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Mechanisms of Multidrug Resistance in Cancer

  • Jean-Pierre Gillet
  • Michael M. GottesmanEmail author
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 596)

Abstract

The development of multidrug resistance (MDR) to chemotherapy remains a major challenge in the treatment of cancer. Resistance exists against every effective anticancer drug and can develop by numerous mechanisms including decreased drug uptake, increased drug efflux, activation of detoxifying systems, activation of DNA repair mechanisms, evasion of drug-induced apoptosis, etc. In the first part of this chapter, we briefly summarize the current knowledge on individual cellular mechanisms responsible for MDR, with a special emphasis on ATP-binding cassette transporters, perhaps the main theme of this textbook. Although extensive work has been done to characterize MDR mechanisms in vitro, the translation of this knowledge to the clinic has not been crowned with success. Therefore, identifying genes and mechanisms critical to the development of MDR in vivo and establishing a reliable method for analyzing clinical samples could help to predict the development of resistance and lead to treatments designed to circumvent it. Our thoughts about translational research needed to achieve significant progress in the understanding of this complex phenomenon are therefore discussed in a third section. The pleotropic response of cancer cells to chemotherapy is summarized in a concluding diagram.

Key words:

Multidrug resistance Uptake transport ABC transporters Drug metabolism DNA repair Vaults Microenvironment Translational research 

Notes

Acknowledgments

This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. We would like to thank George Leiman for editorial assistance.

References

  1. 1.
    Lage H (2008) An overview of cancer multidrug resistance: a still unsolved problem. Cell Mol Life Sci 65:3145–3167PubMedCrossRefGoogle Scholar
  2. 2.
    Mellor HR, Callaghan R (2008) Resistance to chemotherapy in cancer: a complex and integrated cellular response. Pharmacology 81:275–300PubMedCrossRefGoogle Scholar
  3. 3.
    Mimeault M, Hauke R, Batra SK (2008) Recent advances on the molecular mechanisms involved in the drug resistance of cancer cells and novel targeting therapies. Clin Pharmacol Ther 83:673–691PubMedCrossRefGoogle Scholar
  4. 4.
    Flaten GE, Dhanikula AB, Luthman K, Brandl M (2006) Drug permeability across a phospholipid vesicle based barrier: a novel approach for studying passive diffusion. Eur J Pharm Sci 27:80–90PubMedCrossRefGoogle Scholar
  5. 5.
    Dobson PD, Kell DB (2008) Carrier-mediated cellular uptake of pharmaceutical drugs: an exception or the rule? Nat Rev Drug Discov 7:205–220PubMedCrossRefGoogle Scholar
  6. 6.
    Assaraf YG (2007) Molecular basis of antifolate resistance. Cancer Metastasis Rev 26:153–181PubMedCrossRefGoogle Scholar
  7. 7.
    Hediger MA, Romero MF, Peng JB et al (2004) The ABCs of solute carriers: physiological, pathological and therapeutic implications of human membrane transport proteins. Pflugers Arch 447:465–468PubMedCrossRefGoogle Scholar
  8. 8.
    Gray JH, Owen RP, Giacomini KM (2004) The concentrative nucleoside transporter family, SLC28. Pflugers Arch 447:728–734PubMedCrossRefGoogle Scholar
  9. 9.
    Young JD, Yao SY, Sun L, Cass CE, Baldwin SA (2008) Human equilibrative nucleoside transporter (ENT) family of nucleoside and nucleobase transporter proteins. Xenobiotica 38:995–1021PubMedCrossRefGoogle Scholar
  10. 10.
    Zhang J, Visser F, King KM et al (2007) The role of nucleoside transporters in cancer chemotherapy with nucleoside drugs. Cancer Metastasis Rev 26:85–110PubMedCrossRefGoogle Scholar
  11. 11.
    Mackey JR, Mani RS, Selner M et al (1998) Functional nucleoside transporters are required for gemcitabine influx and manifestation of toxicity in cancer cell lines. Cancer Res 58:4349–4357PubMedGoogle Scholar
  12. 12.
    Farrell JJ, Elsaleh H, Garcia M et al (2009) Human equilibrative nucleoside transporter 1 levels predict response to gemcitabine in patients with pancreatic cancer. Gastroenterology 136: 187–195PubMedCrossRefGoogle Scholar
  13. 13.
    Smith NF, Acharya MR, Desai N, Figg WD, Sparreboom A (2005) Identification of OATP1B3 as a high-affinity hepatocellular transporter of paclitaxel. Cancer Biol Ther 4:815–818PubMedCrossRefGoogle Scholar
  14. 14.
    Smith NF, Marsh S, Scott-Horton TJ et al (2007) Variants in the SLCO1B3 gene: interethnic distribution and association with paclitaxel pharmacokinetics. Clin Pharmacol Ther 81:76–82PubMedCrossRefGoogle Scholar
  15. 15.
    Hall MD, Okabe M, Shen DW, Liang XJ, Gottesman MM (2008) The role of cellular accumulation in determining sensitivity to platinum-based chemotherapy. Annu Rev Pharmacol Toxicol 48:495–535PubMedCrossRefGoogle Scholar
  16. 16.
    Wang DS, Jonker JW, Kato Y et al (2002) Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. J Pharmacol Exp Ther 302:510–515PubMedCrossRefGoogle Scholar
  17. 17.
    Kimura N, Masuda S, Tanihara Y et al (2005) Metformin is a superior substrate for renal organic cation transporter OCT2 rather than hepatic OCT1. Drug Metab Pharmacokinet 20:379–386PubMedCrossRefGoogle Scholar
  18. 18.
    Okabe M, Szakacs G, Reimers MA et al (2008) Profiling SLCO and SLC22 genes in the NCI-60 cancer cell lines to identify drug uptake transporters. Mol Cancer Ther 7:3081–3091PubMedCrossRefGoogle Scholar
  19. 19.
    Scherf U, Ross DT, Waltham M et al (2000) A gene expression database for the molecular pharmacology of cancer. Nat Genet 24:236–244PubMedCrossRefGoogle Scholar
  20. 20.
    Rabow AA, Shoemaker RH, Sausville EA, Covell DG (2002) Mining the National Cancer Institute’s tumor-screening database: identification of compounds with similar cellular activities. J Med Chem 45:818–840PubMedCrossRefGoogle Scholar
  21. 21.
    Shi LM, Fan Y, Lee JK et al (2000) Mining and visualizing large anticancer drug discovery databases. J Chem Inf Comput Sci 40:367–379PubMedGoogle Scholar
  22. 22.
    Weinstein JN, Kohn KW, Grever MR et al (1992) Neural computing in cancer drug development: predicting mechanism of action. Science 258:447–451PubMedCrossRefGoogle Scholar
  23. 23.
    Weinstein JN, Myers TG, O’Connor PM et al (1997) An information-intensive approach to the molecular pharmacology of cancer. Science 275:343–349PubMedCrossRefGoogle Scholar
  24. 24.
    Gillet JP, Efferth T, Remacle J (2007) Chemotherapy-induced resistance by ATP-binding cassette transporter genes. Biochim Biophys Acta 1775:237–262PubMedGoogle Scholar
  25. 25.
    Szakacs G, Paterson JK, Ludwig JA, Booth-Genthe C, Gottesman MM (2006) Targeting multidrug resistance in cancer. Nat Rev Drug Discov 5:219–234PubMedCrossRefGoogle Scholar
  26. 26.
    Callaghan R, Crowley E, Potter S, Kerr ID (2008) P-glycoprotein: so many ways to turn it on. J Clin Pharmacol 48:365–378PubMedCrossRefGoogle Scholar
  27. 27.
    Deeley RG, Westlake C, Cole SP (2006) Transmembrane transport of endo- and xenobiotics by mammalian ATP-binding cassette multidrug resistance proteins. Physiol Rev 86:849–899PubMedCrossRefGoogle Scholar
  28. 28.
    Polgar O, Robey RW, Bates SE (2008) ABCG2: structure, function and role in drug response. Expert Opin Drug Metab Toxicol 4:1–15PubMedCrossRefGoogle Scholar
  29. 29.
