Apatinib (YN968D1) Reverses Multidrug Resistance by Inhibiting the Efflux Function of Multiple ATP-Binding Cassette Transporters
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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 [125I]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. Cancer Res; 70(20); 7981–91. ©2010 AACR.
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While many cancers are driven by aberrant kinase activity, it is thought that targeting the PPIs that regulate the activity of a specific kinase is a more viable approach to develop selective kinase inhibitors than targeting the conserved ATP binding site of kinases directly.
“Furthermore, while many cancers are driven by aberrant kinase activity, it is thought that targeting the PPIs that regulate the activity of a specific kinase is a more viable approach to develop selective kinase inhibitors than targeting the conserved ATP binding site of kinases directly [4, 102, 103].”
From The design and development of covalent protein-protein interaction inhibitors for cancer treatment (2020) · cites this paper as [103]
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Cites
Bradford, M. M. (1976) · Analytical Biochemistry · doi:10.1016/0003-2697(76)90527-3 · Cited by 255,302 · see citing works
A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants
Juliano, R. L., & Ling, V. W. T. (1976) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/0005-2736(76)90160-7 · Cited by 3,317 · see citing works
A multidrug resistance transporter from human MCF-7 breast cancer cells
Doyle, L. A., Yang, W., Abruzzo, L. V., Krogmann, T. A., Gao, Y., Rishi, A. K., & Ross, D. D. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.26.15665 · Cited by 2,319 · see citing works
BIOCHEMICAL, CELLULAR, AND PHARMACOLOGICAL ASPECTS OF THE MULTIDRUG TRANSPORTER
Ambudkar, S. V., Dey, S., Hrycyna, C. A., Ramachandra, M., Pastan, I. H., & Gottesman, M. M. (1999) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.39.1.361 · Cited by 2,059 · see citing works
Self-citationThe Human ATP-Binding Cassette (ABC) Transporter SuperfamilyPreprint
Dean, M. C., Rzhetsky, A., & Allikmets, R. L. (2001) · Genome Research · doi:10.1101/gr.184901 · Cited by 1,758 · see citing works
Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2)
Doyle, L. A., & Ross, D. D. (2003) · Oncogene · doi:10.1038/sj.onc.1206938 · Cited by 1,056 · see citing works
Miyake, K., Mickley, L. A., Litman, T., Zhan, Z., Robey, R. W., Cristensen, B., Brangi, M., Greenberger, L., Dean, M. C., Fojo, T., et al. (1999) · PubMed · Cited by 819 · see citing works
Allikmets, R., Schriml, L. M., Hutchinson, A. A., Romano-Spica, V., & Dean, M. C. (1998) · PubMed · Cited by 798 · see citing works
Litman, T., Druley, T. E., Stein, W. D., & Bates, S. E. (2001) · Cellular and Molecular Life Sciences · doi:10.1007/pl00000912 · Cited by 687 · see citing works
Activation of the PI3K/Akt pathway and chemotherapeutic resistance
West, K. A., Castillo, S. S., & Dennis, P. A. (2002) · Drug Resistance Updates · doi:10.1016/s1368-7646(02)00120-6 · Cited by 583 · see citing works
Characterization of a Side Population of Cancer Cells from Human Gastrointestinal System
Haraguchi, N., Utsunomiya, T., Inoue, H., Tanaka, F., Mimori, K., Barnard, G. F., & Mori, M. (2005) · Stem Cells · doi:10.1634/stemcells.2005-0282 · Cited by 566 · see citing works
Multidrug Resistance: Retrospect and Prospects in Anti-Cancer Drug Treatment
Pérez‐Tomás, R. (2006) · Current Medicinal Chemistry · doi:10.2174/092986706777585077 · Cited by 509 · see citing works
Choi, C.-H. (2005) · Cancer Cell International · doi:10.1186/1475-2867-5-30 · Cited by 505 · see citing works
