Molecular Biotechnology

, Volume 46, Issue 3, pp 308–316 | Cite as

Multiple Drug Resistance Mechanisms in Cancer

  • Bruce C. Baguley


Multiple drug resistance (multidrug resistance; MDR), a phenomenon whereby human tumours that acquire resistance to one type of therapy are found to be resistant to several other drugs that are often quite different in both structure and mode of action, has been recognised clinically for several decades. An important advance in our understanding of MDR came with the identification of P-glycoprotein and other related transporters that were expressed in some cancer cells and could recognise and catalyse the efflux of diverse anticancer drugs from cells. A second advance came from an understanding of the mechanism of programmed cell death or apoptosis, leading to MDR mediated by increased to resistance to anticancer drug-induced apoptosis. A third advance came with the finding that the proliferation of human tumours was driven by a small population of self-renewing tumour cells, focussing attention on the MDR properties of these so-called tumour stem cells rather than on the cells that comprised the majority of the tumour population. A fourth advance was the delineation of features of the tumour microenvironment, including immunosuppression, which essentially provided tumour stem cells with an MDR phenotype. Most published work on the overcoming of MDR has concentrated on inhibition of drug transporters but the complexity of mechanisms contributing demands a broad strategy for the development of methods to overcome MDR in a clinical setting.


Cytokinetics ABC transporters Drug diffusion Apoptosis Tumour dormancy Macrophages Niche Microenvironment 


  1. 1.
    Bolhuis, H., Van Veen, H. W., Poolman, B., Driessen, A. J., & Konings, W. N. (1997). Mechanisms of multidrug transporters. FEMS Microbiology Reviews, 21, 55–84.CrossRefGoogle Scholar
  2. 2.
    Kawase, M., & Motohashi, N. (2003). New multidrug resistance reversal agents. Current Drug Targets, 4, 31–43.CrossRefGoogle Scholar
  3. 3.
    Szakacs, G., Paterson, J. K., Ludwig, J. A., Booth-Genthe, C., & Gottesman, M. M. (2006). Targeting multidrug resistance in cancer. Nature Reviews Drug Discovery, 5, 219–234.CrossRefGoogle Scholar
  4. 4.
    Ozben, T. (2006). Mechanisms and strategies to overcome multiple drug resistance in cancer. FEBS Letters, 580, 2903–2909.CrossRefGoogle Scholar
  5. 5.
    Dubikovskaya, E. A., Thorne, S. H., Pillow, T. H., Contag, C. H., & Wender, P. A. (2008). Overcoming multidrug resistance of small-molecule therapeutics through conjugation with releasable octaarginine transporters. Proceedings of the National Academy of Sciences of the United States of America, 105, 12128–12133.CrossRefGoogle Scholar
  6. 6.
    Baguley, B. C. (2010). Multidrug resistance in cancer. Methods in Molecular Biology, 596, 1–14.CrossRefGoogle Scholar
  7. 7.
    Baguley, B. C. (2002). Novel strategies for overcoming multidrug resistance in cancer. BioDrugs, 16, 97–103.CrossRefGoogle Scholar
  8. 8.
    Baguley, B. C., & Marshall, E. S. (2008). The use of human tumour cell lines in the discovery of new cancer chemotherapeutic drugs. Expert Opinion on Drug Discovery, 3, 153–161.CrossRefGoogle Scholar
  9. 9.
    Meads, M. B., Hazlehurst, L. A., & Dalton, W. S. (2008). The bone marrow microenvironment as a tumor sanctuary and contributor to drug resistance. Clinical Cancer Research, 14, 2519–2526.CrossRefGoogle Scholar
  10. 10.
    Parmar, K., Mauch, P., Vergilio, J., Sackstein, R., & Down, J. D. (2007). Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia. Proceedings of the National Academy of Sciences of the United States of America, 104, 5431–5436.CrossRefGoogle Scholar
  11. 11.
    Huls, M., Russel, F. G., & Masereeuw, R. (2009). The role of ABC transporters in tissue defense and organ regeneration. Journal of Pharmacology and Experimental Therapeutics, 328, 3–9.CrossRefGoogle Scholar
  12. 12.
    Turco, M. C., Romano, M. F., Petrella, A., Bisogni, R., Tassone, P., & Venuta, S. (2004). NF-kappaB/Rel-mediated regulation of apoptosis in hematologic malignancies and normal hematopoietic progenitors. Leukemia, 18, 11–17.CrossRefGoogle Scholar
  13. 13.