    Awasthi S, Singhal SS, Awasthi YC et al (2008) RLIP76 and Cancer. Clin Cancer Res 14:4372–4377PubMedCrossRefGoogle Scholar
  30. 30.
    Kuo MT, Chen HH, Song IS, Savaraj N, Ishikawa T (2007) The roles of copper transporters in cisplatin resistance. Cancer Metastasis Rev 26:71–83PubMedCrossRefGoogle Scholar
  31. 31.
    Drake KJ, Singhal J, Yadav S et al (2007) RALBP1/RLIP76 mediates multidrug resistance. Int J Oncol 30:139–144PubMedGoogle Scholar
  32. 32.
    Singhal SS, Singhal J, Nair MP et al (2007) Doxorubicin transport by RALBP1 and ABCG2 in lung and breast cancer. Int J Oncol 30:717–725PubMedGoogle Scholar
  33. 33.
    Gouaze-Andersson V, Cabot MC (2006) Glycosphingolipids and drug resistance. Biochim Biophys Acta 1758:2096–2103PubMedCrossRefGoogle Scholar
  34. 34.
    Hendrich AB, Michalak K (2003) Lipids as a target for drugs modulating multidrug resistance of cancer cells. Curr Drug Targets 4:23–30PubMedCrossRefGoogle Scholar
  35. 35.
    Thevissen K, Francois IE, Winderickx J, Pannecouque C, Cammue BP (2006) Ceramide involvement in apoptosis and apoptotic diseases. Mini Rev Med Chem 6:699–709PubMedCrossRefGoogle Scholar
  36. 36.
    Gouaze-Andersson V, Yu JY, Kreitenberg AJ et al (2007) Ceramide and glucosylceramide upregulate expression of the multidrug resistance gene MDR1 in cancer cells. Biochim Biophys Acta 1771:1407–1417PubMedGoogle Scholar
  37. 37.
    Liu YY, Yu JY, Yin D et al (2008) A role for ceramide in driving cancer cell resistance to doxorubicin. FASEB J 22:2541–2551PubMedCrossRefGoogle Scholar
  38. 38.
    Shen DW, Akiyama S, Schoenlein P, Pastan I, Gottesman MM (1995) Characterisation of high-level cisplatin-resistant cell lines established from a human hepatoma cell line and human KB adenocarcinoma cells: cross-resistance and protein changes. Br J Cancer 71:676–683PubMedGoogle Scholar
  39. 39.
    Shen D, Pastan I, Gottesman MM (1998) Cross-resistance to methotrexate and metals in human cisplatin-resistant cell lines results from a pleiotropic defect in accumulation of these compounds associated with reduced plasma membrane binding proteins. Cancer Res 58:268–275PubMedGoogle Scholar
  40. 40.
    Shen DW, Goldenberg S, Pastan I, Gottesman MM (2000) Decreased accumulation of (14C)carboplatin in human cisplatin-resistant cells results from reduced energy-dependent uptake. J Cell Physiol 183:108–116PubMedCrossRefGoogle Scholar
  41. 41.
    Shen DW, Su A, Liang XJ, Pai-Panandiker A, Gottesman MM (2004) Reduced expression of small GTPases and hypermethylation of the folate binding protein gene in cisplatin-resistant cells. Br J Cancer 91:270–276PubMedGoogle Scholar
  42. 42.
    Liang XJ, Shen DW, Garfield S, Gottesman MM (2003) Mislocalization of membrane proteins associated with multidrug resistance in cisplatin-resistant cancer cell lines. Cancer Res 63:5909–5916PubMedGoogle Scholar
  43. 43.
    Liang XJ, Mukherjee S, Shen DW, Maxfield FR, Gottesman MM (2006) Endocytic recycling compartments altered in cisplatin-resistant cancer cells. Cancer Res 66:2346–2353PubMedCrossRefGoogle Scholar
  44. 44.
    Chauhan SS, Liang XJ, Su AW et al (2003) Reduced endocytosis and altered lysosome function in cisplatin-resistant cell lines. Br J Cancer 88:1327–1334PubMedCrossRefGoogle Scholar
  45. 45.
    Liang XJ, Yin JJ, Zhou JW et al (2004) Changes in biophysical parameters of plasma membranes influence cisplatin resistance of sensitive and resistant epidermal carcinoma cells. Exp Cell Res 293:283–291PubMedCrossRefGoogle Scholar
  46. 46.
    Brown CM, Reisfeld B, Mayeno AN (2008) Cytochromes P450: a structure-based summary of biotransformations using representative substrates. Drug Metab Rev 40:1–100PubMedCrossRefGoogle Scholar
  47. 47.
    Oyama T, Kagawa N, Kunugita N et al (2004) Expression of cytochrome P450 in tumor tissues and its association with cancer development. Front Biosci 9:1967–1976PubMedCrossRefGoogle Scholar
  48. 48.
    Purnapatre K, Khattar SK, Saini KS (2008) Cytochrome P450s in the development of target-based anticancer drugs. Cancer Lett 259:1–15PubMedCrossRefGoogle Scholar
  49. 49.
    van Schaik RH (2008) CYP450 pharmacogenetics for personalizing cancer therapy. Drug Resist Updat 11:77–98PubMedCrossRefGoogle Scholar
  50. 50.
    Xie HJ, Yasar U, Lundgren S et al (2003) Role of polymorphic human CYP2B6 in cyclophosphamide bioactivation. Pharma­cogenomics J 3:53–61PubMedCrossRefGoogle Scholar
  51. 51.
    Xie H, Griskevicius L, Stahle L et al (2006) Pharmacogenetics of cyclophosphamide in patients with hematological malignancies. Eur J Pharm Sci 27:54–61PubMedCrossRefGoogle Scholar
  52. 52.
    Rodriguez-Novoa S, Barreiro P, Rendon A et al (2005) Influence of 516G>T polymorphisms at the gene encoding the CYP450–2B6 isoenzyme on efavirenz plasma concentrations in HIV-infected subjects. Clin Infect Dis 40:1358–1361PubMedCrossRefGoogle Scholar
  53. 53.
    Rotger M, Colombo S, Furrer H et al (2005) Influence of CYP2B6 polymorphism on plasma and intracellular concentrations and toxicity of efavirenz and nevirapine in HIV-infected patients. Pharmacogenet Genomics 15:1–5PubMedCrossRefGoogle Scholar
  54. 54.
    Wang J, Sonnerborg A, Rane A et al (2006) Identification of a novel specific CYP2B6 allele in Africans causing impaired metabolism of the HIV drug efavirenz. Pharmacogenet Genomics 16:191–198PubMedCrossRefGoogle Scholar
  55. 55.
    Huttunen KM, Mahonen N, Raunio H, Rautio J (2008) Cytochrome P450-activated prodrugs: targeted drug delivery. Curr Med Chem 15:2346–2365PubMedCrossRefGoogle Scholar
  56. 56.
    Pal D, Mitra AK (2006) MDR- and CYP3A4-mediated drug-drug interactions. J Neuro­immune Pharmacol 1:323–339PubMedCrossRefGoogle Scholar
  57. 57.
    Ghezzi P, Di Simplicio P (2007) Glutathiony­lation pathways in drug response. Curr Opin Pharmacol 7:398–403PubMedCrossRefGoogle Scholar
  58. 58.
    Iyanagi T (2007) Molecular mechanism of phase I and phase II drug-metabolizing enzymes: implications for detoxification. Int Rev Cytol 260:35–112PubMedCrossRefGoogle Scholar
  59. 59.
    Hemmerich S, Verdugo D, Rath VL (2004) Strategies for drug discovery by targeting sulfation pathways. Drug Discov Today 9:967–975PubMedCrossRefGoogle Scholar
  60. 60.
    Townsend DM, Findlay VL, Tew KD (2005) Glutathione S-transferases as regulators of kinase pathways and anticancer drug targets. Methods Enzymol 401:287–307PubMedCrossRefGoogle Scholar
  61. 61.
    Sorich MJ, Smith PA, Miners JO, Mackenzie PI, McKinnon RA (2008) Recent advances in the in silico modelling of UDP glucuronosyltransferase substrates. Curr Drug Metab 9:60–69PubMedCrossRefGoogle Scholar
  62. 62.
