title: Apatinib (YN968D1) reverses multidrug resistance by inhibiting the efflux function of multiple ATP-binding cassette transporters.
abstract: Apatinib, a small-molecule multitargeted tyrosine kinase inhibitor, is in phase III clinical trial for the treatment of patients with non-small-cell lung cancer and gastric cancer in China. In this study, we determined the effect of apatinib on the interaction of specific antineoplastic compounds with P-glycoprotein (ABCB1), multidrug resistance protein 1 (MRP1, ABCC1), and breast cancer resistance protein (BCRP, ABCG2). Our results showed that apatinib significantly enhanced the cytotoxicity of ABCB1 or ABCG2 substrate drugs in KBv200, MCF-7/adr, and HEK293/ABCB1 cells overexpressing ABCB1 and in S1-M1-80, MCF-7/FLV1000, and HEK293/ABCG2-R2 cells overexpressing ABCG2 (wild-type). In contrast, apatinib did not alter the cytotoxicity of specific substrates in the parental cells and cells overexpressing ABCC1. Apatinib significantly increased the intracellular accumulation of rhodamine 123 and doxorubicin in the multidrug resistance (MDR) cells. Furthermore, apatinib significantly inhibited the photoaffinity labeling of both ABCB1 and ABCG2 with [(125)I]iodoarylazidoprazosin in a concentration-dependent manner. The ATPase activity of both ABCB1 and ABCG2 was significantly increased by apatinib. However, apatinib, at a concentration that produced a reversal of MDR, did not significantly alter the ABCB1 or ABCG2 protein or mRNA expression levels or the phosphorylation of AKT and extracellular signal-regulated kinase 1/2 (ERK1/2). Importantly, apatinib significantly enhanced the effect of paclitaxel against the ABCB1-resistant KBv200 cancer cell xenografts in nude mice. In conclusion, apatinib reverses ABCB1- and ABCG2-mediated MDR by inhibiting their transport function, but not by blocking the AKT or ERK1/2 pathway or downregulating ABCB1 or ABCG2 expression. Apatinib may be useful in circumventing MDR to other conventional antineoplastic drugs.
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Yan-Jun
authors.initials: YJ
authors.lastname: Mi
authors.forename: Yong-Ju
authors.initials: YJ
authors.lastname: Liang
authors.forename: Hong-Bing
authors.initials: HB
authors.lastname: Huang
authors.forename: Hong-Yun
authors.initials: HY
authors.lastname: Zhao
authors.forename: Chung-Pu
authors.initials: CP
authors.lastname: Wu
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.forename: Li-Yang
authors.initials: LY
authors.lastname: Tao
authors.forename: Chuan-Zhao
authors.initials: CZ
authors.lastname: Zhang
authors.forename: Chun-Ling
authors.initials: CL
authors.lastname: Dai
authors.forename: Amit K
authors.initials: AK
authors.lastname: Tiwari
authors.forename: Xiao-Xu
authors.initials: XX
authors.lastname: Ma
authors.forename: Kenneth Kin Wah
authors.initials: KK
authors.lastname: To
authors.forename: Suresh V
authors.initials: SV
authors.lastname: Ambudkar
authors.forename: Zhe-Sheng
authors.initials: ZS
authors.lastname: Chen
authors.forename: Li-Wu
authors.initials: LW
authors.lastname: Fu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000187:drug effects; D000251:Adenosine Triphosphatases / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D004791:Enzyme Inhibitors; D011725:Pyridines; C553458:apatinib; D004317:Doxorubicin; D011505:Protein-Tyrosine Kinases; D000251:Adenosine Triphosphatases