The Reciprocal Interaction of Small Molecule Protein Kinase Inhibitors and ATP-Binding Cassette Transporters in Targeted Cancer Therapy


  • Hong-Ye Zhao Key Laboratory of Agricultural Biodiversity and Plant Disease Management of China Education Ministry, Yunnan Agricultural University, Kunming 650201, China
  • Hongjiang Wei College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China
  • Xin Wang College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China



Protein Kinase Inhibitors, ABC Transporters, P-gp/ABCB1, BCRP/ABCG2, Targeted Cancer Therapy.


 Protein kinaseshave become the second most important group of drug targets, after G-protein-coupled receptors. Currently,15 small molecule protein kinase inhibitors (PKIs) have received food and drug administrator (FDA) approval to be used as cancer treatments. However, in the course of clinical use of these small molecule PKIs, drug resistance has become a recurring problem. Their therapeutic potential depends on access to their intracellular targets, which significantly affected by certain membrane ATP-binding cassette(ABC) transporters. ABC transporters were major causesof clinical multiple drug resistance (MDR) and might be resulting in the development of resistance to PKIs in cancer patients. Some PKIs could modulate the activity of ABC transporters and affect the metabolism of themselves and other chemically unrelated drugs. Moreover, it has been recently reported that some PKIs could regulate the expression of ABC transporters in tumor cells, thereby affect their intracellular accumulation and antitumor efficacy. In this review,the reciprocal interaction of clinically important PKIs with the MDR-related ABC transporters, in particular ABCB1 and ABCG2,wassummarized. Keyword:Protein Kinase Inhibitors, ABC Transporters, P-gp/ABCB1, BCRP/ABCG2, Targeted Cancer Therapy.


Gray-Schopfer V, Wellbrock C, Marais R. Melanoma biology and new targeted therapy. Nature 2007; 445: 851-7.

Becker J, Ugurel S, Schrama D. Strategies to optimize the use of targeted agents for tumor therapy. J Dtsch Dermatol Ges 2008; 6: 281-5.

Chahrour O, Cairns D, Omran Z. Small molecule kinase inhibitors as anti-cancer therapeutics. Mini Rev Med Chem 2012; 12: 399-11.

Ozvegy-Laczka C, Cserepes J, Elkind NB, Sarkadi B. Tyrosine kinase inhibitor resistance in cancer: role of ABC multidrug transporters. Drug Resist Updat 2005; 8: 15-26.

Hegedus C, Ozvegy-Laczka C, Szakács G, Sarkadi B. Interaction of ABC multidrug transporters with anticancer protein kinase inhibitors: substrates and/or inhibitors? Curr Cancer Drug Targets 2009; 9: 252-72.

Shukla S, Chen Z, Ambudkar S. Tyrosine kinase inhibitors as modulators of ABC transporter-mediated drug resistance. Drug Resist Updat 2012; 15: 70-80.

Brózik A, Hegedüs C, Erdei Z, Hegedus T, Özvegy-Laczka C, Szakács G, et al. Tyrosine kinase inhibitors as modulators of ATP binding cassette multidrug transporters: substrates, chemosensitizers or inducers of acquired multidrug resistance? Expert Opin Drug Metab Toxicol 2011; 7: 623-42.

Wang XK, Fu LW. Interaction of tyrosine kinase inhibitors with the MDR- related ABC transporter proteins. Curr Drug Metab 2010; 11: 618-28. query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20812904

Hegedus T, Orfi L, Seprodi A, Varadi A, Sarkadi B, Keri G. Interaction of tyrosine kinase inhibitors with the human multidrug transporter proteins, MDR1 and MRP1. Biochim Biophys Acta 2002; 1587: 318-25. http://www.ncbi.nlm.

Shukla S, Sauna Z, Ambudkar S. Evidence for the interaction of imatinib at the transport-substrate site(s) of the multidrug-resistance-linked ABC drug transporters ABCB1 (P-glycoprotein) and ABCG2. Leukemia 2008; 22: 445-7.

Chen Y, Agarwal S, Shaik NM, Chen C, Yang Z, Elmquist WF. P-glycoprotein and breast cancer resistance protein influence brain distribution of dasatinib. J Pharmacol Exp Ther 2009; 330: 956-63. query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19491323

van Erp NP, Gelderblom H, Guchelaar HJ. Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev 2009; 35: 692-706. query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19733976

Noble M, Endicott J, Johnson L. Protein kinase inhibitors: insights into drug design from structure. Science 2004; 303: 1800-5.

