The effects of ultrasound exposure on P-glycoprotein-mediated multidrug resistance in vitro and in vivo

作者：Chixiong Huang, Senlin Huang, Hairui Li, Xinzhong Li, Bing Li, Lintao Zhong, Junfeng Wang, Meishen Zou, Xiang He, Hao Zheng, Xiaoyun Si, Wangjun Liao, Yulin Liao, Li Yang, Jianping Bin · 发表于：Journal of Experimental & Clinical Cancer Research · 年份：2018 · DOI：10.1186/s13046-018-0900-6 · 被引用次数：25 · 研究领域：Drug Transport and Resistance Mechanisms、Ultrasound and Hyperthermia Applications、Nanoparticle-Based Drug Delivery

BACKGROUND: Multidrug resistance (MDR) is often responsible for the failure of chemotherapy treatment, and current strategies for cancer MDR are not adequately satisfying as to their efficacy and safety. In this study, we sought to determine the anti-MDR effects of ultrasound (US) irradiation and its underlying mechanisms against drug-resistance. METHODS: MDR variant MCF-7/ADR cell lines and endothelial cell lines were used to determine the appropriate ultrasound intensity for in vitro experiments. MCF-7/ADR cell and HEPG2/ADM cells were used to assess the anti-MDR effect of US irradiation. Intracellular adriamycin (ADM) accumulation, Cell viability, cell proliferation and cell apoptosis were evaluated after ADM + US treatment or ADM treatment alone. MCF-7/ADR xenograft mice were used to investigate the appropriate ultrasound intensity for in vivo experiments and its effect on the long-term prognosis. Underlining mechanisms by which ultrasound exposure reversing MDR phenotype were investigated both in vitro and in vivo. RESULTS: US irradiation enhanced ADM intracellular concentration and nuclear accumulation in MCF-7/ADR and HEPG2/ADM cells, compared to those treated with ADM alone. Enhanced cellular ADM uptake and nuclei localization was associated with increased cytotoxicity of ADM to ADM-resistant cells, lower ADM-resistant cell viability and proliferative cell ratio, and higher apoptotic cell ratio. More importantly, US exposure increased the effectiveness of ADM to inhib...