Effect of abemaciclib (LY2835219) on enhancement of chemotherapeutic agents in ABCB1 and ABCG2 overexpressing cells in vitro and in vivo
Effect of abemaciclib (LY2835219) on enhancement of chemotherapeutic agents in ABCB1 and ABCG2 overexpressing cells in vitro and in vivo
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abemaciclib (LY2835219)对ABCB1和ABCG2过表达细胞体内外增强化疗药物的作用
DOI：
10.1016/j.bcp.2016.10.015
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发表时间：
2017-01
影响因子：
5.8
通讯作者：
Fu LW
中科院分区：
文献类型：
--
作者：
Wu Tong;Cheng Bin;Wu Tong;Chen Zhen;Fang Xiaona;Wang Fang;Fu Liwu;To Kenneth K. W.;Cheng B;Fu LW
多药耐药（MDR）是肿瘤化疗成功的主要障碍。ATP结合盒（ABC）转运蛋白，特别是ABCB 1和ABCG 2的过表达，通过将抗癌药物泵出癌细胞而在介导MDR中发挥重要作用。Abemaciclib（LY 2835219）是一种口服生物可利用的CDK 4/6抑制剂，正在进行III期临床试验。在此，我们发现LY 2835219在体外和体内显著增强化疗药物对ABCB 1或ABCG 2过表达癌细胞的疗效。此外，LY 2835219通过抑制ABCB 1或ABCG 2介导的转运蛋白过表达细胞中的药物外排，显著增加了多柔比星（DOX）和罗丹明123（Rho 123）的细胞内蓄积。从机制上讲，LY 2835219可能是ABCB 1和ABCG 2的竞争性抑制剂，因为它与[125 I]-碘芳基齐唑嗪竞争转运蛋白的光亲和标记。另一方面，在转运蛋白抑制浓度下，LY 2835219没有改变亲本细胞及其耐药细胞中ABCB 1和ABCG 2的表达水平以及视网膜母细胞瘤（Rb）通路的磷酸化状态。结论：LY 2835219具有逆转ABCB 1或ABCG 2介导的MDR的新作用，对MDR肿瘤患者的联合治疗有一定的指导意义。
Multidrug resistance (MDR) is the major obstacle of the success in cancer chemotherapy. The overexpression of ATP-binding cassette (ABC) transporters, particularly ABCB1 and ABCG2, play a significant role in mediating MDR by pumping anticancer drugs out of cancer cells. Abemaciclib (LY2835219) is an orally bioavailable CDK4/6 inhibitor under phase III clinical trials. Here, we found that LY2835219 remarkably enhanced the efficacy of chemotherapeutic drugs in ABCB1 or ABCG2 over-expressing cancer cellsin vitroandin vivo. Furthermore, LY2835219 significantly increased the intracellular accumulation of doxorubicin (DOX) and rhodamine 123 (Rho 123) by inhibiting ABCB1 or ABCG2-mediated drug efflux in the transporters-overexpressing cells. Mechanistically, LY2835219 is likely a competitive inhibitor of ABCB1 and ABCG2 for its competition with [125I]-iodoarylazidoprazosin for photo affinity labeling of the transporters. On the other hand, at the transporters-inhibiting concentrations, LY2835219 did not alter the expression level of ABCB1 and ABCG2, and the phosphorylation status of retinoblastoma (Rb) pathway in both parental and their resistant cells. In conclusion, these findings revealed a novel role of LY2835219 in reversing ABCB1 or ABCG2-mediated MDR, which may be benefit to the patients with MDR cancer for combinational therapy.
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影响因子：
11.2
作者：
Dai CL;Tiwari AK;Wu CP;Su XD;Wang SR;Liu DG;Ashby CR Jr;Huang Y;Robey RW;Liang YJ;Chen LM;Shi CJ;Ambudkar SV;Chen ZS;Fu LW
通讯作者：
Fu LW
影响因子：
3.6
作者：
Jian-ye Zhang;Hai-Ying Wu;X. Xia;Yong‐ju Liang;Yan-yan Yan-Yan-yan-Yan-3522947;Z. She;Yong‐cheng Lin;L. Fu
通讯作者：
Jian-ye Zhang;Hai-Ying Wu;X. Xia;Yong‐ju Liang;Yan-yan Yan-Yan-yan-Yan-3522947;Z. She;Yong‐cheng Lin;L. Fu
从咪唑衍生物中筛选新型、有效的多重耐药调节剂。
影响因子：
3.1
作者：
Chen, LM;Wu, XP;Fu, LW
通讯作者：
Fu, LW
DOI：
--
发表时间：
2012
期刊：
--
影响因子：
--
作者：
Kevin G. Chen;B. Sikic
通讯作者：
Kevin G. Chen;B. Sikic
影响因子：
3
作者：
Fu, LW;Liang, YJ;Pan, QC
通讯作者：
Pan, QC