Thaimattam R, Banerjee R, Miglani R, Iqbal J. Protein kinase inhibitors: structural insights into selectivity. Curr Pharm Des 2007; 13: 2751-65.

Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. The protein kinase complement of the human genome. Science 2002; 298: 1912-34. entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12471243

Torkamani A, Schork N. Distribution analysis of nonsynonymous polymorphisms within the human kinase gene family. Genomics 2007; 90: 49-58.

Martin J, Anamika K, Srinivasan N. Classification of protein kinases on the basis of both kinase and non-kinase regions. PLoS One 2010; 5: e12460.

Zhang J, Yang PL, Gray NS. Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer 2009; 9: 28-39.

Paul MK, Mukhopadhyay AK. Tyrosine kinase - Role and significance in Cancer. Int J Med Sci 2004; 1: 101-15.

Catalanotti F, Reyes G, Jesenberger V, Galabova-Kovacs G, de Matos Simoes R, Carugo O, et al. A Mek1-Mek2 heterodimer determines the strength and duration of the Erk signal. Nat Struct Mol Biol 2009; 16: 294-303.

Anamika K, Garnier N, Srinivasan N. Functional diversity of human protein kinase splice variants marks significant expansion of human kinome. BMC Genomics 2009; 10: 622.

Eglen RM, Reisine T. The current status of drug discovery against the human kinome. Assay Drug Dev Technol 2009; 7: 22-43. cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19382888

Barouch-Bentov R, Sauer K. Mechanisms of drug resistance in kinases. Expert Opin Investig Drugs 2011; 20: 153-208.

Garuti L, Roberti M, Bottegoni G. Non-ATP competitive protein kinase inhibitors. Curr Med Chem 2010; 17: 2804-21.

Deeley RG, Westlake C, Cole SP. Transmembrane transport of endo- and xenobiotics by mammalian ATP-binding cassette multidrug resistance proteins. Physiol Rev 2006; 86: 849-99. Retrieve&db=PubMed&dopt=Citation&list_uids=16816140

Szakacs G, Paterson JK, Ludwig JA, Booth-Genthe C, Gottesman MM. Targeting multidrug resistance in cancer. Nat Rev Drug Discov 2006; 5: 219-34. http://www.ncbi.nlm.

Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer 2002; 2: 48-58. fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11902585

Stavrovskaya AA, Stromskaya TP. Transport proteins of the ABC family and multidrug resistance of tumor cells. Biochemistry (Mosc) 2008; 73: 592-604. http://www.ncbi.nlm.

Sharom FJ. ABC multidrug transporters: structure, function and role in chemoresistance. Pharmacogenomics 2008; 9: 105-27. cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18154452

Choudhuri S, Klaassen CD. Structure, function, expression, genomic organization, and single nucleotide polymorphisms of human ABCB1 (MDR1), ABCC (MRP), and ABCG2 (BCRP) efflux transporters. Int J Toxicol 2006; 25: 231-59.

Juliano RL, Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta 1976; 455: 152-62. http://www.ncbi.nlm.nih. gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=990323

Sauna ZE, Kim IW, Ambudkar SV. Genomics and the mechanism of P-glycoprotein (ABCB1). J Bioenerg Biomembr 2007; 39: 481-7. http://www.ncbi.nlm.nih. gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18058211

Fromm MF. P-glycoprotein: a defense mechanism limiting oral bioavailability and CNS accumulation of drugs. Int J Clin Pharmacol Ther 2000; 38: 69-74. http://www.ncbi.nlm.nih. gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10706193

Chan H, Haddad G, Thorner P, DeBoer G, Lin Y, Ondrusek N, et al. P-glycoprotein expression as a predictor of the outcome of therapy for neuroblastoma. N Engl J Med 1991; 325: 1608-14.

Cole SP, Bhardwaj G, Gerlach JH, Mackie JE, Grant CE, Almquist KC, et al. Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science 1992; 258: 1650-4. query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1360704

Deeley RG, Cole SP. Substrate recognition and transport by multidrug resistance protein 1 (ABCC1). FEBS Lett 2006; 580: 1103-11. query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16387301

Keppler D, Leier I, Jedlitschky G. Transport of glutathione conjugates and glucuronides by the multidrug resistance proteins MRP1 and MRP2. Biol Chem 1997; 378: 787-91.

