Skip to main content
SpringerLink
Log in

Molecular Determinants of Intrinsic Multidrug Resistance in Cancer Cells and Tumors

  • Chapter
Cancer Drug Resistance

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

Intrinsic drug or multidrug resistance in previously untreated tumors is often the major obstacle to the success of cancer chemotherapy. Understanding the molecular mechanisms underlying these conditions is a prerequisite to the design of novel strategies aimed at improving current clinical protocols. This chapter focuses on recent experimental evidence concerning two of the features most commonly encountered in multidrug resistant cancer cells: (over)expression of multidrug transporters and disabling of apoptotic pathways.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Gottesman MM. Mechanisms of cancer drug resistance. Annu Rev Med 2002; 53:516–527.

    Article  Google Scholar 

  2. Durand RE, Sutherland RM. Effects of intercellular contact on repair of radiation damage. Exp Cell Res 1972; 71:75–80.

    Article  PubMed  CAS  Google Scholar 

  3. Teicher B A, Herman TS, Holden SA, et al. Tumor resistance to alkylating agents conferred by mechanisms operative only in vivo. Science 1990; 247:1457–1461.

    Article  PubMed  CAS  Google Scholar 

  4. Desoize B, Jardillier J-C. Multicellular resistance: a paradigm for clinical resistance? Crit Rev Oncol Hematol 2000; 36:193–207.

    Article  PubMed  CAS  Google Scholar 

  5. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer 2003; 3:721–732.

    Article  PubMed  CAS  Google Scholar 

  6. Harris AL. Hypoxia-a key regulatory factor in tumor growth. Nature Rev Cancer 2002; 3:712–732.

    Google Scholar 

  7. Wartenberg M, Frey C, Diedershagen H, et al. Development of an intrinsic P-glycoprotein-mediated doxorubicin resistance in quiescent cell layers of large, multicellular prostate tumor spheroids. Int J Cancer 1998; 75:855–863.

    Article  PubMed  CAS  Google Scholar 

  8. Francia G, Man S, Teicher B, et al. Gene expression analysis of tumor spheroids reveals a role for suppressed DNA mismatch repair in multicellular resistance to alkylating agents. Mol Cell Biol 2004; 24:6837–6849.

    Article  PubMed  CAS  Google Scholar 

  9. Wartenberg M, Ling FC, Müschen M, et al. Regulation of the multidrug resistance transporter P-glycoprotein in multicellular tumor spheroids by hypoxia-inducible factor (HIF-1) and reactive oxygen species. FASEB J 2003; 17:503–505.

    PubMed  CAS  Google Scholar 

  10. Mihaylova VT, Bindra RS, Yuan J, et al. Decreased expression of the DNA mismatch repair gene Mlh1 under hypoxic stress in mammalian cells. Mol Cell Biol 2003; 23:3265–3273.

    Article  PubMed  CAS  Google Scholar 

  11. Green SK, Francia G, Isidoro C, Kerbel RS. Antiadhesive antibodies targeting E-cadherin sensitize multicellular tumor spheroids to chemotherapy in vitro. Mol Cancer Ther 2004; 3:149–159.

    PubMed  CAS  Google Scholar 

  12. Damiano JS. Integrins as novel drug targets for overcoming innate drug resistance. Curr Cancer Drug Targets 2002; 2:37–43.

    Article  PubMed  CAS  Google Scholar 

  13. Giaccia A, Siim BG, Johnson RS. HIF-1 as a target for drug development. Nat Rev Drug Discov 2003; 2:803–811.

    Article  PubMed  CAS  Google Scholar 

  14. Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer 2002; 2:48–58.

    Article  PubMed  CAS  Google Scholar 

  15. Juliano RL, Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta 1976; 455:162–152.

    Google Scholar 

  16. Cole SP, Bhardwaj G, Gerlach JH, et al. Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science 1992; 258:1650–1654.

    Article  PubMed  CAS  Google Scholar 

  17. Borst P, Evers R, Kool M, Wijnholds J. A family of drug transporters: the multidrug resistance-associated proteins. J Natl Cancer Inst 2000; 92:1295–1302.

    Article  PubMed  CAS  Google Scholar 

  18. Dolfini E, Dasdia T, Arancia G, et al. Characterization of a clonal human colon adenocarcinoma line intrinsically resistant to doxorubicin. Br J Cancer 1997; 76:67–76.