    Gamage N, Barnett A, Hempel N et al (2006) Human sulfotransferases and their role in chemical metabolism. Toxicol Sci 90:5–22PubMedCrossRefGoogle Scholar
  63. 63.
    Butcher NJ, Tiang J, Minchin RF (2008) Regulation of arylamine N-acetyltransferases. Curr Drug Metab 9:498–504PubMedCrossRefGoogle Scholar
  64. 64.
    Ekhart C, Rodenhuis S, Smits PH, Beijnen JH, Huitema AD (2009) An overview of the relations between polymorphisms in drug metabolising enzymes and drug transporters and survival after cancer drug treatment. Cancer Treat Rev 35:18–31PubMedCrossRefGoogle Scholar
  65. 65.
    Safaei R, Larson BJ, Cheng TC et al (2005) Abnormal lysosomal trafficking and enhanced exosomal export of cisplatin in drug-resistant human ovarian carcinoma cells. Mol Cancer Ther 4:1595–1604PubMedCrossRefGoogle Scholar
  66. 66.
    Liang XJ, Shen DW, Chen KG et al (2005) Trafficking and localization of platinum complexes in cisplatin-resistant cell lines monitored by fluorescence-labeled platinum. J Cell Physiol 202:635–641PubMedCrossRefGoogle Scholar
  67. 67.
    Safaei R, Katano K, Larson BJ et al (2005) Intracellular localization and trafficking of fluorescein-labeled cisplatin in human ovarian carcinoma cells. Clin Cancer Res 11:756–767PubMedGoogle Scholar
  68. 68.
    Kalayda GV, Wagner CH, Buss I, Reedijk J, Jaehde U (2008) Altered localisation of the copper efflux transporters ATP7A and ATP7B associated with cisplatin resistance in human ovarian carcinoma cells. BMC Cancer 8:175PubMedCrossRefGoogle Scholar
  69. 69.
    Chen KG, Valencia JC, Lai B et al (2006) Melanosomal sequestration of cytotoxic drugs contributes to the intractability of malignant melanomas. Proc Natl Acad Sci USA 103:9903–9907PubMedCrossRefGoogle Scholar
  70. 70.
    Chen KG, Szakacs G, Annereau JP et al (2005) Principal expression of two mRNA isoforms (ABCB 5alpha and ABCB 5beta ) of the ATP-binding cassette transporter gene ABCB 5 in melanoma cells and melanocytes. Pigment Cell Res 18:102–112PubMedCrossRefGoogle Scholar
  71. 71.
    Steinbach D, Gillet JP, Sauerbrey A et al (2006) ABCA3 as a possible cause of drug resistance in childhood acute myeloid leukemia. Clin Cancer Res 12:4357–4363PubMedCrossRefGoogle Scholar
  72. 72.
    Chapuy B, Koch R, Radunski U et al (2008) Intracellular ABC transporter A3 confers multidrug resistance in leukemia cells by lysosomal drug sequestration. Leukemia 22:1576–1586PubMedCrossRefGoogle Scholar
  73. 73.
    Cheong N, Madesh M, Gonzales LW et al (2006) Functional and trafficking defects in ATP binding cassette A3 mutants associated with respiratory distress syndrome. J Biol Chem 281:9791–9800PubMedCrossRefGoogle Scholar
  74. 74.
    Theocharis SE, Margeli AP, Klijanienko JT, Kouraklis GP (2004) Metallothionein expression in human neoplasia. Histopathology 45:103–118PubMedCrossRefGoogle Scholar
  75. 75.
    Thirumoorthy N, Manisenthil Kumar KT, Shyam Sundar A, Panayappan L, Chatterjee M (2007) Metallothionein: an overview. World J Gastroenterol 13:993–996PubMedGoogle Scholar
  76. 76.
    Harper JW, Elledge SJ (2007) The DNA damage response: ten years after. Mol Cell 28:739–745PubMedCrossRefGoogle Scholar
  77. 77.
    Ashwell S, Zabludoff S (2008) DNA damage detection and repair pathways–recent advances with inhibitors of checkpoint kinases in cancer therapy. Clin Cancer Res 14:4032–4037PubMedCrossRefGoogle Scholar
  78. 78.
    Martin LP, Hamilton TC, Schilder RJ (2008) Platinum resistance: the role of DNA repair pathways. Clin Cancer Res 14:1291–1295PubMedCrossRefGoogle Scholar
  79. 79.
    Sarkaria JN, Kitange GJ, James CD et al (2008) Mechanisms of chemoresistance to alkylating agents in malignant glioma. Clin Cancer Res 14:2900–2908PubMedCrossRefGoogle Scholar
  80. 80.
    Hakem R (2008) DNA-damage repair; the good, the bad, and the ugly. EMBO J 27:589–605PubMedCrossRefGoogle Scholar
  81. 81.
    Helleday T, Petermann E, Lundin C, Hodgson B, Sharma RA (2008) DNA repair pathways as targets for cancer therapy. Nat Rev Cancer 8:193–204PubMedCrossRefGoogle Scholar
  82. 82.
    Dabholkar M, Bostick-Bruton F, Weber C et al (1992) ERCC1 and ERCC2 expression in malignant tissues from ovarian cancer patients. J Natl Cancer Inst 84:1512–1517PubMedCrossRefGoogle Scholar
  83. 83.
    Kang S, Ju W, Kim JW et al (2006) Association between excision repair cross-complementation group 1 polymorphism and clinical outcome of platinum-based chemotherapy in patients with epithelial ovarian cancer. Exp Mol Med 38:320–324PubMedGoogle Scholar
  84. 84.
    Olaussen KA, Dunant A, Fouret P et al (2006) DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 355:983–991PubMedCrossRefGoogle Scholar
  85. 85.
    Metzger R, Leichman CG, Danenberg KD et al (1998) ERCC1 mRNA levels complement thymidylate synthase mRNA levels in predicting response and survival for gastric cancer patients receiving combination cisplatin and fluorouracil chemotherapy. J Clin Oncol 16:309–316PubMedGoogle Scholar
  86. 86.
    Fink D, Nebel S, Norris PS et al (1998) Enrichment for DNA mismatch repair-deficient cells during treatment with cisplatin. Int J Cancer 77:741–746PubMedCrossRefGoogle Scholar
  87. 87.
    Strathdee G, MacKean MJ, Illand M, Brown R (1999) A role for methylation of the hMLH1 promoter in loss of hMLH1 expression and drug resistance in ovarian cancer. Oncogene 18:2335–2341PubMedCrossRefGoogle Scholar
  88. 88.
    Karran P, Marinus MG (1982) Mismatch correction at O6-methylguanine residues in E. coli DNA. Nature 296:868–869PubMedCrossRefGoogle Scholar
  89. 89.
    Yoshioka K, Yoshioka Y, Hsieh P (2006) ATR kinase activation mediated by MutSalpha and MutLalpha in response to cytotoxic O6-methylguanine adducts. Mol Cell 22:501–510PubMedCrossRefGoogle Scholar
  90. 90.
    Verbeek B, Southgate TD, Gilham DE, Margison GP (2008) O6-Methylguanine-DNA methyltransferase inactivation and chemotherapy. Br Med Bull 85:17–33PubMedCrossRefGoogle Scholar
  91. 91.
    Okada H, Mak TW (2004) Pathways of apoptotic and non-apoptotic death in tumour cells. Nat Rev Cancer 4:592–603PubMedCrossRefGoogle Scholar
  92. 92.
    Broker LE, Kruyt FA, Giaccone G (2005) Cell death independent of caspases: a review. Clin Cancer Res 11:3155–3162PubMedCrossRefGoogle Scholar
  93. 93.
    Falschlehner C, Emmerich CH, Gerlach B, Walczak H (2007) TRAIL signalling: decisions between life and death. Int J Biochem Cell Biol 39:1462–1475PubMedCrossRefGoogle Scholar
  94. 94.
    Tait SW, Green DR (2008) Caspase-independent cell death: leaving the set without the final cut. Oncogene 27:6452–6461PubMedCrossRefGoogle Scholar
  95. 95.