Wijnholds J, Evers R, van Leusden MR, Mol CA, Zaman GJ, Mayer U, et al. Increased sensitivity to anticancer drugs and decreased inflammatory response in mice lacking the multidrug resistance-associated protein. Nat Med 1997; 3: 1275-9. cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9359705

Doyle LA, Yang W, Abruzzo LV, Krogmann T, Gao Y, Rishi AK, et al. A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc Natl Acad Sci U S A 1998; 95: 15665-70. cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9861027

Bauer B, Wolfger H, Kuchler K. Inventory and function of yeast ABC proteins: about sex, stress, pleiotropic drug and heavy metal resistance. Biochim Biophys Acta 1999; 1461: 217-36.

Miyake K, Mickley L, Litman T, Zhan Z, Robey R, Cristensen B, et al. Molecular cloning of cDNAs which are highly overexpressed in mitoxantrone-resistant cells: demonstration of homology to ABC transport genes. Cancer Res 1999; 59: 8-13.

Scharenberg C, Harkey M, Torok-Storb B. The ABCG2 transporter is an efficient Hoechst 33342 efflux pump and is preferentially expressed by immature human hematopoietic progenitors. Blood 2002; 99: 507-12.

Noguchi K, Katayama K, Mitsuhashi J, Sugimoto Y. Functions of the breast cancer resistance protein (BCRP/ABCG2) in chemotherapy. Adv Drug Deliv Rev 2009; 61: 26-33. fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19111841

Robey RW, Polgar O, Deeken J, To KW, Bates SE. ABCG2: determining its relevance in clinical drug resistance. Cancer Metastasis Rev 2007; 26: 39-57. entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17323127

Robert J, Jarry C. Multidrug resistance reversal agents. J Med Chem 2003; 46: 4805-17. entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14584929

Tan B, Piwnica-Worms D, Ratner L. Multidrug resistance transporters and modulation. Curr Opin Oncol 2000; 12: 450-8. Retrieve&db=PubMed&dopt=Citation&list_uids=10975553

Teodori E, Dei S, Martelli C, Scapecchi S, Gualtieri F. The functions and structure of ABC transporters: implications for the design of new inhibitors of Pgp and MRP1 to control multidrug resistance (MDR). Curr Drug Targets 2006; 7: 893-909. Retrieve&db=PubMed&dopt=Citation&list_uids=16842220

Ksienski D. Imatinib mesylate: past successes and future challenges in the treatment of gastrointestinal stromal tumors. Clin Med Insights Oncol 2011; 5: 365-79.

Dohse M, Scharenberg C, Shukla S, Robey RW, Volkmann T, Deeken JF, et al. Comparison of ATP-binding cassette transporter interactions with the tyrosine kinase inhibitors imatinib, nilotinib, and dasatinib. Drug Metab Dispos 2010; 38: 1371-80. cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20423956

Druker BJ, Guilhot F, O'Brien SG, Gathmann I, Kantarjian H, Gattermann N, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006; 355: 2408-17. cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17151364

Dai H, Marbach P, Lemaire M, Hayes M, Elmquist W. Distribution of STI-571 to the brain is limited by P-glycoprotein-mediated efflux. J Pharmacol Exp Ther 2003; 304: 1085-92.

Mahon FX, Belloc F, Lagarde V, Chollet C, Moreau-Gaudry F, Reiffers J, et al. MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. Blood 2003; 101: 2368-73. entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12609962

Illmer T, Schaich M, Platzbecker U, Freiberg-Richter J, Oelschlägel U, von Bonin M, et al. P-glycoprotein-mediated drug efflux is a resistance mechanism of chronic myelogenous leukemia cells to treatment with imatinib mesylate. Leukemia 2004; 18: 401-8.

Mahon FX, Deininger MW, Schultheis B, Chabrol J, Reiffers J, Goldman JM, et al. Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance. Blood 2000; 96: 1070-9. http://www.ncbi.nlm.nih. gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10910924

Hamada A, Miyano H, Watanabe H, Saito H. Interaction of imatinib mesilate with human P-glycoprotein. J Pharmacol Exp Ther 2003; 307: 824-8. entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12975485

Burger H, van Tol H, Boersma A, Brok M, Wiemer E, Stoter G, et al. Imatinib mesylate (STI571) is a substrate for the breast cancer resistance protein (BCRP)/ABCG2 drug pump. Blood 2004; 104: 2940-2.

