Department of Hematology, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China.
Biochem Pharmacol. 2012 Mar 1;83(5):586-97. doi: 10.1016/j.bcp.2011.12.007. Epub 2011 Dec 16.
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.
P-糖蛋白（P-gp，ABCB1）过表达和干细胞样细胞的富集与肿瘤患者的预后不良有关。在这项研究中，我们研究了阿帕替尼对体外、体内和离体条件下多靶点酪氨酸激酶抑制剂（TKI）对侧群（SP）细胞和 ABCB1 过表达白血病细胞中常规抗癌药物疗效的影响。我们的结果表明，阿帕替尼显著增强了从 K562 细胞中分选的 SP 细胞中阿霉素诱导的细胞毒性和细胞凋亡。此外，阿帕替尼还强烈逆转了 K562/ADR 细胞的多药耐药性（MDR），而原发性白血病母细胞过表达 ABCB1 时，与化疗药物在 MRP1、MRP4、MRP7 和 LRP 过表达细胞中无协同作用。阿帕替尼治疗显著增加了 K562/ADR 细胞中阿霉素和罗丹明 123 的细胞内积累，以及 ABCB1 过表达的原发性白血病母细胞中罗丹明 123 的积累。阿帕替尼以剂量依赖的方式刺激 P-gp 的 ATP 酶活性，但不改变 ABCB1 在 mRNA 和蛋白水平的表达。阿帕替尼处理后，敏感和 MDR 细胞中 AKT 和 ERK1/2 的磷酸化水平保持不变。重要的是，阿帕替尼显著增强了荷 K562/ADR 异种移植瘤裸鼠体内阿霉素的抗肿瘤活性。综上所述，我们的结果表明，阿帕替尼可以靶向 SP 细胞和 ABCB1 过表达的白血病细胞，增强化疗药物的疗效。这些发现对于阿帕替尼与化疗药物联合应用于临床具有重要意义。