Zhou, S., Morris, J. J., Barnes, Y., Lan, L.-B., Schuetz, J. D., & Sorrentino, B. P. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.192276999 · Cited by 503 · see citing works
Rabindran, S. K., Ross, D. D., Doyle, L. A., Yang, W., & Greenberger, L. M. (2000) · PubMed · Cited by 487 · see citing works
HER2/PI-3K/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cells
Knuefermann, C., Lü, Y., Liu, B., Jin, W., Liang, K., Wu, L., Schmidt, M., Mills, G. B., Mendelsohn, J. M., & Fan, Z. (2003) · Oncogene · doi:10.1038/sj.onc.1206394 · Cited by 452 · see citing works
Honjo, Y., Hrycyna, C. A., Yan, Q. W., Medina-Pérez, W. Y., Robey, R. W., van de Laar, A., Litman, T., Dean, M. C., & Bates, S. E. (2001) · PubMed · Cited by 429 · see citing works
Mechanisms and strategies to overcome multiple drug resistance in cancer
Özben, T. (2006) · FEBS Letters · doi:10.1016/j.febslet.2006.02.020 · Cited by 407 · see citing works
Dai, C.-L., Tiwari, A. K., Wu, C.-P., Su, X.-D., Wang, S.-R., Liu, D.-G., Ashby, C. R., Huang, Y., Robey, R. W., Liang, Y.-J., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-0499 · Cited by 386 · see citing works
Self-citationMutations at amino-acid 482 in the ABCG2 gene affect substrate and antagonist specificity
Robey, R. W., Honjo, Y., Morisaki, K., Nadjem, T., Runge, S., Risbood, M., Poruchynsky, M. S., & Bates, S. E. (2003) · British Journal of Cancer · doi:10.1038/sj.bjc.6601370 · Cited by 367 · see citing works
Structure and regulation of Kit protein-tyrosine kinase—The stem cell factor receptor
Roskoski, R. J. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.09.150 · Cited by 345 · see citing works
Robey, R. W., Medina-Pérez, W. Y., Nishiyama, K., Lahusen, T. J., Miyake, K., Litman, T., Senderowicz, A. M., Ross, D. D., & Bates, S. E. (2001) · PubMed · Cited by 341 · see citing works
Shi, Z., Peng, X.-X., Kim, I., Shukla, S., Si, Q.-S., Robey, R. W., Bates, S. E., Shen, T., Ashby, C. R., Fu, L., et al. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-2686 · Cited by 315 · see citing works
Self-citationRepacking of the transmembrane domains of P‐glycoprotein during the transport ATPase cycle
Rosenberg, M. F., Velarde, G., Ford, R. C., et al. (2001) · The EMBO Journal · doi:10.1093/emboj/20.20.5615 · Cited by 295 · see citing works
EGFR family: Structure physiology signalling and therapeutic targets <sup>†</sup>
Burgess, A. W. (2008) · Growth Factors · doi:10.1080/08977190802312844 · Cited by 288 · see citing works
Shukla, S., Robey, R. W., Bates, S. E., & Ambudkar, S. V. (2008) · Drug Metabolism and Disposition · doi:10.1124/dmd.108.024612 · Cited by 226 · see citing works
Self-citationErlichman, C., Boerner, S. A., Hallgren, C. G., Spieker, R. S., Wang, X., James, C. D., Scheffer, G. L., Maliepaard, M., Ross, D. D., Bible, K. C., et al. (2001) · PubMed · Cited by 224 · see citing works
Elkind, N. B., Szentpétery, Z., Apáti, Á., Özvegy‐Laczka, C., Várady, G., Ujhelly, O., Szabó, K., Homolya, L., Váradi, A., Buday, L., et al. (2005) · Cancer Research · doi:10.1158/0008-5472.can-04-3303 · Cited by 223 · see citing works
Tiwari, A. K., Sodani, K. S., Wang, S., Kuang, Y., Ashby, C. R., Chen, X. '., & Chen, Z. (2009) · Biochemical Pharmacology · doi:10.1016/j.bcp.2009.04.002 · Cited by 210 · see citing works
Self-citationHegedűs, T., Őrfi, L., Seprődi, A., Váradi, A., Sarkadi, B., & Kéri, G. (2002) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/s0925-4439(02)00095-9 · Cited by 207 · see citing works
[37] Drug-stimulatable ATPase activity in crude membranes of human MDR1-transfected mammalian cells
