Multidrug Resistance in Cancer

Part of the Methods in Molecular Biology book series (MIMB, volume 596)


It is becoming increasingly clear that the proliferation of human tumours is driven by a small proportion of cells, termed tumour stem cells, which have the properties of self-renewal. On analogy with stem cells for normal tissues, there are likely to be multiple mechanisms, involving both intrinsic cellular properties and microenvironmental factors, which enable tumour stem cells to resist potentially genotoxic agents. Intrinsic properties include maintenance of cells in a predominantly non-cycling state, expression of transport proteins such as P-glycoprotein, protection from induced apoptosis or other forms of cell death, and limitation of diffusion of potential cytotoxins from the bloodstream. In addition, tumour stem cells are likely to contain multiple genetic changes that will potentially activate host immune mechanisms, which are designed to respond to such changes, and the methods by which tumours suppress such mechanisms are of great relevance to drug resistance. A number of methods of overcoming intrinsic multidrug resistance of tumours have been developed but methods for overcoming tumour resistance mediated by host cells are still at an early stage and require further research.

Key words:

Cytokinetics ABC transporters Drug diffusion Apoptosis Tumour dormancy Macrophages Apoptosis Niche Microenvironment 


  1. 1.
    Bolhuis H, Van Veen HW, Poolman B, Driessen AJ, Konings WN (1997) Mechanisms of multidrug transporters. FEMS Microbiol Rev 21:55–84CrossRefPubMedGoogle Scholar
  2. 2.
    Baguley BC, Marshall ES (2008) The use of human tumour cell lines in the discovery of new cancer chemotherapeutic drugs. Expert Opin Drug Discov 3:153–161CrossRefGoogle Scholar
  3. 3.
    Meads MB, Hazlehurst LA, Dalton WS (2008) The bone marrow microenvironment as a tumor sanctuary and contributor to drug resistance. Clin Cancer Res 14:2519–2526CrossRefPubMedGoogle Scholar
  4. 4.
    Parmar K, Mauch P, Vergilio J, Sackstein R, Down JD (2007) Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia. Proc Natl Acad Sci USA 104:5431–5436CrossRefPubMedGoogle Scholar
  5. 5.
    Huls M, Russel FG, Masereeuw R (2009) The role of ABC transporters in tissue defense and organ regeneration. J Pharmacol Exp Ther 328:3–9CrossRefPubMedGoogle Scholar
  6. 6.
    Turco MC, Romano MF, Petrella A et al (2004) NF-kappaB/Rel-mediated regulation of apoptosis in hematologic malignancies and normal hematopoietic progenitors. Leukemia 18:11–17CrossRefPubMedGoogle Scholar
  7. 7.
    Massague J (2008) TGFbeta in Cancer. Cell 134:215–230CrossRefPubMedGoogle Scholar
  8. 8.
    MacKie RM, Reid R, Junor B (2003) Fatal melanoma transferred in a donated kidney 16 years after melanoma surgery. N Engl J Med 348:567–568CrossRefPubMedGoogle Scholar
  9. 9.
    Aguirre-Ghiso JA (2007) Models, mechanisms and clinical evidence for cancer dormancy. Nat Rev Cancer 7:834–846CrossRefPubMedGoogle Scholar
  10. 10.
    Demicheli R, Retsky MW, Hrushesky WJ, Baum M (2007) Tumor dormancy and surgery-driven interruption of dormancy in breast cancer: learning from failures. Nat Clin Pract Oncol 4:699–710CrossRefPubMedGoogle Scholar
  11. 11.
    Koebel CM, Vermi W, Swann JB et al (2007) Adaptive immunity maintains occult cancer in an equilibrium state. Nature 450:903–907CrossRefPubMedGoogle Scholar
  12. 12.
