阿法替尼逆转卵巢癌多药耐药性的机制研究（英文）

【作者】 王胜奇； Bo-xin Zhao； Fu-heng Yang； Ya-tian Wang； Qian-ying Liang； Ya-bin Sun； Yuan Liu； Zhi-hua Song； Yun Cai； 李国锋；

【Author】 Sheng-qi Wang;Bo-xin Zhao;Fu-heng Yang;Ya-tian Wang;Qian-ying Liang;Ya-bin Sun;Yuan Liu;Zhi-hua Song;Yun Cai;Guo-feng Li;Department of Pharmacy,Nanfang Hospital,Southern Medical University;GCP Center,Nanfang Hospital,Southern Medical University;

【机构】 南方医科大学南方医院药学部； GCP Center,Nanfang Hospital,Southern Medical University；

【摘要】 ABCB1-mediated multidrug resistance(MDR)remains a major obstacle to successful chemotherapy in ovarian cancer.Herein,afatinibat nontoxic concentrations significantly reversed ABCB1-mediated MDR in ovarian cancer cells in vitro(p<0.05).Combining paclitaxel andafatinibcaused tumor regressions and tumor necrosis in A2780 T xenograftsin vivo.More interestingly,unlike reversible TKIs,afatinib had a distinctivedual-mode action.Afatinibnot only inhibited the effluxfunction of ABCB1,but also attenuated its expression transcriptionally via down-regulation of PI3 K/AKT and MAPK/p38-dependent activation of NF-κB.Furthermore,apart froma substrate binding domain,afatinib could also bind to an ATP binding domain of ABCB1 through forming hydrogen bonds with Gly533,Gly534,Lys536 and Ala560 sites.Importantly,mutations in these four binding sites of ABCB1 and the tyrosine kinase domain of EGFR were notcorrelatedwith the reversal activity of afatinib on MDR.Given that afatinib is a clinically approved drug,our results suggest combining afatinib with chemotherapeutic drugs in ovarian cancer.This study can facilitate the rediscovery of superior MDR reversal agents from molecular targeted drugs to provide a more effective and safer way of resensitizing MDR.更多还原

【Abstract】 ABCB1-mediated multidrug resistance(MDR)remains a major obstacle to successful chemotherapy in ovarian cancer.Herein,afatinibat nontoxic concentrations significantly reversed ABCB1-mediated MDR in ovarian cancer cells in vitro(p<0.05).Combining paclitaxel andafatinibcaused tumor regressions and tumor necrosis in A2780 T xenograftsin vivo.More interestingly,unlike reversible TKIs,afatinib had a distinctivedual-mode action.Afatinibnot only inhibited the effluxfunction of ABCB1,but also attenuated its expression transcriptionally via down-regulation of PI3 K/AKT and MAPK/p38-dependent activation of NF-κB.Furthermore,apart froma substrate binding domain,afatinib could also bind to an ATP binding domain of ABCB1 through forming hydrogen bonds with Gly533,Gly534,Lys536 and Ala560 sites.Importantly,mutations in these four binding sites of ABCB1 and the tyrosine kinase domain of EGFR were notcorrelatedwith the reversal activity of afatinib on MDR.Given that afatinib is a clinically approved drug,our results suggest combining afatinib with chemotherapeutic drugs in ovarian cancer.This study can facilitate the rediscovery of superior MDR reversal agents from molecular targeted drugs to provide a more effective and safer way of resensitizing MDR.更多还原