Ticagrelor reverses multidrug resistance in breast cancer by inhibiting PI3K/AKT/mTOR pathway and suppressing ABCB1 expression and function.

Multidrug resistance (MDR) continues to pose a fundamental challenge to successful chemotherapy in breast cancer, primarily mediated by ATP-binding cassette (ABC) transporter-driven drug efflux. Drug repurposing offers a promising strategy to overcome MDR. Ticagrelor, a P2Y12 receptor antagonist used as an antiplatelet agent, has recently garnered attention for its potential anti-cancer metastasis effect. Our present study aims to investigate the efficacy of Ticagrelor in reversing breast cancer MDR and elucidate its underlying molecular mechanisms. The data demonstrated that MCF-7/Adr cells displayed resistance to multiple structurally distinct chemotherapeutic agents and showed elevated expression of MDR-related proteins. Ticagrelor synergistically enhanced the cytotoxicity of Adriamycin (Adr) and Paclitaxel (PTX) in MCF-7/Adr and MCF-7/PTX cells, respectively. Mechanistically, Ticagrelor combined with Adr downregulated PI3K/mTORC1 and PI3K/mTORC2 signaling pathways, reduced ABC subfamily B member 1 (ABCB1) expression, and suppressed epithelial mesenchymal transition (EMT)-related protein levels, whereas Adr alone showed little effects. In addition, Ticagrelor inhibited ABCB1 efflux function and increased intracellular Adr accumulation. In MCF-7/Adr xenograft model, the combination of Ticagrelor and Adr significantly suppressed tumor growth compared to Adr monotherapy. In conclusion, Ticagrelor reverses breast cancer MDR by concurrently inhibiting PI3K/AKT/mTOR signaling, downregulating ABCB1 expression and function. Our findings highlight the potential of Ticagrelor as a dual-acting agent that not only targets tumor metastasis but also overcomes chemoresistance, providing a new strategic direction for combination therapy in refractory breast cancer.