    Kortylewski M, Komyod W, Kauffmann ME et al (2004) Interferon-gamma-mediated growth regulation of melanoma cells: involvement of STAT1-dependent and STAT1-independent signals. J Invest Dermatol 122:414–422CrossRefPubMedGoogle Scholar
  13. 13.
    Muller-Hermelink N, Braumuller H, Pichler B et al (2008) TNFR1 signaling and IFN-gamma signaling determine whether T cells induce tumor dormancy or promote multistage carcinogenesis. Cancer Cell 13:507–518CrossRefPubMedGoogle Scholar
  14. 14.
    Finlay GJ, Baguley BC (2000) Effects of protein binding on the in vitro activity of antitumour acridine derivatives and related anticancer drugs. Cancer Chemother Pharmacol 45:417–422CrossRefPubMedGoogle Scholar
  15. 15.
    Hicks KO, Pruijn FB, Baguley BC, Wilson WR (2001) Extravascular transport of the DNA intercalator and topoisomerase poison N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA): diffusion and metabolism in multicellular layers of tumor cells. J Pharmacol Exp Ther 297:1088–1098PubMedGoogle Scholar
  16. 16.
    Nakagawa T, Inoue Y, Kodama H et al (2008) Expression of copper-transporting P-type adenosine triphosphatase (ATP7B) correlates with cisplatin resistance in human non-small cell lung cancer xenografts. Oncol Rep 20:265–270PubMedGoogle Scholar
  17. 17.
    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 103:9903–9907CrossRefPubMedGoogle Scholar
  18. 18.
    Ling V (1997) Multidrug resistance: molecular mechanisms and clinical relevance. Cancer Chemother Pharmacol 40(Suppl):S3–S8CrossRefPubMedGoogle Scholar
  19. 19.
    Gillet JP, Efferth T, Remacle J (2007) Chemotherapy-induced resistance by ATP-binding cassette transporter genes. Biochim Biophys Acta 1775:237–262PubMedGoogle Scholar
  20. 20.
    Ejendal KF, Hrycyna CA (2002) Multidrug resistance and cancer: the role of the human ABC transporter ABCG2. Curr Protein Pept Sci 3:503–511CrossRefPubMedGoogle Scholar
  21. 21.
    Sarkadi B, Ozvegy-Laczka C, Nemet K, Varadi A (2004) ABCG2 – a transporter for all seasons. FEBS Lett 567:116–120CrossRefPubMedGoogle Scholar
  22. 22.
    Loebinger MR, Giangreco A, Groot KR et al (2008) Squamous cell cancers contain a side population of stem-like cells that are made chemosensitive by ABC transporter blockade. Br J Cancer 98:380–387CrossRefPubMedGoogle Scholar
  23. 23.
    Sharma SV, Gajowniczek P, Way IP et al (2006) A common signaling cascade may underlie “addiction” to the Src, BCR-ABL, and EGF receptor oncogenes. Cancer Cell 10:425–435CrossRefPubMedGoogle Scholar
  24. 24.
    Olson JM, Hallahan AR (2004) p38 MAP kinase: a convergence point in cancer therapy. Trends Mol Med 10:125–129CrossRefPubMedGoogle Scholar
  25. 25.
    Hersey P, Zhuang L, Zhang XD (2006) Current strategies in overcoming resistance of cancer cells to apoptosis melanoma as a model. Int Rev Cytol 251:131–158CrossRefPubMedGoogle Scholar
  26. 26.
    Danial NN (2007) BCL-2 family proteins: critical checkpoints of apoptotic cell death. Clin Cancer Res 13:7254–7263CrossRefPubMedGoogle Scholar
  27. 27.
    Forte M, Bernardi P (2006) The permeability transition and BCL-2 family proteins in apoptosis: co-conspirators or independent agents? Cell Death Differ 13:1287–1290CrossRefPubMedGoogle Scholar
  28. 28.
    Pham CG, Bubici C, Zazzeroni F et al (2007) Upregulation of Twist-1 by NF-kappaB blocks cytotoxicity induced by chemotherapeutic drugs. Mol Cell Biol 27:3920–3935CrossRefPubMedGoogle Scholar