Ozvegy-Laczka C, Hegedus T, Varady G, Ujhelly O, Schuetz JD, Varadi A, et al. High-affinity interaction of tyrosine kinase inhibitors with the ABCG2 multidrug transporter. Mol Pharmacol 2004; 65: 1485-95. entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15155841

Houghton PJ, Germain GS, Harwood FC, Schuetz JD, Stewart CF, Buchdunger E, et al. Imatinib mesylate is a potent inhibitor of the ABCG2 (BCRP) transporter and reverses resistance to topotecan and SN-38 in vitro. Cancer Res 2004; 64: 2333-7. query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15059881

Brendel C, Scharenberg C, Dohse M, Robey RW, Bates SE, Shukla S, et al. Imatinib mesylate and nilotinib (AMN107) exhibit high-affinity interaction with ABCG2 on primitive hematopoietic stem cells. Leukemia 2007; 21: 1267-75.

Mukai M, Che XF, Furukawa T, Sumizawa T, Aoki S, Ren XQ, et al. Reversal of the resistance to STI571 in human chronic myelogenous leukemia K562 cells. Cancer Sci 2003; 94: 557-63. cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12824882

Melo J. Imatinib and ABCG2: who controls whom? Blood 2006; 108: 1116-7.

Burger H, van Tol H, Brok M, Wiemer EA, de Bruijn EA, Guetens G, et al. Chronic imatinib mesylate exposure leads to reduced intracellular drug accumulation by induction of the ABCG2 (BCRP) and ABCB1 (MDR1) drug transport pumps. Cancer Biol Ther 2005; 4: 747-52. http://www.ncbi.nlm.

Nakanishi T, Shiozawa K, Hassel B, Ross D. Complex interaction of BCRP/ABCG2 and imatinib in BCR-ABL-expressing cells: BCRP-mediated resistance to imatinib is attenuated by imatinib-induced reduction of BCRP expression. Blood 2006; 108: 678-84.

Gao L, Chen L, Fei XH, Qiu HY, Zhou H, Wang JM. STI571 combined with vincristine greatly suppressed the tumor formation of multidrug-resistant K562 cells in a human-nude mice xenograft model. Chin Med J (Engl) 2006; 119: 911-8.

Oostendorp R, Buckle T, Beijnen J, van Tellingen O, Schellens J. The effect of P-gp (Mdr1a/1b), BCRP (Bcrp1) and P-gp/BCRP inhibitors on the in vivo absorption, distribution, metabolism and excretion of imatinib. Invest New Drugs 2009; 27: 31-40.

Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001; 344: 1031-7. entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11287972

Bihorel S, Camenisch G, Lemaire M, Scherrmann JM. Influence of breast cancer resistance protein (Abcg2) and p-glycoprotein (Abcb1a) on the transport of imatinib mesylate (Gleevec) across the mouse blood-brain barrier. J Neurochem 2007; 102: 1749-57. http://www.ncbi.nlm.nih. gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17696988

Bihorel S, Camenisch G, Lemaire M, Scherrmann J. Modulation of the brain distribution of imatinib and its metabolites in mice by valspodar, zosuquidar and elacridar. Pharm Res 2007; 24: 1720-8.

Zhou L, Schmidt K, Nelson FR, Zelesky V, Troutman MD, Feng B. The effect of breast cancer resistance protein and P-glycoprotein on the brain penetration of flavopiridol, imatinib mesylate (Gleevec), prazosin, and 2-methoxy-3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)propanoic acid (PF-407288) in mice. Drug Metab Dispos 2009; 37: 946-55.

Breedveld P, Pluim D, Cipriani G, Wielinga P, van Tellingen O, Schinkel A, et al. The effect of Bcrp1 (Abcg2) on the in vivo pharmacokinetics and brain penetration of imatinib mesylate (Gleevec): implications for the use of breast cancer resistance protein and P-glycoprotein inhibitors to enable the brain penetration of imatinib in patients. Cancer Res 2005; 65: 2577-82.

