Apatinib (YN968D1) enhances the efficacy of conventional chemotherapeutical drugs in side population cells and ABCB1-overexpressing leukemia cells

• Published in: Biochemical pharmacology Vol. 83; no. 5; pp. 586 - 597
• Main Authors: Tong, Xiu-zhen, Wang, Fang, Liang, Shu, Zhang, Xu, He, Jie-hua, Chen, Xing-Gui, Liang, Yong-ju, Mi, Yan-jun, To, Kenneth Kin Wah, Fu, Li-wu
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.03.2012
• Subjects: adenosinetriphosphatase; Animals; anticarcinogenic activity; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; apoptosis; ATP Binding Cassette Transporter, Sub-Family B; ATP-binding cassette transporter; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Cell Line; cytotoxicity; doxorubicin; Drug Resistance, Neoplasm; Drug Therapy, Combination; Gene Expression Regulation, Neoplastic; Humans; leukemia; Leukemia - drug therapy; Leukemia stem-like cells; Male; Mice; Mice, Nude; Molecular Structure; Multidrug resistance; multiple drug resistance; Neoplasms, Experimental - drug therapy; P-glycoprotein; patients; phosphorylation; prognosis; Pyridines - administration & dosage; Pyridines - pharmacology; stem cells; tyrosine; Xenograft; P-glycoprotein; Xenograft; Leukemia stem-like cells; ATP-binding cassette transporter; Multidrug resistance
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2011.12.007

Apatinib increases the intracellular accumulation of anti-cancer drugs (D) that are substrates of ABCB1 and ABCG2 via directly inhibiting the drug transport function. 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.