  29. 29.
    Osford SM, Dallman CL, Johnson PW, Ganesan A, Packham G (2004) Current strategies to target the anti-apoptotic Bcl-2 protein in cancer cells. Curr Med Chem 11:1031–1039CrossRefPubMedGoogle Scholar
  30. 30.
    Kramer A, Lukas J, Bartek J (2004) Checking out the centrosome. Cell Cycle 3:1390–1393PubMedGoogle Scholar
  31. 31.
    McDermott KM, Zhang J, Holst CR et al (2006) p16(INK4a) prevents centrosome dysfunction and genomic instability in primary cells. PLoS Biol 4:e51CrossRefPubMedGoogle Scholar
  32. 32.
    Loeb LA, Bielas JH, Beckman RA (2008) Cancers exhibit a mutator phenotype: clinical implications. Cancer Res 68:3551–3557CrossRefPubMedGoogle Scholar
  33. 33.
    Kuilman T, Michaloglou C, Vredeveld LC et al (2008) Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133:1019–1031CrossRefPubMedGoogle Scholar
  34. 34.
    Acosta JC, O’Loghlen A, Banito A, Raguz S, Gil J (2008) Control of senescence by CXCR2 and its ligands. Cell Cycle 7:2956–2959PubMedGoogle Scholar
  35. 35.
    Smyth MJ, Godfrey DI, Trapani JA (2001) A fresh look at tumor immunosurveillance and immunotherapy. Nat Immunol 2:293–299CrossRefPubMedGoogle Scholar
  36. 36.
    Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G (2008) Immunological aspects of cancer chemotherapy. Nat Rev Immunol 8:59–73CrossRefPubMedGoogle Scholar
  37. 37.
    Baguley BC (2006) Tumor stem cell niches: a new functional framework for the action of anticancer drugs. Recent Pat Anticancer Drug Discov 1:121–127CrossRefPubMedGoogle Scholar
  38. 38.
    Fonseca C, Dranoff G (2008) Capitalizing on the immunogenicity of dying tumor cells. Clin Cancer Res 14:1603–1608CrossRefPubMedGoogle Scholar
  39. 39.
    Hadnagy A, Gaboury L, Beaulieu R, Balicki D (2006) SP analysis may be used to identify cancer stem cell populations. Exp Cell Res 312:3701–3710CrossRefPubMedGoogle Scholar
  40. 40.
    Keshet GI, Goldstein I, Itzhaki O et al (2008) MDR1 expression identifies human melanoma stem cells. Biochem Biophys Res Commun 368:930–936CrossRefPubMedGoogle Scholar
  41. 41.
    Ozben T (2006) Mechanisms and strategies to overcome multiple drug resistance in cancer. FEBS Lett 580:2903–2909CrossRefPubMedGoogle Scholar
  42. 42.
    Szakacs G, Paterson JK, Ludwig JA, Booth-Genthe C, Gottesman MM (2006) Targeting multidrug resistance in cancer. Nat Rev Drug Discov 5:219–234CrossRefPubMedGoogle Scholar
  43. 43.
    Baguley BC (2002) Novel strategies for overcoming multidrug resistance in cancer. BioDrugs 16:97–103CrossRefPubMedGoogle Scholar
  44. 44.
    Dubikovskaya EA, Thorne SH, Pillow TH, Contag CH, Wender PA (2008) Overcoming multidrug resistance of small-molecule therapeutics through conjugation with releasable octaarginine transporters. Proc Natl Acad Sci USA 105:12128–12133CrossRefPubMedGoogle Scholar
  45. 45.
    Robbie MA, Baguley BC, Denny WA, Gavin JB, Wilson WR (1988) Mechanism of resistance of noncycling mammalian cells to 4′-(9- acridinylamino)methanesulfon-m-anisidide: comparison of uptake, metabolism, and DNA breakage in log- and plateau-phase Chinese hamster fibroblast cell cultures. Cancer Res 48:310–319PubMedGoogle Scholar
  46. 46.
    Haldane A, Finlay GJ, Hay MP, Denny WA, Baguley BC (1999) Cellular uptake of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA). Anticancer Drug Des 14:275–280PubMedGoogle Scholar
  47. 47.