Gardner ER, Smith NF, Figg WD, Sparreboom A. Influence of the dual ABCB1 and ABCG2 inhibitor tariquidar on the disposition of oral imatinib in mice. J Exp Clin Cancer Res 2009; 28: 99. fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19591692

Picard S, Titier K, Etienne G, Teilhet E, Ducint D, Bernard M, et al. Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood 2007; 109: 3496-9.

Gardner ER, Burger H, van Schaik RH, van Oosterom AT, de Bruijn EA, Guetens G, et al. Association of enzyme and transporter genotypes with the pharmacokinetics of imatinib. Clin Pharmacol Ther 2006; 80: 192-201. http://www.ncbi.

Gurney H, Wong M, Balleine RL, Rivory LP, McLachlan AJ, Hoskins JM, et al. Imatinib disposition and ABCB1 (MDR1, P-glycoprotein) genotype. Clin Pharmacol Ther 2007; 82: 33-40. Retrieve&db=PubMed&dopt=Citation&list_uids=17495881

Petain A, Kattygnarath D, Azard J, Chatelut E, Delbaldo C, Geoerger B, et al. Population pharmacokinetics and pharmacogenetics of imatinib in children and adults. Clin Cancer Res 2008; 14: 7102-9. entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18981009

Dulucq S, Bouchet S, Turcq B, Lippert E, Etienne G, Reiffers J, et al. Multidrug resistance gene (MDR1) polymorphisms are associated with major molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood 2008; 112: 2024-7. =Retrieve&db=PubMed&dopt=Citation&list_uids=18524988

Weisberg E, Manley PW, Breitenstein W, Bruggen J, Cowan-Jacob SW, Ray A, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 2005; 7: 129-41. fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15710326

Mahon F, Hayette S, Lagarde V, Belloc F, Turcq B, Nicolini F, et al. Evidence that resistance to nilotinib may be due to BCR-ABL, Pgp, or Src kinase overexpression. Cancer Res 2008; 68: 9809-16.

Tiwari AK, Sodani K, Wang SR, Kuang YH, Ashby CR, Jr., Chen X, et al. Nilotinib (AMN107, Tasigna) reverses multidrug resistance by inhibiting the activity of the ABCB1/Pgp and ABCG2/BCRP/MXR transporters. Biochem Pharmacol 2009; 78: 153-61. http://www.ncbi.nlm.nih. gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19427995

Shukla S, Skoumbourdis AP, Walsh MJ, Hartz AM, Fung KL, Wu CP, et al. Synthesis and characterization of a BODIPY conjugate of the BCR-ABL kinase inhibitor Tasigna (nilotinib): evidence for transport of Tasigna and its fluorescent derivative by ABC drug transporters. Mol Pharm 2011; 8: 1292-302. cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21630681

Davies A, Jordanides N, Giannoudis A, Lucas C, Hatziieremia S, Harris R, et al. Nilotinib concentration in cell lines and primary CD34(+) chronic myeloid leukemia cells is not mediated by active uptake or efflux by major drug transporters. Leukemia 2009; 23: 1999-2006.

Hegedus C, Ozvegy-Laczka C, Apati A, Magocsi M, Nemet K, Orfi L, et al. Interaction of nilotinib, dasatinib and bosutinib with ABCB1 and ABCG2: implications for altered anti-cancer effects and pharmacological properties. Br J Pharmacol 2009; 158: 1153-64. query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19785662

White D, Saunders V, Dang P, Engler J, Zannettino A, Cambareri A, et al. OCT-1-mediated influx is a key determinant of the intracellular uptake of imatinib but not nilotinib (AMN107): reduced OCT-1 activity is the cause of low in vitro sensitivity to imatinib. Blood 2006; 108: 697-704.

Cortes JE, Kantarjian HM, Brummendorf TH, Kim DW, Turkina AG, Shen ZX, et al. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood 2006; 118: 4567-76.

Quintas-Cardama A, Kantarjian H, Cortes J. Bosutinib for the treatment of chronic myeloid leukemia in chronic phase. Drugs Today (Barc) 2012; 48: 177-88. http://www.ncbi.

Cohen MH, Williams GA, Sridhara R, Chen G, McGuinn WD, Jr., Morse D, et al. United States Food and Drug Administration Drug Approval summary: Gefitinib (ZD1839; Iressa) tablets. Clin Cancer Res 2004; 10: 1212-8.

