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It is widely accepted that high-intensity focused ultrasound (HIFU) is a minimally invasive treatment option for different tumors,but its roles and the corresponding mechanism in cisplatin (DDP) chemoresistance in lung adenocarcinoma (LA) remain unclear.In this study,we investigated the response of DDP-resistant LA cells to HIFU and its underlying molecular mechanisms using molecular biology techniques.It was found that HIFU exposure inhibited the proliferation of DDP-resistant A549 (A549/DDP) cells through arresting cell cycle at the G1/G0 phase via the Cyclin-dependent pathway and promoting apoptosis in a Bcl-2-dependent manner.Furthermore,the results also showed that HIFU exposure could down-regulate the expressions of MDR1,MRP1,and LRP mRNAs,as well as P-gp,MRP1,and LRP proteins related to drug resistance in A549/DDP cells.In vivo experiments also demonstrated that HIFU could reduce the size and mass of subcutaneously transplanted tumors produced by A549/DDP cells through mediating Cyclin-dependent and Bcl-2-dependent pathways.These results suggested that HIFU treatment could inhibit the proliferation of DDP-resistant lung cancer cells and might be a novel therapeutic method for patients with DDP resistance.