    Suzuki, E., Kapoor, V., Jassar, A. S., Kaiser, L. R., & Albelda, S. M. (2005). Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clinical Cancer Research, 11, 6713–6721.CrossRefGoogle Scholar
  14. 14.
    Finlay, G. J., & Baguley, B. C. (2000). Effects of protein binding on the in vitro activity of antitumour acridine derivatives and related anticancer drugs. Cancer Chemotherapy and Pharmacology, 45, 417–422.CrossRefGoogle Scholar
  15. 15.
    Hicks, K. O., Pruijn, F. B., Baguley, B. C., & Wilson, W. R. (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. Journal of Pharmacology and Experimental Therapeutics, 297, 1088–1098.Google Scholar
  16. 16.
    Nakagawa, T., Inoue, Y., Kodama, H., Yamazaki, H., Kawai, K., Suemizu, 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. Oncology Reports, 20, 265–270.Google Scholar
  17. 17.
    Chen, K. G., Valencia, J. C., Lai, B., Zhang, G., Paterson, J. K., Rouzaud, F., et al. (2006). Melanosomal sequestration of cytotoxic drugs contributes to the intractability of malignant melanomas. Proceedings of the National Academy of Sciences of the United States of America, 103, 9903–9907.CrossRefGoogle Scholar
  18. 18.
    Ling, V. (1997). Multidrug resistance: Molecular mechanisms and clinical relevance. Cancer Chemotherapy and Pharmacology, 40, S3–S8.CrossRefGoogle Scholar
  19. 19.
    Gillet, J. P., Efferth, T., & Remacle, J. (2007). Chemotherapy-induced resistance by ATP-binding cassette transporter genes. Biochimica et Biophysica Acta, 1775, 237–262.Google Scholar
  20. 20.
    Ejendal, K. F., & Hrycyna, C. A. (2002). Multidrug resistance and cancer: The role of the human ABC transporter ABCG2. Current Protein & Peptide Science, 3, 503–511.CrossRefGoogle Scholar
  21. 21.
    Sarkadi, B., Ozvegy-Laczka, C., Nemet, K., & Varadi, A. (2004). ABCG2—a transporter for all seasons. FEBS Letters, 567, 116–120.CrossRefGoogle Scholar
  22. 22.
    Loebinger, M. R., Giangreco, A., Groot, K. R., Prichard, L., Allen, K., Simpson, C., et al. (2008). Squamous cell cancers contain a side population of stem-like cells that are made chemosensitive by ABC transporter blockade. British Journal of Cancer, 98, 380–387.CrossRefGoogle Scholar
  23. 23.
    Hadnagy, A., Gaboury, L., Beaulieu, R., & Balicki, D. (2006). SP analysis may be used to identify cancer stem cell populations. Experimental Cell Research, 312, 3701–3710.CrossRefGoogle Scholar
  24. 24.
    Keshet, G. I., Goldstein, I., Itzhaki, O., Cesarkas, K., Shenhav, L., Yakirevitch, A., et al. (2008). MDR1 expression identifies human melanoma stem cells. Biochemical and Biophysical Research Communications, 368, 930–936.CrossRefGoogle Scholar
  25. 25.
    Gandhi, L., Harding, M. W., Neubauer, M., Langer, C. J., Moore, M., Ross, H. J., et al. (2007). A phase II study of the safety and efficacy of the multidrug resistance inhibitor VX-710 combined with doxorubicin and vincristine in patients with recurrent small cell lung cancer. Cancer, 109, 924–932.CrossRefGoogle Scholar
  26. 26.
    Abraham, J., Edgerly, M., Wilson, R., Chen, C., Rutt, A., Bakke, S., et al. (2009). A phase I study of the P-glycoprotein antagonist tariquidar in combination with vinorelbine. Clinical Cancer Research, 15, 3574–3582.CrossRefGoogle Scholar
  27. 27.
    Ruff, P., Vorobiof, D. A., Jordaan, J. P., Demetriou, G. S., Moodley, S. D., Nosworthy, A. L., et al. (2009). A randomized, placebo-controlled, double-blind phase 2 study of docetaxel compared to docetaxel plus zosuquidar (LY335979) in women with metastatic or locally recurrent breast cancer who have received one prior chemotherapy regimen. Cancer Chemotherapy and Pharmacology, 64, 763–768.CrossRefGoogle Scholar
  28. 28.