Ambudkar, S. V. (1998) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(98)92039-0 · Cited by 199 · see citing works
Self-citationKitazaki, T., Oka, M., Nakamura, Y., Tsurutani, J., Doi, S., Yasunaga, M., Takemura, M., Yabuuchi, H., Soda, H., & Kohno, S. (2005) · Lung Cancer · doi:10.1016/j.lungcan.2005.03.035 · Cited by 182 · see citing works
Shen, G., Xu, C., Hu, R., Jain, M. R., Gopalkrishnan, A., Nair, S., Huang, M., Chan, J. Y., & Kong, A. T. (2006) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-05-0293 · Cited by 179 · see citing works
Robey, R. W., Shukla, S., Finley, E. M., Oldham, R. K., Barnett, D., Ambudkar, S. V., Fojo, T., & Bates, S. E. (2008) · Biochemical Pharmacology · doi:10.1016/j.bcp.2007.12.001 · Cited by 159 · see citing works
Self-citationShibuya, M. (2006) · Endothelium · doi:10.1080/10623320600697955 · Cited by 151 · see citing works
Characterization of tetrandrine, a potent inhibitor of P-glycoprotein-mediated multidrug resistance
Fu, L., Liang, Y.-J., Deng, L., Ding, Y. P., Chen, L., Ye, Y.-L., Yang, X., & Pan, Q. (2004) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-003-0742-5 · Cited by 145 · see citing works
Self-citationShi, Z., Liang, Y.-J., Chen, Z., Wang, X., Wang, X., Ding, Y. P., Chen, L., Yang, X.-P., & Fu, L. (2006) · Cancer Biology & Therapy · doi:10.4161/cbt.5.1.2236 · Cited by 141 · see citing works
Self-citationGagnon, V., Themsche, C. V., Turner, S., Leblanc, V., & Asselin, É. (2007) · APOPTOSIS · doi:10.1007/s10495-007-0165-6 · Cited by 123 · see citing works
Taguchi, Y., Yoshida, A., Takada, Y., Komano, T., & Ueda, K. (1997) · FEBS Letters · doi:10.1016/s0014-5793(96)01421-4 · Cited by 121 · see citing works
Dai, C.-L., Liang, Y.-J., Wang, Y.-S., Tiwari, A. K., Yan, Y., Wang, F., Chen, Z., Tong, X.-Z., & Fu, L. (2009) · Cancer Letters · doi:10.1016/j.canlet.2009.01.027 · Cited by 120 · see citing works
Self-citationDrug transporters: recent advances concerning BCRP and tyrosine kinase inhibitors
Lemos, C., Jansen, G., & Peters, G. J. (2008) · British Journal of Cancer · doi:10.1038/sj.bjc.6604213 · Cited by 115 · see citing works
Shukla, S., Robey, R. W., Bates, S. E., & Ambudkar, S. V. (2006) · Biochemistry · doi:10.1021/bi060552f · Cited by 103 · see citing works
Self-citationZheng, L.-S., Wang, F., Li, Y., Zhang, X., Chen, L., Liang, Y.-J., Dai, C.-L., Yan, Y., Tao, L.-Y., Mi, Y., et al. (2009) · PLoS ONE · doi:10.1371/journal.pone.0005172 · Cited by 92 · see citing works
Self-citationHeymach, J. V., Nilsson, M. B., Blumenschein, G., Papadimitrakopoulou, V. A., & Herbst, R. S. (2006) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-0286 · Cited by 89 · see citing works
Correction: Reversal of Multidrug Resistance by Lapatinib
(2008) · Cancer Research · doi:10.1158/0008-5472.can-68-24-cor · Cited by 86 · see citing works
Özvegy‐Laczka, C., Köblös, G., Sarkadi, B., & Váradi, A. (2004) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2004.11.005 · Cited by 80 · see citing works
Zhang, J., Wu, H.-Y., Xia, X.-K., et al. (2007) · Cancer Biology & Therapy · doi:10.4161/cbt.6.9.4543 · Cited by 73 · see citing works
ZD6474 reverses multidrug resistance by directly inhibiting the function of P-glycoprotein
Mi, Y., & Lou, L. (2007) · British Journal of Cancer · doi:10.1038/sj.bjc.6603985 · Cited by 68 · see citing works
Self-citationReversal of P-gp mediated multidrug resistance in-vitro and in-vivo by FG020318
Chen, L., Liang, Y.-J., Ruan, J., Ding, Y. P., Wang, X., Shi, Z., Gu, L., Yang, X.-P., & Fu, L. (2004) · Journal of Pharmacy and Pharmacology · doi:10.1211/0022357043879 · Cited by 61 · see citing works
