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 acti...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 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.展开更多
对抗肿瘤药奥莫替尼(1)的合成工艺进行了优化。以3-氨基噻吩-2-羧酸甲酯和尿素为起始原料,经环合制得噻吩并嘧啶母核,再经氯代、亲核取代、还原等反应合成1,其结构经1 H NMR和IR确证。与专利报道的以3-氨基噻吩-2-羧酸甲酯为起始原料的...对抗肿瘤药奥莫替尼(1)的合成工艺进行了优化。以3-氨基噻吩-2-羧酸甲酯和尿素为起始原料,经环合制得噻吩并嘧啶母核,再经氯代、亲核取代、还原等反应合成1,其结构经1 H NMR和IR确证。与专利报道的以3-氨基噻吩-2-羧酸甲酯为起始原料的工艺路线相比,优化后的工艺路线具有后处理操作简单,总收率较高(25.7%)等优点。展开更多
基金supported by the National Natural Science Foundation of China (No. 81473233)Guangzhou Technology Program Foundation (No. 201604020079)+1 种基金The Science and Technology Project of Guangdong Province (No. 2016A030312014)The Scientific and Technological Leading Talent Project of Guangdong Province (2015)
文摘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 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.
文摘对抗肿瘤药奥莫替尼(1)的合成工艺进行了优化。以3-氨基噻吩-2-羧酸甲酯和尿素为起始原料,经环合制得噻吩并嘧啶母核,再经氯代、亲核取代、还原等反应合成1,其结构经1 H NMR和IR确证。与专利报道的以3-氨基噻吩-2-羧酸甲酯为起始原料的工艺路线相比,优化后的工艺路线具有后处理操作简单,总收率较高(25.7%)等优点。
