Apatinib (YN968D1) enhances the efficacy of conventional chemotherapeutical drugs in side population cells and ABCB1-overexpressing leukemia cells
Apatinib (YN968D1) enhances the efficacy of conventional chemotherapeutical drugs in side population cells and ABCB1-overexpressing leukemia cells
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DOI：
10.1016/j.bcp.2011.12.007
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发表时间：
2012-03-01
影响因子：
5.8
通讯作者：
Fu, Li-wu
中科院分区：
文献类型：
--
作者：
Tong, Xiu-zhen;Wang, Fang;Fu, Li-wu
P-糖蛋白（P-gp，ABCB 1）过表达和干细胞样细胞富集与肿瘤患者预后不良有关。在这项研究中，我们研究了阿帕替尼（一种口服多靶点酪氨酸激酶抑制剂（TKI））在体外、体内和离体增强传统抗癌药物在侧群（SP）细胞和ABCB 1过表达白血病细胞中疗效的作用。我们的研究结果表明，阿帕替尼显着增强阿霉素诱导的SP细胞的细胞毒性和细胞凋亡从K562细胞分选。此外，阿帕替尼还强烈逆转了K562/ADR细胞和过表达ABCB 1的原代白血病母细胞中的多药耐药（MDR），而在MRP 1、MRP 4、MRP 7和LRP过表达细胞中未显示出与化疗药物的协同相互作用。阿帕替尼治疗显著增加了K562/ADR细胞中阿霉素和罗丹明123的细胞内蓄积，以及ABCB 1过表达的原发性白血病母细胞中罗丹明123的蓄积。阿帕替尼以剂量依赖性方式刺激P-gp的ATP酶活性，但在mRNA和蛋白水平上均不改变ABCB 1的表达。在敏感和MDR细胞中，阿帕替尼处理后AKT和ERK 1/2的磷酸化水平保持不变。重要的是，阿帕替尼显着增强了阿霉素在携带K562/ADR异种移植物的裸小鼠中的抗肿瘤活性。综上所述，我们的研究结果表明，阿帕替尼可以靶向SP细胞和ABCB 1过表达的白血病细胞，以提高化疗药物的疗效。这些发现对于阿帕替尼与化疗药物的联合应用具有重要的临床意义。(C)2011 Elsevier Inc. All rights reserved.
P-glycoprotein (P-gp, ABCB1) overexpression and enrichment of stem-like cells are linked to poor prognosis in tumor patients. In this study, we investigated the effect of apatinib, an oral multi-targeted tyrosine kinase inhibitor (TKI) on enhancing the efficacy of conventional anticancer drugs in side population (SP) cells and ABCB1-overexpressing leukemia cells in vitro, in vivo and ex vivo. Our results showed that apatinib significantly enhanced the cytotoxicity and cell apoptosis induced by doxorubicin in SP cells sorted from K562 cells. Furthermore, apatinib also strongly reversed multidrug resistance (MDR) in K562/ADR cells, and the primary leukemia blasts overexpressing ABCB1 while showed no synergistic interactions with chemotherapeutic agents in MRP1-, MRP4-, MRP7- and LRP-overexpressing cells. Apatinib treatment markedly increased the intracellular accumulation of doxorubicin and rhodamine 123 in K562/ADR cells and the accumulation of rhodamine 123 in the primary leukemia blasts with ABCB1 overexpression. Apatinib stimulated the ATPase activity of P-gp in a dose-dependent manner but did not alter the expression of ABCB1 at both mRNA and protein levels. The phosphorylation level of AKT and ERK1/2 remained unchanged after apatinib treatment in both sensitive and MDR cells. Importantly, apatinib significantly enhanced the antitumor activity of doxorubicin in nude mice bearing K562/ADR xenografts. Taken together, our results suggest that apatinib could target to SP cells and ABCB1-overexpressing leukemia cells to enhance the efficacy of chemotherapeutic drugs. These findings should be useful for the combination of apatinib and chemotherapeutic agents in the clinic. (C) 2011 Elsevier Inc. All rights reserved.