    Robbie, M. A., Baguley, B. C., Denny, W. A., Gavin, J. B., & Wilson, W. R. (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 Research, 48, 310–319.Google Scholar
  29. 29.
    Haldane, A., Finlay, G. J., Hay, M. P., Denny, W. A., & Baguley, B. C. (1999). Cellular uptake of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA). Anti-Cancer Drug Design, 14, 275–280.Google Scholar
  30. 30.
    Davey, R. A., Su, G. M., Hargrave, R. M., Harvie, R. M., Baguley, B. C., & Davey, M. W. (1997). The potential of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide to circumvent three multidrug-resistance phenotypes in vitro. Cancer Chemotherapy and Pharmacology, 39, 424–430.CrossRefGoogle Scholar
  31. 31.
    Hanahan, D., & Weinberg, R. A. (2000). The hallmarks of cancer. Cell, 100, 57–70.CrossRefGoogle Scholar
  32. 32.
    Sharma, S. V., Gajowniczek, P., Way, I. P., Lee, D. Y., Jiang, J., Yuza, Y., et al. (2006). A common signaling cascade may underlie “addiction” to the Src, BCR-ABL, and EGF receptor oncogenes. Cancer Cell, 10, 425–435.CrossRefGoogle Scholar
  33. 33.
    Olson, J. M., & Hallahan, A. R. (2004). p38 MAP kinase: A convergence point in cancer therapy. Trends in Molecular Medicine, 10, 125–129.CrossRefGoogle Scholar
  34. 34.
    Danial, N. N. (2007). BCL-2 family proteins: Critical checkpoints of apoptotic cell death. Clinical Cancer Research, 13, 7254–7263.CrossRefGoogle Scholar
  35. 35.
    Forte, M., & Bernardi, P. (2006). The permeability transition and BCL-2 family proteins in apoptosis: Co-conspirators or independent agents? Cell Death and Differentiation, 13, 1287–1290.CrossRefGoogle Scholar
  36. 36.
    Pham, C. G., Bubici, C., Zazzeroni, F., Knabb, J. R., Papa, S., Kuntzen, C., et al. (2007). Upregulation of twist-1 by NF-kappaB blocks cytotoxicity induced by chemotherapeutic drugs. Molecular and Cellular Biology, 27, 3920–3935.CrossRefGoogle Scholar
  37. 37.
    Osford, S. M., Dallman, C. L., Johnson, P. W., Ganesan, A., & Packham, G. (2004). Current strategies to target the anti-apoptotic Bcl-2 protein in cancer cells. Current Medicinal Chemistry, 11, 1031–1039.CrossRefGoogle Scholar
  38. 38.
    Foster, B. A., Coffey, H. A., Morin, M. J., & Rastinejad, F. (1999). Pharmacological rescue of mutant p53 conformation and function. Science, 286, 2507–2510.CrossRefGoogle Scholar
  39. 39.
    Sebolt-Leopold, J. S. (2004). MEK inhibitors: A therapeutic approach to targeting the Ras-MAP kinase pathway in tumors. Current Pharmaceutical Design, 10, 1907–1914.CrossRefGoogle Scholar
  40. 40.
    Serra, V., Markman, B., Scaltriti, M., Eichhorn, P. J., Valero, V., Guzman, 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 Research, 68, 8022–8030.CrossRefGoogle Scholar
  41. 41.
    Nguyen, M., Marcellus, R. C., Roulston, A., Watson, M., Serfass, L., Murthy Madiraju, S. R., et al. (2007). Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis. Proceedings of the National Academy of Sciences of the United States of America, 104, 19512–19517.CrossRefGoogle Scholar
  42. 42.
    Nakanishi, C., & Toi, M. (2005). Nuclear factor-kappaB inhibitors as sensitizers to anticancer drugs. Nature Reviews Cancer, 5, 297–309.CrossRefGoogle Scholar
  43. 43.
    Wang, W., McLeod, H. L., & Cassidy, J. (2003). Disulfiram-mediated inhibition of NF-kappaB activity enhances cytotoxicity of 5-fluorouracil in human colorectal cancer cell lines. International Journal of Cancer, 104, 504–511.CrossRefGoogle Scholar
  44. 44.
