Dihydroartemisinin overcomes cisplatin resistance in bladder cancer via suppression of the PI3K/AKT/ABCB1 signaling Axis

Abstract

Cisplatin resistance substantially limits the efficacy of bladder cancer chemotherapy, and effective strategies to overcome resistance remain insufficient. In this study, we demonstrate that dihydroartemisinin (DHA) restores cisplatin sensitivity in resistant bladder cancer cells by suppressing the PI3K/AKT/ABCB1 signaling axis. A cisplatin-resistant 5637&Cis cell line was established from parental 5637 cells and exhibited stable resistance, with an IC₅₀ of 15.41 µg/mL compared with 2.85 µg/mL in parental cells. DHA at 10 µg/mL showed limited intrinsic cytotoxicity but enhanced cisplatin sensitivity in a time-dependent manner, producing reversal folds of 1.19, 2.07, and 5.14 at 24, 48, and 72 h, respectively, and promoting apoptosis. Integrated bioinformatics analysis identified PI3K/AKT signaling as a key enriched pathway and ABCB1, AKT1, and STAT3 as resistance-related hub genes. Molecular docking and 100-ns molecular dynamics simulations suggested stable binding between DHA and ABCB1. DHA downregulated ABCB1 expression, inhibited PI3K and AKT phosphorylation, increased intracellular Rhodamine 123 accumulation, and reduced P-glycoprotein-mediated efflux. These effects were attenuated by 740 Y-P and mimicked by PKI-402. In xenograft models, DHA inhibited tumor growth by 60.54% without apparent systemic toxicity and promoted the expression of apoptotic markers. These findings suggest that DHA may serve as a low-toxicity chemosensitizer for cisplatin-resistant bladder cancer and warrant further validation in additional models and combination-treatment studies.