Multidrug Resistance in Cancer: Genetics of ABC Transporters

Toshihisa Ishikawa, Tokyo Institute of Technology, Yokohama, Japan

Published online: January 2006

DOI: 10.1038/npg.els.0006083

Multidrug resistance in human cancer is the major obstacle to long-term, sustained response of a patient to chemotherapy. It has been convincingly documented that several adenosine triphosphate-binding cassette transporters cause multidrug resistance in cancer cells by actively extruding the clinically administered chemotherapeutic drugs.

Keywords: cancer; chemotherapy; drug response; ABC transporter; pharmacogenomics

Figure 1. Schematic illustration of ABCB1 (P-glycoprotein (P-gp)/MDR1), ABCC1 (MRP1), ABCC2 (MRP2/cMOAT) and ABCG2 (BCRPz/MXR1/ABCP).
Figure 2. Phylogenetic tree of ABCC subfamily members.
Figure 3. Three different modes in ABCC1-mediated transport of xeno- and endobiotics: (a) transport of GSH conjugates; (b) transport of multivalent organic anions; (c) cotransport of drugs with GSH. GSH: glutathione; GS-DNP: dinitrophenyl-S-glutathione conjugate; PGA1: prostaglandin A1; LTC4: leukotriene C4; GSSG: glutathione disulfide; BSP: bromosulfophthalein; ATP: adenosine triphosphate; ADP: adenosine diphosphate; Pi: inorganic phosphate.
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 References
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    Borst P, Evers R, Kool M and Wijnholds J (1999) The multidrug resistance protein family. Biochimica et Biophysica Acta 1461: 347–357.
    Bunting KD (2002) ABC transporters as phenotypic markers and functional regulators of stem cells. Stem Cells 20: 11–20.
    Hoffmeyer S, Burk O, von Richter O, et al. (2000) Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proceedings of the National Academy of Sciences of the United States of America 97: 3473–3478.
    book Kalow W, Meyer UA and Tyndale RF (eds.) (2000) Pharmacogenomics New York, NY: Marcel Dekker.
    Kuo MT, Bao J-J, Curley SA, et al. (1996) Frequent coordinated overexpression of the MRP/GS-X pump and -glutamylcysteine synthetase in human colorectal cancers. Cancer Research 56: 3642–3644.
    Mickisch GH, Merlino GT, Galski H, Gottesman MM and Pastan I (1991) Transgenic mice that express the human multidrug-resistance gene in bone marrow enable a rapid identification of agents that reverse drug resistance. Proceedings of the National Academy of Sciences of the United States of America 88: 547–551.
    Paulusma CC, Bosma PJ, Zaman GJR, et al. (1996) Congenital jaundice in rats with a mutation in a multidrug resistance-associated protein gene. Science 271: 1126–1128.
    Wada M, Toh S, Taniguchi K, et al. (1998) Mutations in the canilicular multispecific organic anion transporter (cMOAT) gene, a novel ABC transporter, in patients with hyperbilirubinemia II/Dubin–Johnson syndrome. Human Molecular Genetics 7: 203–207.
    Zaman GJR, Lankelma J, van Tellingen O, et al. (1995) Role of glutathione in the export of compounds from cells by the multidrug-resistance-associated protein. Proceedings of the National Academy of Sciences of the United States of America 92: 7690–7694.
    Zhou S, Schuetz JD, Bunting KD, et al. (2001) The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nature Medicine 7: 1028–1034.
 Web Links
    ePath HGNC Gene Family Nomenclature. Human ABC transporter genes http://www.gene.ucl.ac.uk/nomenclature/genefamily/abc.html
    ePath ATP-binding cassette, sub-family B (MDR/TAP), member 1 (ABCB1); Locus ID: 5243. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=5243
    ePath ATP-binding cassette, sub-family B (MDR/TAP), member 4 (ABCB4); Locus ID: 5244. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=5244
    ePath ATP-binding cassette, sub-family C (CFTR/MRP), member 1 (ABCC1); Locus ID: 4363. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=4363
    ePath ATP-binding cassette, sub-family C (CFTR/MRP), member 2 (ABCC2); Locus ID: 1244. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=1244
    ePath ATP-binding cassette, sub-family G (WHITE), member 2 (ABCG2); Locus ID: 9429. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=9429
    ePath ATP-binding cassette, sub-family B (MDR/TAP), member 1 (ABCB1); MIM number: 171050. OMIM: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?171050
    ePath ATPhyphen;binding cassette, sub-family B (MDR/TAP), member 4 (ABCB4); MIM number: 171060. OMIM: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?171060
    ePath ATPhyphen;binding cassette, sub-family C (CFTR/MRP), member 1 (ABCC1); MIM number: 158343. OMIM: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?158343
    ePath ATPhyphen;binding cassette, sub-family C (CFTR/MRP), member 2 (ABCC2); MIM number: 601107. OMIM: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?601107
    ePath ATPhyphen;binding cassette, sub-family G (WHITE), member 2 (ABCG2); MIM number: 603756. OMIM: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?603756

Related Sub-Topics:

Cellular Transport | Cell Biology of Cancer | Cancer Genetics | Pharmacogenetics and Pharmacogenomics | Inter-Individual Variation and Polymorphism | Proteomic Studies of Genetic Disease | Proteins: Structure, Function, Metabolism | Other Biomolecules: Structure, Function, Metabolism | Enzymes: Structure and Action Mechanism | Molecular Transport
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Article Title: Multidrug Resistance in Cancer: Genetics of ABC Transporters
 
How to Cite close
Ishikawa, Toshihisa(Jan 2006) Multidrug Resistance in Cancer: Genetics of ABC Transporters. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0006083]