    Rodriguez-Nieto S, Zhivotovsky B (2006) Role of alterations in the apoptotic machinery in sensitivity of cancer cells to treatment. Curr Pharm Des 12:4411–4425PubMedCrossRefGoogle Scholar
  96. 96.
    Viktorsson K, Lewensohn R, Zhivotovsky B (2005) Apoptotic pathways and therapy resistance in human malignancies. Adv Cancer Res 94:143–196PubMedCrossRefGoogle Scholar
  97. 97.
    Sjostrom J, Blomqvist C, von Boguslawski K et al (2002) The predictive value of bcl-2, bax, bcl-xL, bag-1, fas, and fasL for chemotherapy response in advanced breast cancer. Clin Cancer Res 8:811–816PubMedGoogle Scholar
  98. 98.
    Malamou-Mitsi V, Gogas H, Dafni U et al (2006) Evaluation of the prognostic and predictive value of p53 and Bcl-2 in breast cancer patients participating in a randomized study with dose-dense sequential adjuvant chemotherapy. Ann Oncol 17:1504–1511PubMedCrossRefGoogle Scholar
  99. 99.
    Krug LM, Miller VA, Filippa DA et al (2003) Bcl-2 and bax expression in advanced non-small cell lung cancer: lack of correlation with chemotherapy response or survival in patients treated with docetaxel plus vinorelbine. Lung Cancer 39:139–143PubMedCrossRefGoogle Scholar
  100. 100.
    Bonetti A, Zaninelli M, Leone R et al (1998) Bcl-2 but not p53 expression is associated with resistance to chemotherapy in advanced breast cancer. Clin Cancer Res 4:2331–2336PubMedGoogle Scholar
  101. 101.
    Buchholz TA, Davis DW, McConkey DJ et al (2003) Chemotherapy-induced apoptosis and Bcl-2 levels correlate with breast cancer response to chemotherapy. Cancer J 9:33–41PubMedCrossRefGoogle Scholar
  102. 102.
    Kedersha NL, Rome LH (1986) Isolation and characterization of a novel ribonucleoprotein particle: large structures contain a single species of small RNA. J Cell Biol 103:699–709PubMedCrossRefGoogle Scholar
  103. 103.
    Kedersha NL, Heuser JE, Chugani DC, Rome LH (1991) Vaults. III. Vault ribonucleoprotein particles open into flower-like structures with octagonal symmetry. J Cell Biol 112:225–235PubMedCrossRefGoogle Scholar
  104. 104.
    Rome L, Kedersha N, Chugani D (1991) Unlocking vaults: organelles in search of a function. Trends Cell Biol 1:47–50PubMedCrossRefGoogle Scholar
  105. 105.
    Kedersha NL, Miquel MC, Bittner D, Rome LH (1990) Vaults. II. Ribonucleoprotein structures are highly conserved among higher and lower eukaryotes. J Cell Biol 110:895–901PubMedCrossRefGoogle Scholar
  106. 106.
    van Zon A, Mossink MH, Scheper RJ, Sonneveld P, Wiemer EA (2003) The vault complex. Cell Mol Life Sci 60:1828–1837PubMedCrossRefGoogle Scholar
  107. 107.
    Izquierdo MA, Scheffer GL, Flens MJ et al (1996) Broad distribution of the multidrug resistance-related vault lung resistance protein in normal human tissues and tumors. Am J Pathol 148:877–887PubMedGoogle Scholar
  108. 108.
    Kickhoefer VA, Rajavel KS, Scheffer GL et al (1998) Vaults are up-regulated in multidrug-resistant cancer cell lines. J Biol Chem 273:8971–8974PubMedCrossRefGoogle Scholar
  109. 109.
    Mossink MH, van Zon A, Scheper RJ, Sonneveld P, Wiemer EA (2003) Vaults: a ribonucleoprotein particle involved in drug resistance? Oncogene 22:7458–7467PubMedCrossRefGoogle Scholar
  110. 110.
    Steiner E, Holzmann K, Elbling L, Micksche M, Berger W (2006) Cellular functions of vaults and their involvement in multidrug resistance. Curr Drug Targets 7:923–934PubMedCrossRefGoogle Scholar
  111. 111.
    Berger W, Steiner E, Grusch M, Elbling L, Micksche M (2009) Vaults and the major vault protein: novel roles in signal pathway regulation and immunity. Cell Mol Life Sci 66:43–61PubMedCrossRefGoogle Scholar
  112. 112.
    Scheper RJ, Broxterman HJ, Scheffer GL et al (1993) Overexpression of a M(r) 110,000 vesicular protein in non-P-glycoprotein-mediated multidrug resistance. Cancer Res 53:1475–1479PubMedGoogle Scholar
  113. 113.
    Kitazono M, Okumura H, Ikeda R et al (2001) Reversal of LRP-associated drug resistance in colon carcinoma SW-620 cells. Int J Cancer 91:126–131PubMedCrossRefGoogle Scholar
  114. 114.
    Kitazono M, Sumizawa T, Takebayashi Y et al (1999) Multidrug resistance and the lung resistance-related protein in human colon carcinoma SW-620 cells. J Natl Cancer Inst 91:1647–1653PubMedCrossRefGoogle Scholar
  115. 115.
    Laurencot CM, Scheffer GL, Scheper RJ, Shoemaker RH (1997) Increased LRP mRNA expression is associated with the MDR phenotype in intrinsically resistant human cancer cell lines. Int J Cancer 72:1021–1026PubMedCrossRefGoogle Scholar
  116. 116.
    Scheffer GL, Wijngaard PL, Flens MJ et al (1995) The drug resistance-related protein LRP is the human major vault protein. Nat Med 1:578–582PubMedCrossRefGoogle Scholar
  117. 117.
    Siva AC, Raval-Fernandes S, Stephen AG et al (2001) Up-regulation of vaults may be necessary but not sufficient for multidrug resistance. Int J Cancer 92:195–202PubMedCrossRefGoogle Scholar
  118. 118.
    van Zon A, Mossink MH, Schoester M et al (2004) Efflux kinetics and intracellular distribution of daunorubicin are not affected by major vault protein/lung resistance-related protein (vault) expression. Cancer Res 64:4887–4892PubMedCrossRefGoogle Scholar
  119. 119.
    Mossink MH, van Zon A, Franzel-Luiten E et al (2002) Disruption of the murine major vault protein (MVP/LRP) gene does not induce hypersensitivity to cytostatics. Cancer Res 62:7298–7304PubMedGoogle Scholar
  120. 120.
    Mossink MH, de Groot J, van Zon A et al (2003) Unimpaired dendritic cell functions in MVP/LRP knockout mice. Immunology 110:58–65PubMedCrossRefGoogle Scholar
  121. 121.
    Jin S, Scotto KW (1998) Transcriptional regulation of the MDR1 gene by histone acetyltransferase and deacetylase is mediated by NF-Y. Mol Cell Biol 18:4377–4384PubMedGoogle Scholar
  122. 122.
    Li H, Liu H, Wang Z et al (2008) The role of transcription factors Sp1 and YY1 in proximal promoter region in initiation of transcription of the mu opioid receptor gene in human lymphocytes. J Cell Biochem 104:237–250PubMedCrossRefGoogle Scholar
  123. 123.
    Tlsty TD, Coussens LM (2006) Tumor stroma and regulation of cancer development. Annu Rev Pathol 1:119–150PubMedCrossRefGoogle Scholar
  124. 124.
    Cosse JP, Michiels C (2008) Tumour hypoxia affects the responsiveness of cancer cells to chemotherapy and promotes cancer progression. Anticancer Agents Med Chem 8:790–797PubMedGoogle Scholar
  125. 125.
    Netti PA, Berk DA, Swartz MA, Grodzinsky AJ, Jain RK (2000) Role of extracellular matrix assembly in interstitial transport in solid tumors. Cancer Res 60:2497–2503PubMedGoogle Scholar
  126. 126.
    Heldin CH, Rubin K, Pietras K, Ostman A (2004) High interstitial fluid pressure – an obstacle in cancer therapy. Nat Rev Cancer 4:806–813PubMedCrossRefGoogle Scholar
  127. 127.