    Davey RA, Su GM, Hargrave RM et al (1997) The potential of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide to circumvent three multidrug-resistance phenotypes in vitro. Cancer Chemother Pharmacol 39:424–430CrossRefPubMedGoogle Scholar
  48. 48.
    Foster BA, Coffey HA, Morin MJ, Rastinejad F (1999) Pharmacological rescue of mutant p53 conformation and function. Science 286:2507–2510CrossRefPubMedGoogle Scholar
  49. 49.
    Sebolt-Leopold JS (2004) MEK inhibitors: a therapeutic approach to targeting the Ras-MAP kinase pathway in tumors. Curr Pharm Des 10:1907–1914CrossRefPubMedGoogle Scholar
  50. 50.
    Serra V, Markman B, Scaltriti M et al (2008) NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res 68:8022–8030CrossRefPubMedGoogle Scholar
  51. 51.
    Nguyen M, Marcellus RC, Roulston A et al (2007) Small molecule obatoclax (GX15–070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis. Proc Natl Acad Sci USA 104:19512–19517CrossRefPubMedGoogle Scholar
  52. 52.
    Nakanishi C, Toi M (2005) Nuclear factor-kappaB inhibitors as sensitizers to anticancer drugs. Nat Rev Cancer 5:297–309CrossRefPubMedGoogle Scholar
  53. 53.
    Wang W, McLeod HL, Cassidy J (2003) Disulfiram-mediated inhibition of NF-kappaB activity enhances cytotoxicity of 5-fluorouracil in human colorectal cancer cell lines. Int J Cancer 104:504–511CrossRefPubMedGoogle Scholar
  54. 54.
    Claus R, Lubbert M (2003) Epigenetic targets in hematopoietic malignancies. Oncogene 22:6489–6496CrossRefPubMedGoogle Scholar
  55. 55.
    Chen R, Alvero AB, Silasi DA, Steffensen KD, Mor G (2008) Cancers take their Toll – the function and regulation of Toll-like receptors in cancer cells. Oncogene 27:225–233CrossRefPubMedGoogle Scholar
  56. 56.
    Hicks AM, Riedlinger G, Willingham MC et al (2006) Transferable anticancer innate immunity in spontaneous regression/complete resistance mice. Proc Natl Acad Sci USA 103:7753–7758CrossRefPubMedGoogle Scholar
  57. 57.
    Panaretakis T, Joza N, Modjtahedi N et al (2008) The co-translocation of ERp57 and calreticulin determines the immunogeni­city of cell death. Cell Death Differ 15:1499–1509CrossRefPubMedGoogle Scholar
  58. 58.
    Baguley BC, Marshall ES (2004) In vitro modelling of human tumour behaviour in drug discovery programmes. Eur J Cancer 40:794–801CrossRefPubMedGoogle Scholar
  59. 59.
    Sotiriou C, Piccart MJ (2007) Taking gene-expression profiling to the clinic: when will molecular signatures become relevant to patient care? Nat Rev Cancer 7:545–553CrossRefPubMedGoogle Scholar
  60. 60.
    Samson DJ, Seidenfeld J, Ziegler K, Aronson N (2004) Chemotherapy sensitivity and resistance assays: a systematic review. J Clin Oncol 22:3618–3630CrossRefPubMedGoogle Scholar
  61. 61.
    Garcia-Barros M, Paris F, Cordon-Cardo C et al (2003) Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science 300:1155–1159CrossRefPubMedGoogle Scholar
  62. 62.
    Vit JP, Rosselli F (2003) Role of the ceramide-signaling pathways in ionizing radiation-induced apoptosis. Oncogene 22:8645–8652CrossRefPubMedGoogle Scholar
  63. 63.
    Duff MD, Mestre J, Maddali S et al (2007) Analysis of gene expression in the tumor-associated macrophage. J Surg Res 142:119–128CrossRefPubMedGoogle Scholar

Copyright information

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

Authors and Affiliations

  1. 1.Auckland Cancer Society Research CentreThe University of AucklandAucklandNew Zealand

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