Cohen MH, Williams GA, Sridhara R, Chen G, Pazdur R. FDA drug approval summary: gefitinib (ZD1839) (Iressa) tablets. Oncologist 2003; 8: 303-6. http://www.ncbi.nlm.nih. gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12897327

Sierra JR, Cepero V, Giordano S. Molecular mechanisms of acquired resistance to tyrosine kinase targeted therapy. Mol Cancer 2010; 9: 75. query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20385023

Colabufo NA, Contino M, Niso M, Berardi F, Leopoldo M, Perrone R. EGFR tyrosine kinase inhibitors and multidrug resistance: perspectives. Front Biosci 2011; 16: 1811-23.

Azzariti A, Porcelli L, Simone GM, Quatrale AE, Colabufo NA, Berardi F, et al. Tyrosine kinase inhibitors and multidrug resistance proteins: interactions and biological consequences. Cancer Chemother Pharmacol 2010; 65: 335-46. =Retrieve&db=PubMed&dopt=Citation&list_uids=19495754

Kitazaki T, Oka M, Nakamura Y, Tsurutani J, Doi S, Yasunaga M, et al. Gefitinib, an EGFR tyrosine kinase inhibitor, directly inhibits the function of P-glycoprotein in multidrug resistant cancer cells. Lung Cancer 2005; 49: 337-43. Retrieve&db=PubMed&dopt=Citation&list_uids=15955594

Elkind N, Szentpétery Z, Apáti A, Ozvegy-Laczka C, Várady G, Ujhelly O, et al. Multidrug transporter ABCG2 prevents tumor cell death induced by the epidermal growth factor receptor inhibitor Iressa (ZD1839, Gefitinib). Cancer Res 2005; 65: 1770-7.

Leggas M, Panetta JC, Zhuang Y, Schuetz JD, Johnston B, Bai F, et al. Gefitinib modulates the function of multiple ATP-binding cassette transporters in vivo. Cancer Res 2006; 66: 4802-7. Retrieve&db=PubMed&dopt=Citation&list_uids=16651435

Yanase K, Tsukahara S, Asada S, Ishikawa E, Imai Y, Sugimoto Y. Gefitinib reverses breast cancer resistance protein-mediated drug resistance. Mol Cancer Ther 2004; 3: 1119-25. Retrieve&db=PubMed&dopt=Citation&list_uids=15367706

O'Connor R. The pharmacology of cancer resistance. Anticancer Res 2007; 27: 1267-72. http://www.ncbi.nlm.nih. gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17593618

Gillet JP, Efferth T, Remacle J. Chemotherapy-induced resistance by ATP-binding cassette transporter genes. Biochim Biophys Acta 2007; 1775: 237-62. http://www.ncbi.

Nakamura Y, Oka M, Soda H, Shiozawa K, Yoshikawa M, Itoh A, et al. Gefitinib ("Iressa", ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, reverses breast cancer resistance protein/ABCG2-mediated drug resistance. Cancer Res 2005; 65: 1541-6. http://www.ncbi.

Yang CH, Huang CJ, Yang CS, Chu YC, Cheng AL, Whang-Peng J, et al. Gefitinib reverses chemotherapy resistance in gefitinib-insensitive multidrug resistant cancer cells expressing ATP-binding cassette family protein. Cancer Res 2005; 65: 6943-9. fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16061679

Li J, Cusatis G, Brahmer J, Sparreboom A, Robey RW, Bates SE, et al. Association of variant ABCG2 and the pharmacokinetics of epidermal growth factor receptor tyrosine kinase inhibitors in cancer patients. Cancer Biol Ther 2007; 6: 432-8. query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17312388

Usuda J, Ohira T, Suga Y, Oikawa T, Ichinose S, Inoue T, et al. Breast cancer resistance protein (BCRP) affected acquired resistance to gefitinib in a "never-smoked" female patient with advanced non-small cell lung cancer. Lung Cancer 2007; 58: 296-9. query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17618705




How to Cite

Hong-Ye Zhao, Hongjiang Wei, & Xin Wang. (2013). The Reciprocal Interaction of Small Molecule Protein Kinase Inhibitors and ATP-Binding Cassette Transporters in Targeted Cancer Therapy . Journal of Cancer Research Updates, 2(1),  68–86.