    Tredan O, Galmarini CM, Patel K, Tannock IF (2007) Drug resistance and the solid tumor microenvironment. J Natl Cancer Inst 99:1441–1454PubMedCrossRefGoogle Scholar
  128. 128.
    Magzoub M, Jin S, Verkman AS (2008) Enhanced macromolecule diffusion deep in tumors after enzymatic digestion of extracellular matrix collagen and its associated proteoglycan decorin. FASEB J 22:276–284PubMedCrossRefGoogle Scholar
  129. 129.
    Padera TP, Stoll BR, Tooredman JB et al (2004) Pathology: cancer cells compress intratumour vessels. Nature 427:695PubMedCrossRefGoogle Scholar
  130. 130.
    Jain RK (1988) Determinants of tumor blood flow: a review. Cancer Res 48:2641–2658PubMedGoogle Scholar
  131. 131.
    Netti PA, Hamberg LM, Babich JW et al (1999) Enhancement of fluid filtration across tumor vessels: implication for delivery of macromolecules. Proc Natl Acad Sci USA 96:3137–3142PubMedCrossRefGoogle Scholar
  132. 132.
    Leu AJ, Berk DA, Lymboussaki A, Alitalo K, Jain RK (2000) Absence of functional lymphatics within a murine sarcoma: a molecular and functional evaluation. Cancer Res 60:4324–4327PubMedGoogle Scholar
  133. 133.
    Salnikov AV, Iversen VV, Koisti M et al (2003) Lowering of tumor interstitial fluid pressure specifically augments efficacy of chemotherapy. FASEB J 17:1756–1758PubMedGoogle Scholar
  134. 134.
    Roos A (1978) Weak acids, weak bases and intracellular pH. Respir Physiol 33:27–30PubMedCrossRefGoogle Scholar
  135. 135.
    Gerweck LE, Vijayappa S, Kozin S (2006) Tumor pH controls the in vivo efficacy of weak acid and base chemotherapeutics. Mol Cancer Ther 5:1275–1279PubMedCrossRefGoogle Scholar
  136. 136.
    Boyer MJ (1997) Bioreductive agents: a clinical update. Oncol Res 9:391–395PubMedGoogle Scholar
  137. 137.
    Lluis JM, Morales A, Blasco C et al (2005) Critical role of mitochondrial glutathione in the survival of hepatocytes during hypoxia. J Biol Chem 280:3224–3232PubMedCrossRefGoogle Scholar
  138. 138.
    Murphy BJ, Laderoute KR, Chin RJ, Sutherland RM (1994) Metallothionein IIA is up-regulated by hypoxia in human A431 squamous carcinoma cells. Cancer Res 54:5808–5810PubMedGoogle Scholar
  139. 139.
    Comerford KM, Wallace TJ, Karhausen J et al (2002) Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene. Cancer Res 62:3387–3394PubMedGoogle Scholar
  140. 140.
    Liu L, Ning X, Sun L et al (2008) Hypoxia-inducible factor-1 alpha contributes to hypoxia-induced chemoresistance in gastric cancer. Cancer Sci 99:121–128PubMedGoogle Scholar
  141. 141.
    Han HK, Han CY, Cheon EP, Lee J, Kang KW (2007) Role of hypoxia-inducible factor-alpha in hepatitis-B-virus X protein-mediated MDR1 activation. Biochem Biophys Res Commun 357:567–573PubMedCrossRefGoogle Scholar
  142. 142.
    Song X, Liu X, Chi W et al (2006) Hypoxia-induced resistance to cisplatin and doxorubicin in non-small cell lung cancer is inhibited by silencing of HIF-1alpha gene. Cancer Chemother Pharmacol 58:776–784PubMedCrossRefGoogle Scholar
  143. 143.
    Krishnamurthy P, Ross DD, Nakanishi T et al (2004) The stem cell marker Bcrp/ABCG2 enhances hypoxic cell survival through interactions with heme. J Biol Chem 279:24218–24225PubMedCrossRefGoogle Scholar
  144. 144.
    Alkatout I, Kabelitz D, Kalthoff H, Tiwari S (2008) Prowling wolves in sheep’s clothing: the search for tumor stem cells. Biol Chem 389:799–811PubMedCrossRefGoogle Scholar
  145. 145.
    Trumpp A, Wiestler OD (2008) Mechanisms of Disease: cancer stem cells–targeting the evil twin. Nat Clin Pract Oncol 5:337–347PubMedGoogle Scholar
  146. 146.
    Kim M, Turnquist H, Jackson J et al (2002) The multidrug resistance transporter ABCG2 (breast cancer resistance protein 1) effluxes Hoechst 33342 and is overexpressed in hematopoietic stem cells. Clin Cancer Res 8:22–28PubMedGoogle Scholar
  147. 147.
    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. Nat Med 7:1028–1034PubMedCrossRefGoogle Scholar
  148. 148.
    Bunting KD (2002) ABC transporters as phenotypic markers and functional regulators of stem cells. Stem Cells 20:11–20PubMedCrossRefGoogle Scholar
  149. 149.
    Hirschmann-Jax C, Foster AE, Wulf GG et al (2004) A distinct “side population” of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci USA 101:14228–14233PubMedCrossRefGoogle Scholar
  150. 150.
    Schatton T, Murphy GF, Frank NY et al (2008) Identification of cells initiating human melanomas. Nature 451:345–349PubMedCrossRefGoogle Scholar
  151. 151.
    Frank NY, Margaryan A, Huang Y et al (2005) ABCB5-mediated doxorubicin transport and chemoresistance in human malignant melanoma. Cancer Res 65:4320–4333PubMedCrossRefGoogle Scholar
  152. 152.
    Frank NY, Pendse SS, Lapchak PH et al (2003) Regulation of progenitor cell fusion by ABCB5 P-glycoprotein, a novel human ATP-binding cassette transporter. J Biol Chem 278:47156–47165PubMedCrossRefGoogle Scholar
  153. 153.
    Fromm MF (2004) Importance of P-glyco­protein at blood-tissue barriers. Trends Pharmacol Sci 25:423–429PubMedCrossRefGoogle Scholar
  154. 154.
    Borst P, Elferink RO (2002) Mammalian ABC transporters in health and disease. Annu Rev Biochem 71:537–592PubMedCrossRefGoogle Scholar
  155. 155.
    Trowsdale J, Hanson I, Mockridge I et al (1990) Sequences encoded in the class II region of the MHC related to the ‘ABC’ superfamily of transporters. Nature 348:741–744PubMedCrossRefGoogle Scholar
  156. 156.
    Abele R, Tampe R (2004) The ABCs of immunology: structure and function of TAP, the transporter associated with antigen processing. Physiology (Bethesda) 19:216–224Google Scholar
  157. 157.
    Takahashi K, Kimura Y, Nagata K et al (2005) ABC proteins: key molecules for lipid homeostasis. Med Mol Morphol 38:2–12PubMedCrossRefGoogle Scholar
  158. 158.
    Juliano RL, Ling V (1976) A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta 455:152–162PubMedCrossRefGoogle Scholar
  159. 159.
    Ueda K, Cardarelli C, Gottesman MM, Pastan I (1987) Expression of a full-length cDNA for the human “MDR1” gene confers resistance to colchicine, doxorubicin, and vinblastine. Proc Natl Acad Sci USA 84:3004–3008PubMedCrossRefGoogle Scholar
  160. 160.
    Ueda K, Clark DP, Chen CJ et al (1987) The human multidrug resistance (mdr1) gene. cDNA cloning and transcription initiation. J Biol Chem 262:505–508PubMedGoogle Scholar
  161. 161.
    Cole SP, Bhardwaj G, Gerlach JH et al (1992) Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science 258:1650–1654PubMedCrossRefGoogle Scholar
  162. 162.
    Doyle LA, Yang W, Abruzzo LV et al (1998) A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc Natl Acad Sci USA 95:15665–15670PubMedCrossRefGoogle Scholar
  163. 163.
