulated ABCB1 ATPase activity. In addition, reserpine enhanced docetaxel-induced apoptosis and G₂/M arrest in resistant prostate cancer cells. Conclusion: Our Reserpine was identified as a promising natural small molecule capable of overcoming ABCB1-dependent docetaxel resistance, warranting further evaluation for prostate cancer therapy.