Self-citationMüller, M., Yong, M., Peng, X.-H., Petre, B., Arora, S., & Ambudkar, S. V. (2002) · Biochemistry · doi:10.1021/bi026075s · Cited by 55 · see citing works
Self-citationERK activation by Thymosin-beta-4 (TB4) overexpression induces paclitaxel-resistance
Oh, S.-Y., Song, J.-H., Gil, J.-E., Kim, J. H., Yeom, Y., & Moon, E. (2006) · Experimental Cell Research · doi:10.1016/j.yexcr.2006.01.030 · Cited by 55 · see citing works
Tao, L.-Y., Liang, Y.-J., Wang, F., Chen, L., Yan, Y., Dai, C.-L., & Fu, L. (2009) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-009-0949-1 · Cited by 55 · see citing works
Self-citationVascular Endothelial Growth Factor and Its Receptor as Drug Targets in Hematological Malignancies
Keßler, T., Fehrmann, F., Bieker, R., et al. (2007) · Current Drug Targets · doi:10.2174/138945007779940089 · Cited by 51 · see citing works
Screening Novel, Potent Multidrug-Resistant Modulators From Imidazole Derivatives
Chen, L., Wu, X.-P., Ruan, J., Liang, Y.-J., Ding, Y. P., Shi, Z., Wang, X., Gu, L., & Fu, L. (2004) · Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics · doi:10.3727/0965040041292378 · Cited by 50 · see citing works
Self-citationA comparison of the parameter estimating procedures for the Michaelis-Menten model
Tseng, S., & Hsu, J. (1990) · Journal of Theoretical Biology · doi:10.1016/s0022-5193(05)80481-3 · Cited by 31 · see citing works
Improved methodology for intracellular enzyme reaction and inhibition kinetics by flow cytometry
Dive, C., Workman, P., & Watson, J. E. M. (1987) · Cytometry · doi:10.1002/cyto.990080604 · Cited by 22 · see citing works
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Self-citation
- Authors
- Mi, Y.-J., Liang, Y.-J., Huang, H.-B., Zhao, H.-Y., Wu, C.-P., Wang, F., Tao, L.-Y., Zhang, C.-Z., Dai, C.-L., Tiwari, A. K., Ma, X.-X., To, K. K. W., Ambudkar, S. V., Chen, Z.-S., & Fu, L.-W.
- Affiliations
- National Institutes of Health (US)
- St. John's University (US)
- Authors' Affiliations: 1State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China; 2Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland; 3Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, New York; and 4School of Pharmacy, The Chinese University of Hong Kong, Hong Kong, P.R. China
- ORCID
- Venue
- Cancer Research
- Published
- 2010-10-13
- Volume
- 70
- Issue
- 20
- Pages
- 7981-7991
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC2969180
- OpenAlex
- W2105968397
- Cited by
- 337
- References
- 56
- Citations by year
- 2026: 8 · 2025: 7 · 2024: 25 · 2023: 14 · 2022: 28 · 2021: 28 · 2020: 37 · 2019: 29 · 2018: 36 · 2017: 35 · 2016: 18 · 2015: 16 · 2014: 18 · 2013: 16 · 2012: 17
- FWCI
- 5.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Kagoshima University
- National Institutes of Health
- National Cancer Institute (Z01BC010030)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Antibiotic Resistance in Bacteria
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- apatinib, multidrug resistance reversal, P-glycoprotein, ABCG2, multidrug resistance protein 1, ABC transporters, drug efflux inhibition, paclitaxel resistance, doxorubicin accumulation, tyrosine kinase inhibitors
- MeSH terms
- Adenosine Triphosphatases, Animals, Breast Neoplasms, Cell Survival, Doxorubicin, Enzyme Inhibitors, Female, Humans, Mice, Inbred BALB C, Mice, Nude, Protein-Tyrosine Kinases, Pyridines, Transplantation, Heterologous, Drug Resistance, Multiple, ATP Binding Cassette Transporter, Subfamily B, ATP-Binding Cassette Transporters, Reverse Transcriptase Polymerase Chain Reaction, ATP Binding Cassette Transporter, Subfamily B, Member 1, Cell Line, Tumor, Mice
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