    Ambudkar SV, Kim IW, Sauna ZE (2006) The power of the pump: mechanisms of action of P-glycoprotein (ABCB1). Eur J Pharm Sci 27:392–400PubMedCrossRefGoogle Scholar
  164. 164.
    Cascorbi I (2006) Role of pharmacogenetics of ATP-binding cassette transporters in the pharmacokinetics of drugs. Pharmacol Ther 112:457–473PubMedCrossRefGoogle Scholar
  165. 165.
    Choudhuri S, Klaassen CD (2006) Structure, function, expression, genomic organization, and single nucleotide polymorphisms of human ABCB1 (MDR1), ABCC (MRP), and ABCG2 (BCRP) efflux transporters. Int J Toxicol 25:231–259PubMedCrossRefGoogle Scholar
  166. 166.
    Ieiri I, Takane H, Otsubo K (2004) The MDR1 (ABCB1) gene polymorphism and its clinical implications. Clin Pharmacokinet 43:553–576PubMedCrossRefGoogle Scholar
  167. 167.
    Kimchi-Sarfaty C, Oh JM, Kim IW et al (2007) A “silent” polymorphism in the MDR1 gene changes substrate specificity. Science 315:525–528PubMedCrossRefGoogle Scholar
  168. 168.
    Fung KL, Gottesman MM (2009) A synonymous polymorphism in a common MDR1 (ABCB1) haplotype shapes protein function. Biochim Biophys Acta 1794:860–871PubMedGoogle Scholar
  169. 169.
    Kohno K, Sato S, Takano H, Matsuo K, Kuwano M (1989) The direct activation of human multidrug resistance gene (MDR1) by anticancer agents. Biochem Biophys Res Commun 165:1415–1421PubMedCrossRefGoogle Scholar
  170. 170.
    Chaudhary PM, Roninson IB (1993) Induction of multidrug resistance in human cells by transient exposure to different chemotherapeutic drugs. J Natl Cancer Inst 85:632–639PubMedCrossRefGoogle Scholar
  171. 171.
    Robey RW, Polgar O, Deeken J, To KW, Bates SE (2007) ABCG2: determining its relevance in clinical drug resistance. Cancer Metastasis Rev 26:39–57PubMedCrossRefGoogle Scholar
  172. 172.
    Hirose M, Hosoi E, Hamano S, Jalili A (2003) Multidrug resistance in hematological malignancy. J Med Invest 50:126–135PubMedGoogle Scholar
  173. 173.
    Ross DD (2000) Novel mechanisms of drug resistance in leukemia. Leukemia 14:467–473PubMedCrossRefGoogle Scholar
  174. 174.
    van den Heuvel-Eibrink MM, Sonneveld P, Pieters R (2000) The prognostic significance of membrane transport-associated multidrug resistance (MDR) proteins in leukemia. Int J Clin Pharmacol Ther 38:94–110PubMedGoogle Scholar
  175. 175.
    Marie JP, Legrand O (1999) MDR1/P-GP expression as a prognostic factor in acute leukemias. Adv Exp Med Biol 457:1–9PubMedGoogle Scholar
  176. 176.
    Wuchter C, Leonid K, Ruppert V et al (2000) Clinical significance of P-glycoprotein expression and function for response to induction chemotherapy, relapse rate and overall survival in acute leukemia. Haematologica 85:711–721PubMedGoogle Scholar
  177. 177.
    Tafuri A, Gregorj C, Petrucci MT et al (2002) MDR1 protein expression is an independent predictor of complete remission in newly diagnosed adult acute lymphoblastic leukemia. Blood 100:974–981PubMedCrossRefGoogle Scholar
  178. 178.
    Wattel E, Lepelley P, Merlat A et al (1995) Expression of the multidrug resistance P glycoprotein in newly diagnosed adult acute lymphoblastic leukemia: absence of correlation with response to treatment. Leukemia 9:1870–1874PubMedGoogle Scholar
  179. 179.
    Larkin A, O’Driscoll L, Kennedy S et al (2004) Investigation of MRP-1 protein and MDR-1 P-glycoprotein expression in invasive breast cancer: a prognostic study. Int J Cancer 112:286–294PubMedCrossRefGoogle Scholar
  180. 180.
    Leonessa F, Clarke R (2003) ATP binding cassette transporters and drug resistance in breast cancer. Endocr Relat Cancer 10:43–73PubMedCrossRefGoogle Scholar
  181. 181.
    Efferth T, Gillet JP, Sauerbrey A et al (2006) Expression profiling of ATP-binding cassette transporters in childhood T-cell acute lymphoblastic leukemia. Mol Cancer Ther 5:1986–1994PubMedCrossRefGoogle Scholar
  182. 182.
    Gillet JP, Schneider J, Bertholet V et al (2006) Microarray Expression Profiling of ABC Transporters in Human Breast Cancer. Cancer Genom Proteom 3:97–106Google Scholar
  183. 183.
    Gillet JP, Efferth T, Steinbach D et al (2004) Microarray-based detection of multidrug resistance in human tumor cells by expression profiling of ATP-binding cassette transporter genes. Cancer Res 64:8987–8993PubMedCrossRefGoogle Scholar
  184. 184.
    Szakacs G, Annereau JP, Lababidi S et al (2004) Predicting drug sensitivity and resistance: profiling ABC transporter genes in cancer cells. Cancer Cell 6:129–137PubMedCrossRefGoogle Scholar
  185. 185.
    Rhodes DR, Chinnaiyan AM (2005) Integrative analysis of the cancer transcriptome. Nat Genet 37(Suppl):S31–S37PubMedCrossRefGoogle Scholar
  186. 186.
    Rhodes DR, Kalyana-Sundaram S, Mahavisno V et al (2007) Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. Neoplasia 9:166–180PubMedCrossRefGoogle Scholar
  187. 187.
    Rhodes DR, Kalyana-Sundaram S, Tomlins SA et al (2007) Molecular concepts analysis links tumors, pathways, mechanisms, and drugs. Neoplasia 9:443–454PubMedCrossRefGoogle Scholar
  188. 188.
    Rhodes DR, Yu J, Shanker K et al (2004) ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia 6:1–6PubMedGoogle Scholar
  189. 189.
    Annereau JP, Szakacs G, Tucker CJ et al (2004) Analysis of ATP-binding cassette transporter expression in drug-selected cell lines by a microarray dedicated to multidrug resistance. Mol Pharmacol 66:1397–1405PubMedCrossRefGoogle Scholar
  190. 190.
    Orina JN, Calcagno AM, Wu C-P, et al (2009) Evaluation of current methods to analyze the expression profiles of ABC transporters yields an improved drug-discovery database. Mol Cancer Ther 8:2057–2066PubMedCrossRefGoogle Scholar
  191. 191.
    Filipits M, Stranzl T, Pohl G et al (2000) Drug resistance factors in acute myeloid leukemia: a comparative analysis. Leukemia 14:68–76PubMedCrossRefGoogle Scholar
  192. 192.
    Hart SM, Ganeshaguru K, Scheper RJ et al (1997) Expression of the human major vault protein LRP in acute myeloid leukemia. Exp Hematol 25:1227–1232PubMedGoogle Scholar
  193. 193.
    List AF, Spier CS, Grogan TM et al (1996) Overexpression of the major vault transporter protein lung-resistance protein predicts treatment outcome in acute myeloid leukemia. Blood 87:2464–2469PubMedGoogle Scholar
  194. 194.
    Xu D, Arestrom I, Virtala R et al (1999) High levels of lung resistance related protein mRNA in leukaemic cells from patients with acute myelogenous leukaemia are associated with inferior response to chemotherapy and prior treatment with mitoxantrone. Br J Haematol 106:627–633PubMedCrossRefGoogle Scholar
  195. 195.
    Legrand O, Simonin G, Beauchamp-Nicoud A, Zittoun R, Marie JP (1999) Simultaneous activity of MRP1 and Pgp is correlated with in vitro resistance to daunorubicin and with in vivo resistance in adult acute myeloid leukemia. Blood 94:1046–1056PubMedGoogle Scholar
  196. 196.