    Bunney, T. D., & Katan, M. (2010). Phosphoinositide signalling in cancer: Beyond PI3K and PTEN. Nature Reviews Cancer, 10, 342–352.CrossRefGoogle Scholar
  45. 45.
    Cleary, J. M., & Shapiro, G. I. (2010). Development of phosphoinositide-3 kinase pathway inhibitors for advanced cancer. Current Oncology Reports, 12, 87–94.CrossRefGoogle Scholar
  46. 46.
    Hersey, P., Zhuang, L., & Zhang, X. D. (2006). Current strategies in overcoming resistance of cancer cells to apoptosis melanoma as a model. International Review of Cytology, 251, 131–158.CrossRefGoogle Scholar
  47. 47.
    Saini, V., & Shoemaker, R. H. (2010). Potential for therapeutic targeting of tumor stem cells. Cancer Science, 101, 16–21.CrossRefGoogle Scholar
  48. 48.
    Li, L., & Clevers, H. (2010). Coexistence of quiescent and active adult stem cells in mammals. Science, 327, 542–545.CrossRefGoogle Scholar
  49. 49.
    Massague, J. (2008). TGFbeta in cancer. Cell, 134, 215–230.CrossRefGoogle Scholar
  50. 50.
    Vermeulen, L., De Sousa, E. M., van der Heijden, M., Cameron, K., de Jong, J. H., Borovski, T., et al. (2010). Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nature Cell Biology, 12, 468–476.CrossRefGoogle Scholar
  51. 51.
    Roesch, A., Fukunaga-Kalabis, M., Schmidt, E. C., Zabierowski, S. E., Brafford, P. A., Vultur, A., et al. (2010). A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth. Cell, 141, 583–594.CrossRefGoogle Scholar
  52. 52.
    MacKie, R. M., Reid, R., & Junor, B. (2003). Fatal melanoma transferred in a donated kidney 16 years after melanoma surgery. New England Journal of Medicine, 348, 567–568.CrossRefGoogle Scholar
  53. 53.
    Aguirre-Ghiso, J. A. (2007). Models, mechanisms and clinical evidence for cancer dormancy. Nature Reviews Cancer, 7, 834–846.CrossRefGoogle Scholar
  54. 54.
    Demicheli, R., Retsky, M. W., Hrushesky, W. J., & Baum, M. (2007). Tumor dormancy and surgery-driven interruption of dormancy in breast cancer: Learning from failures. Nature Clinical Practice Oncology, 4, 699–710.CrossRefGoogle Scholar
  55. 55.
    Koebel, C. M., Vermi, W., Swann, J. B., Zerafa, N., Rodig, S. J., Old, L. J., et al. (2007). Adaptive immunity maintains occult cancer in an equilibrium state. Nature, 450, 903–907.CrossRefGoogle Scholar
  56. 56.
    Kortylewski, M., Komyod, W., Kauffmann, M. E., Bosserhoff, A., Heinrich, P. C., & Behrmann, I. (2004). Interferon-gamma-mediated growth regulation of melanoma cells: Involvement of STAT1-dependent and STAT1-independent signals. Journal of Investigative Dermatology, 122, 414–422.CrossRefGoogle Scholar
  57. 57.
    Muller-Hermelink, N., Braumuller, H., Pichler, B., Wieder, T., Mailhammer, R., Schaak, K., et al. (2008). TNFR1 signaling and IFN-gamma signaling determine whether T cells induce tumor dormancy or promote multistage carcinogenesis. Cancer Cell, 13, 507–518.CrossRefGoogle Scholar
  58. 58.
    Kramer, A., Lukas, J., & Bartek, J. (2004). Checking out the centrosome. Cell Cycle, 3, 1390–1393.Google Scholar
  59. 59.
    McDermott, K. M., Zhang, J., Holst, C. R., Kozakiewicz, B. K., Singla, V., & Tlsty, T. D. (2006). p16(INK4a) prevents centrosome dysfunction and genomic instability in primary cells. PLoS Biology, 4, e51.CrossRefGoogle Scholar
  60. 60.
    Loeb, L. A., Bielas, J. H., & Beckman, R. A. (2008). Cancers exhibit a mutator phenotype: Clinical implications. Cancer Research, 68, 3551–3557.CrossRefGoogle Scholar
  61. 61.
