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olmutinib(HM61713) reversed multidrug resistance by inhibiting the activity of ATPbinding cassette subfamily G member 2 in vitro and in vivo

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Acta Pharmaceutica Sinica B 2018年第4期8卷 563-574页

作者： Zhiqiang Zhang Xiaoran Guo Kenneth K.W.To Zhen Chen Xiaona Fang Min Luo Chunling Ma Jianhua Xu Shirong Yan Liwu Fu Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine School of Pharmacy Fujian Medical University Hubei University of Medicine School of Pharmacy Faculty of Medicinethe Chinese University of Hong Kong

Overexpressing of ATP-binding cassette(ABC) transporters is the essential cause of multidrug resistance(MDR), which is a significant hurdle to the success of chemotherapy in many ***, inhibiting the activity of ABC transporters may be a logical approach to circumvent *** is an epidermal growth factor receptor(EGFR) tyrosine kinase inhibitor(TKI), which has been approved in South Korea for advanced EGFR T790 M-positive non-small cell lung cancer(NSCLC). Here,we found that olmutinib significantly increased the sensitivity of chemotherapy drug in ABCG2-overexpressing cells. Furthermore, olmutinib could also increase the retention of doxorubicin(DOX) and rhodamine 123(Rho 123) in ABC transporter subfamily G member 2(ABCG2)-overexpressing cells. In addition, olmutinib was found to stimulate ATPase activity and inhibit photolabeling of ABCG2 with [^(125) I]-iodoarylazidoprazosin(IAAP). However, olmutinib neither altered ABCG2 expression at protein and m RNA levels nor blocked EGFR, Her-2 downstream signaling of AKT and ERK. Importantly,olmutinib enhanced the efficacy of topotecan on the inhibition of S1-MI-80 cell xenograft growth. All the results suggest that olmutinib reverses ABCG2-mediated MDR by binding to ATP bind site of ABCG2 and increasing intracellular chemotherapeutic drug accumulation. Our findings encouraged to further clinical investigation on combination therapy of olmutinib with conventional chemotherapeutic drugs in ABCG2-overexpressing cancer patients.

关键词： olmutinib ABCG2 Multidrug resistance Tyrosine kinase inhibitor Chemotherapy ATPase

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