    Leith CP, Kopecky KJ, Chen IM et al (1999) Frequency and clinical significance of the expression of the multidrug resistance proteins MDR1/P-glycoprotein, MRP1, and LRP in acute myeloid leukemia: a Southwest Oncology Group Study. Blood 94:1086–1099PubMedGoogle Scholar
  197. 197.
    Schaich M, Soucek S, Thiede C, Ehninger G, Illmer T (2005) MDR1 and MRP1 gene expression are independent predictors for treatment outcome in adult acute myeloid leukaemia. Br J Haematol 128:324–332PubMedCrossRefGoogle Scholar
  198. 198.
    Sunnaram BL, Gandemer V, Sebillot M et al (2003) LRP overexpression in monocytic lineage. Leuk Res 27:755–759PubMedCrossRefGoogle Scholar
  199. 199.
    van den Heuvel-Eibrink MM, Wiemer EA, Prins A et al (2002) Increased expression of the breast cancer resistance protein (BCRP) in relapsed or refractory acute myeloid leukemia (AML). Leukemia 16:833–839PubMedCrossRefGoogle Scholar
  200. 200.
    Borg AG, Burgess R, Green LM, Scheper RJ, Yin JA (1998) Overexpression of lung-resistance protein and increased P-glycoprotein function in acute myeloid leukaemia cells predict a poor response to chemotherapy and reduced patient survival. Br J Haematol 103:1083–1091PubMedCrossRefGoogle Scholar
  201. 201.
    Filipits M, Pohl G, Stranzl T et al (1998) Expression of the lung resistance protein predicts poor outcome in de novo acute myeloid leukemia. Blood 91:1508–1513PubMedGoogle Scholar
  202. 202.
    Pirker R, Pohl G, Stranzl T et al (1999) The lung resistance protein (LRP) predicts poor outcome in acute myeloid leukemia. Adv Exp Med Biol 457:133–139PubMedGoogle Scholar
  203. 203.
    Oh EJ, Kahng J, Kim Y et al (2003) Expression of functional markers in acute lymphoblastic leukemia. Leuk Res 27:903–908PubMedCrossRefGoogle Scholar
  204. 204.
    Valera ET, Scrideli CA, Queiroz RG, Mori BM, Tone LG (2004) Multiple drug resistance protein (MDR-1), multidrug resistance-related protein (MRP) and lung resistance protein (LRP) gene expression in childhood acute lymphoblastic leukemia. Sao Paulo Med J 122:166–171PubMedCrossRefGoogle Scholar
  205. 205.
    Volm M, Stammler G, Zintl F, Koomagi R, Sauerbrey A (1997) Expression of lung resistance-related protein (LRP) in initial and relapsed childhood acute lymphoblastic leukemia. Anticancer Drugs 8:662–665PubMedCrossRefGoogle Scholar
  206. 206.
    Ohno N, Tani A, Uozumi K et al (2001) Expression of functional lung resistance–related protein predicts poor outcome in adult T-cell leukemia. Blood 98:1160–1165PubMedCrossRefGoogle Scholar
  207. 207.
    Filipits M, Drach J, Pohl G et al (1999) Expression of the lung resistance protein predicts poor outcome in patients with multiple myeloma. Clin Cancer Res 5:2426–2430PubMedGoogle Scholar
  208. 208.
    Raaijmakers HG, Izquierdo MA, Lokhorst HM et al (1998) Lung-resistance-related protein expression is a negative predictive factor for response to conventional low but not to intensified dose alkylating chemotherapy in multiple myeloma. Blood 91:1029–1036PubMedGoogle Scholar
  209. 209.
    Rimsza LM, Campbell K, Dalton WS et al (1999) The major vault protein (MVP), a new multidrug resistance associated protein, is frequently expressed in multiple myeloma. Leuk Lymphoma 34:315–324PubMedGoogle Scholar
  210. 210.
    Brinkhuis M, Izquierdo MA, Baak JP et al (2002) Expression of multidrug resistance-associated markers, their relation to quantitative pathologic tumour characteristics and prognosis in advanced ovarian cancer. Anal Cell Pathol 24:17–23PubMedGoogle Scholar
  211. 211.
    Izquierdo MA, van der Zee AG, Vermorken JB et al (1995) Drug resistance-associated marker Lrp for prediction of response to chemotherapy and prognoses in advanced ovarian carcinoma. J Natl Cancer Inst 87: 1230–1237PubMedCrossRefGoogle Scholar
  212. 212.
    Mayr D, Pannekamp U, Baretton GB et al (2000) Immunohistochemical analysis of drug resistance-associated proteins in ovarian carcinomas. Pathol Res Pract 196:469–475PubMedGoogle Scholar
  213. 213.
    Arts HJ, Katsaros D, de Vries EG et al (1999) Drug resistance-associated markers P-glycoprotein, multidrug resistance-associated protein 1, multidrug resistance-associated protein 2, and lung resistance protein as prognostic factors in ovarian carcinoma. Clin Cancer Res 5:2798–2805PubMedGoogle Scholar
  214. 214.
    Burger H, Foekens JA, Look MP et al (2003) RNA expression of breast cancer resistance protein, lung resistance-related protein, multidrug resistance-associated proteins 1 and 2, and multidrug resistance gene 1 in breast cancer: correlation with chemotherapeutic response. Clin Cancer Res 9:827–836PubMedGoogle Scholar
  215. 215.
    Linn SC, Pinedo HM, van Ark-Otte J et al (1997) Expression of drug resistance proteins in breast cancer, in relation to chemotherapy. Int J Cancer 71:787–795PubMedCrossRefGoogle Scholar
  216. 216.
    Schneider J, Lucas R, Sanchez J et al (2000) Modulation of molecular marker expression by induction chemotherapy in locally advanced breast cancer: correlation with the response to therapy and the expression of MDR1 and LRP. Anticancer Res 20:4373–4377PubMedGoogle Scholar
  217. 217.
    Kanzaki A, Toi M, Nakayama K et al (2001) Expression of multidrug resistance-related transporters in human breast carcinoma. Jpn J Cancer Res 92:452–458PubMedGoogle Scholar
  218. 218.
    Pohl G, Filipits M, Suchomel RW et al (1999) Expression of the lung resistance protein (LRP) in primary breast cancer. Anticancer Res 19:5051–5055PubMedGoogle Scholar
  219. 219.
    Volm M, Mattern J, Koomagi R (1997) Expression of lung resistance-related protein (LRP) in non-small cell lung carcinomas of smokers and non-smokers and its predictive value for doxorubicin resistance. Anticancer Drugs 8:931–936PubMedCrossRefGoogle Scholar
  220. 220.
    Volm M, Rittgen W (2000) Cellular predictive factors for the drug response of lung cancer. Anticancer Res 20:3449–3458PubMedGoogle Scholar
  221. 221.
    Chiou JF, Liang JA, Hsu WH et al (2003) Comparing the relationship of Taxol-based chemotherapy response with P-glycoprotein and lung resistance-related protein expression in non-small cell lung cancer. Lung 181:267–273PubMedCrossRefGoogle Scholar
  222. 222.
    Dingemans AM, van Ark-Otte J, van der Valk P et al (1996) Expression of the human major vault protein LRP in human lung cancer samples and normal lung tissues. Ann Oncol 7:625–630PubMedGoogle Scholar
  223. 223.
    Berger W, Setinek U, Hollaus P et al (2005) Multidrug resistance markers P-glycoprotein, multidrug resistance protein 1, and lung resistance protein in non-small cell lung cancer: prognostic implications. J Cancer Res Clin Oncol 131:355–363PubMedCrossRefGoogle Scholar
  224. 224.
    Diestra JE, Condom E, Del Muro XG et al (2003) Expression of multidrug resistance proteins P-glycoprotein, multidrug resistance protein 1, breast cancer resistance protein and lung resistance related protein in locally advanced bladder cancer treated with neoadjuvant chemotherapy: biological and clinical implications. J Urol 170:1383–1387PubMedCrossRefGoogle Scholar
  225. 225.
    Uozaki H, Horiuchi H, Ishida T et al (1997) Overexpression of resistance-related proteins (metallothioneins, glutathione-S-transferase pi, heat shock protein 27, and lung resistance-related protein) in osteosarcoma. Relationship with poor prognosis. Cancer 79:2336–2344PubMedCrossRefGoogle Scholar
  226. 226.