    Leung, E., Kannan, N., Krissansen, G. W., Findlay, M. P., & Baguley, B. C. (2010). MCF-7 breast cancer cells selected for tamoxifen resistance acquire new phenotypes differing in DNA content, phospho-HER2 and PAX2 expression, and rapamycin sensitivity. Cancer Biology & Therapy, 9(9), 717–724.Google Scholar
  62. 62.
    Kuilman, T., Michaloglou, C., Vredeveld, L. C., Douma, S., van Doorn, R., Desmet, C. J., et al. (2008). Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell, 133, 1019–1031.CrossRefGoogle Scholar
  63. 63.
    Acosta, J. C., O’Loghlen, A., Banito, A., Raguz, S., & Gil, J. (2008). Control of senescence by CXCR2 and its ligands. Cell Cycle, 7, 2956–2959.Google Scholar
  64. 64.
    Smyth, M. J., Godfrey, D. I., & Trapani, J. A. (2001). A fresh look at tumor immunosurveillance and immunotherapy. Nature Immunology, 2, 293–299.CrossRefGoogle Scholar
  65. 65.
    Zitvogel, L., Apetoh, L., Ghiringhelli, F., & Kroemer, G. (2008). Immunological aspects of cancer chemotherapy. Nature Reviews Immunology, 8, 59–73.CrossRefGoogle Scholar
  66. 66.
    Fonseca, C., & Dranoff, G. (2008). Capitalizing on the immunogenicity of dying tumor cells. Clinical Cancer Research, 14, 1603–1608.CrossRefGoogle Scholar
  67. 67.
    Baguley, B. C. (2006). Tumor stem cell niches: A new functional framework for the action of anticancer drugs. Recent Patents on Anti-Cancer Drug Discovery, 1, 121–127.CrossRefGoogle Scholar
  68. 68.
    Chen, R., Alvero, A. B., Silasi, D. A., Steffensen, K. D., & Mor, G. (2008). Cancers take their Toll—the function and regulation of Toll-like receptors in cancer cells. Oncogene, 27, 225–233.CrossRefGoogle Scholar
  69. 69.
    Hicks, A. M., Riedlinger, G., Willingham, M. C., Alexander-Miller, M. A., Kap-Herr, C., Pettenati, M. J., et al. (2006). Transferable anticancer innate immunity in spontaneous regression/complete resistance mice. Proceedings of the National Academy of Sciences of the United States of America, 103, 7753–7758.CrossRefGoogle Scholar
  70. 70.
    Panaretakis, T., Joza, N., Modjtahedi, N., Tesniere, A., Vitale, I., Durchschlag, M., et al. (2008). The co-translocation of ERp57 and calreticulin determines the immunogenicity of cell death. Cell Death and Differentiation, 15, 1499–1509.CrossRefGoogle Scholar
  71. 71.
    Baguley, B. C., & Marshall, E. S. (2004). In vitro modelling of human tumour behaviour in drug discovery programmes. European Journal of Cancer, 40, 794–801.CrossRefGoogle Scholar
  72. 72.
    Sotiriou, C., & Piccart, M. J. (2007). Taking gene-expression profiling to the clinic: When will molecular signatures become relevant to patient care? Nature Reviews Cancer, 7, 545–553.CrossRefGoogle Scholar
  73. 73.
    Samson, D. J., Seidenfeld, J., Ziegler, K., & Aronson, N. (2004). Chemotherapy sensitivity and resistance assays: A systematic review. Journal of Clinical Oncology, 22, 3618–3630.CrossRefGoogle Scholar
  74. 74.
    Claus, R., & Lubbert, M. (2003). Epigenetic targets in hematopoietic malignancies. Oncogene, 22, 6489–6496.CrossRefGoogle Scholar
  75. 75.
    Garcia-Barros, M., Paris, F., Cordon-Cardo, C., Lyden, D., Rafii, S., Haimovitz-Friedman, A., et al. (2003). Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science, 300, 1155–1159.CrossRefGoogle Scholar
  76. 76.
    Vit, J. P., & Rosselli, F. (2003). Role of the ceramide-signaling pathways in ionizing radiation-induced apoptosis. Oncogene, 22, 8645–8652.CrossRefGoogle Scholar
  77. 77.
    Duff, M. D., Mestre, J., Maddali, S., Yan, Z. P., Stapleton, P., & Daly, J. M. (2007). Analysis of gene expression in the tumor-associated macrophage. Journal of Surgical Research, 142, 119–128.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

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

Personalised recommendations