Olmutinib (HM61713) reversed multidrug resistance by inhibiting the activity of ATP-binding cassette subfamily G member 2 in vitro and in vivo.

• 影响指数: 14.903
• 发表时间: Jul 2018
• 来源期刊: Acta Pharm Sin B
• DOI: 10.1016/j.apsb.2018.06.002
• PMID: 30109181
• 文章类型: Journal Article
• 中科院分区: Q3
• 方向: 医学
• 作者列表: Zhang Z,Guo X,To KKW,Chen Z,Fang X,Luo M,Ma C,Xu J,Yan S,Fu L

关键词: ABC, adenosine triphosphate (ATP)-binding cassette; ABCG2; ABCG2, ABC transporter subfamily G member 2; ATPase; Chemotherapy; DDP, cisplatin; DMEM, Dulbecco׳s modified Eagle׳s medium; DMSO, dimethyl sulfoxide; DOX, doxorubicin; FTC, fumitremorgin C; IAAP, iodoarylazidoprazosin; MDR, multidrug resistance; MTT, 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazoliumbromide; MX, methotrexate; Multidrug resistance; Olmutinib; PCR, polymerase chain reaction; Rho 123, rhodamine 123; TKI, tyrosine kinase inhibitor; Tyrosine kinase inhibitor; VRP, verapamil

Abstract

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 cancers. Therefore, inhibiting the activity of ABC transporters may be a logical approach to circumvent MDR. Olmutinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), which has been approved in South Korea for advanced EGFR T790M-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 [125I]-iodoarylazidoprazosin (IAAP). However, olmutinib neither altered ABCG2 expression at protein and mRNA 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.