    Gaumann A, Tews DS, Mentzel T et al (2003) Expression of drug resistance related proteins in sarcomas of the pulmonary artery and poorly differentiated leiomyosarcomas of other origin. Virchows Arch 442:529–537PubMedGoogle Scholar
  227. 227.
    Plaat BE, Hollema H, Molenaar WM et al (2000) Soft tissue leiomyosarcomas and malignant gastrointestinal stromal tumors: differences in clinical outcome and expression of multidrug resistance proteins. J Clin Oncol 18:3211–3220PubMedGoogle Scholar
  228. 228.
    Zurita AJ, Diestra JE, Condom E et al (2003) Lung resistance-related protein as a predictor of clinical outcome in advanced testicular germ-cell tumours. Br J Cancer 88:879–886PubMedCrossRefGoogle Scholar
  229. 229.
    Mandoky L, Geczi L, Doleschall Z et al (2004) Expression and prognostic value of the lung resistance-related protein (LRP) in germ cell testicular tumors. Anticancer Res 24:1097–1104PubMedGoogle Scholar
  230. 230.
    Boonstra R, Timmer-Bosscha H, van Echten-Arends J et al (2004) Mitoxantrone resistance in a small cell lung cancer cell line is associated with ABCA2 upregulation. Br J Cancer 90:2411–2417PubMedGoogle Scholar
  231. 231.
    Vulevic B, Chen Z, Boyd JT et al (2001) Cloning and characterization of human adenosine 5′-triphosphate-binding cassette, sub-family A, transporter 2 (ABCA2). Cancer Res 61:3339–3347PubMedGoogle Scholar
  232. 232.
    Takara K, Sakaeda T, Okumura K (2006) An update on overcoming MDR1-mediated multidrug resistance in cancer chemotherapy. Curr Pharm Des 12:273–286PubMedCrossRefGoogle Scholar
  233. 233.
    Calcagno AM, Kim IW, Wu CP, Shukla S, Ambudkar SV (2007) ABC drug transporters as molecular targets for the prevention of multidrug resistance and drug-drug interactions. Curr Drug Deliv 4:324–333PubMedCrossRefGoogle Scholar
  234. 234.
    Smith AJ, van Helvoort A, van Meer G et al (2000) MDR3 P-glycoprotein, a phosphatidylcholine translocase, transports several cytotoxic drugs and directly interacts with drugs as judged by interference with nucleotide trapping. J Biol Chem 275:23530–23539PubMedCrossRefGoogle Scholar
  235. 235.
    Huang Y, Anderle P, Bussey KJ et al (2004) Membrane transporters and channels: role of the transportome in cancer chemosensitivity and chemoresistance. Cancer Res 64:4294–4301PubMedCrossRefGoogle Scholar
  236. 236.
    Childs S, Yeh RL, Hui D, Ling V (1998) Taxol resistance mediated by transfection of the liver-specific sister gene of P-glycoprotein. Cancer Res 58:4160–4167PubMedGoogle Scholar
  237. 237.
    Deeley RG, Cole SP (2006) Substrate recognition and transport by multidrug resistance protein 1 (ABCC1). FEBS Lett 580:1103–1111PubMedCrossRefGoogle Scholar
  238. 238.
    Guminski AD, Balleine RL, Chiew YE et al (2006) MRP2 (ABCC2) and cisplatin sensitivity in hepatocytes and human ovarian carcinoma. Gynecol Oncol 100:239–246PubMedCrossRefGoogle Scholar
  239. 239.
    Huisman MT, Chhatta AA, van Tellingen O, Beijnen JH, Schinkel AH (2005) MRP2 (ABCC2) transports taxanes and confers paclitaxel resistance and both processes are stimulated by probenecid. Int J Cancer 116:824–829PubMedCrossRefGoogle Scholar
  240. 240.
    Jedlitschky G, Hoffmann U, Kroemer HK (2006) Structure and function of the MRP2 (ABCC2) protein and its role in drug disposition. Expert Opin Drug Metab Toxicol 2:351–366PubMedCrossRefGoogle Scholar
  241. 241.
    Materna V, Stege A, Surowiak P, Priebsch A, Lage H (2006) RNA interference-triggered reversal of ABCC2-dependent cisplatin resistance in human cancer cells. Biochem Biophys Res Commun 348:153–157PubMedCrossRefGoogle Scholar
  242. 242.
    Zelcer N, Saeki T, Reid G, Beijnen JH, Borst P (2001) Characterization of drug transport by the human multidrug resistance protein 3 (ABCC3). J Biol Chem 276:46400–46407PubMedCrossRefGoogle Scholar
  243. 243.
    Zeng H, Chen ZS, Belinsky MG, Rea PA, Kruh GD (2001) Transport of methotrexate (MTX) and folates by multidrug resistance protein (MRP) 3 and MRP1: effect of polyglutamylation on MTX transport. Cancer Res 61:7225–7232PubMedGoogle Scholar
  244. 244.
    Chen ZS, Lee K, Kruh GD (2001) Transport of cyclic nucleotides and estradiol 17-beta-d-glucuronide by multidrug resistance protein 4. Resistance to 6-mercaptopurine and 6-thioguanine. J Biol Chem 276:33747–33754PubMedCrossRefGoogle Scholar
  245. 245.
    Ritter CA, Jedlitschky G, Meyer zu Schwabedissen H et al (2005) Cellular export of drugs and signaling molecules by the ATP-binding cassette transporters MRP4 (ABCC4) and MRP5 (ABCC5). Drug Metab Rev 37:253–278PubMedCrossRefGoogle Scholar
  246. 246.
    Tian Q, Zhang J, Chan SY et al (2006) Topotecan is a substrate for multidrug resistance associated protein 4. Curr Drug Metab 7:105–118PubMedCrossRefGoogle Scholar
  247. 247.
    Tian Q, Zhang J, Tan TM et al (2005) Human multidrug resistance associated protein 4 confers resistance to camptothecins. Pharm Res 22:1837–1853PubMedCrossRefGoogle Scholar
  248. 248.
    Pratt S, Shepard RL, Kandasamy RA et al (2005) The multidrug resistance protein 5 (ABCC5) confers resistance to 5-fluorouracil and transports its monophosphorylated metabolites. Mol Cancer Ther 4:855–863PubMedCrossRefGoogle Scholar
  249. 249.
    Belinsky MG, Chen ZS, Shchaveleva I, Zeng H, Kruh GD (2002) Characterization of the drug resistance and transport properties of multidrug resistance protein 6 (MRP6, ABCC6). Cancer Res 62:6172–6177PubMedGoogle Scholar
  250. 250.
    Naramoto H, Uematsu T, Uchihashi T et al (2007) Multidrug resistance-associated protein 7 expression is involved in cross-resistance to docetaxel in salivary gland adenocarcinoma cell lines. Int J Oncol 30:393–401PubMedGoogle Scholar
  251. 251.
    Hopper-Borge E, Chen ZS, Shchaveleva I, Belinsky MG, Kruh GD (2004) Analysis of the drug resistance profile of multidrug resistance protein 7 (ABCC10): resistance to docetaxel. Cancer Res 64:4927–4930PubMedCrossRefGoogle Scholar
  252. 252.
    Chen ZS, Guo Y, Belinsky MG, Kotova E, Kruh GD (2005) Transport of bile acids, sulfated steroids, estradiol 17-beta-d-glucuronide, and leukotriene C4 by human multidrug resistance protein 8 (ABCC11). Mol Pharmacol 67:545–557PubMedCrossRefGoogle Scholar
  253. 253.
    Guo Y, Kotova E, Chen ZS et al (2003) MRP8, ATP-binding cassette C11 (ABCC11), is a cyclic nucleotide efflux pump and a resistance factor for fluoropyrimidines 2′, 3′-dideoxycytidine and 9′-(2′-phosphonylmethoxyethyl)adenine. J Biol Chem 278:29509–29514PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press, a part of Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Laboratory of Cell BiologyNational Cancer Institute, National Institutes of HealthBethesdaUSA

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