    PubMed  CAS  Google Scholar 

  19. Miyake K, Mickley L, Litman T, et al. Molecular cloning of cDNAs which are highly overexpressed in mitoxantrone-resistant cells. Demonstration of homology to ABC transport genes. Cancer Res 1999; 59:8–13.

    PubMed  CAS  Google Scholar 

  20. Fojo AT, Ueda K, Slamon DJ, et al. Expression of multidrug-resistance gene in human tumors and tissues. Proc Natl Acad Sci U S A 1987; 84:265–269.

    Article  PubMed  CAS  Google Scholar 

  21. Flens MJ, Zaman GJ, van der Valk P, et al. Tissue distribution of the multidrug resistance protein. Am JPathol 1996; 148:1237–1247.

    CAS  Google Scholar 

  22. Allen JD, Brinkhuis RF, van Deemter L, et al. Extensive contribution of the multidrug transporters P-glycoprotein and Mrp1 to basal drug resistance. Cancer Res 2000; 60:5761–5766.

    PubMed  CAS  Google Scholar 

  23. Huang Y, Anderle P, Bussey KJ, et al. Membrane transporters and channels: role of the transportome in cancer chemosensitivity and chemoresistance. Cancer Res 2004; 64:4294–4301.

    Article  PubMed  CAS  Google Scholar 

  24. Szakács G, Annereau JP, Lababidi S, et al. Predicting drug sensitivity and resistance: profiling ABC transporter genes in cancer cells. Cancer Cell 2004; 6:129–137.

    Article  PubMed  Google Scholar 

  25. Trock BJ, Leonessa F, Clarke R. Multidrug resistance in breast cancer: a meta-analysis of Mdr1/gp170 expression and its possible functional significance. J Natl Cancer Inst 1997; 89:917–931.

    Article  PubMed  CAS  Google Scholar 

  26. Bush JA, Li G. Cancer chemoresistance: the relationship between p53 and multidrug transporters. Int J Cancer 2002; 98:323–330.

    Article  PubMed  CAS  Google Scholar 

  27. Meijer GA, Schroeijers AB, Flens MJ, et al. Increased expression of multidrug resistance related proteins Pgp, MRP1, and LRP/MVP occurs early in colorectal carcinogenesis. J Clin Pathol 1999; 52:450–454.

    Article  PubMed  CAS  Google Scholar 

  28. Damiani D, Michelutti A, Michieli M, et al. P-glycoprotein, lung resistance-related protein and multidrug resistance-associated protein in de novo adult acute lymphoblastic leukaemia. Br J Haematol 2002; 116:519–527.

    Article  PubMed  CAS  Google Scholar 

  29. Schuurhuis GJ, Broxterman HJ, Cervantes A, et al. Quantitative determination of factors contributing to doxorubicin resistance in multidrug-resistant cells. J Natl Cancer Inst 1989; 81:1887–1892.

    Article  PubMed  CAS  Google Scholar 

  30. Molinari A, Calcabrini A, Meschini S, et al. Subcellular detection and localization of the drug transporter P-glycoprotein in cultured tumor cells. Curr Protein Pept Sci 2002; 3:653–670.

    Article  PubMed  CAS  Google Scholar 

  31. Larsen AK, Escargueil AE, Skladanowski A. Resistance mechanisms associated with altered intracel-lular distribution of anticancer agents. Pharmacol Ther 2000; 85:217–229.

    Article  PubMed  CAS  Google Scholar 

  32. Molinari A, Calcabrini A, Meschini S, et al. Detection of P-glycoprotein in the Golgi apparatus of drug-untreated human melanoma cells. Int J Cancer 1998; 75:885–893.

    Article  PubMed  CAS  Google Scholar 

  33. Meschini S, Marra M, Calcabrini A, et al. Role of the lung resistance-related protein (LRP) in the drug sensitivity of cultured tumor cells. Toxicol In Vitro 2002; 16:389–398.

    Article  PubMed  CAS  Google Scholar 

  34. Krishnamachary N, Center MS. The MRP gene associated with a non-P-glycoprotein multidrug resistance encodes a 190-kDa membrane bound glycoprotein. Cancer Res 1993; 53:3658–3661.

    PubMed  CAS  Google Scholar 

  35. Scheper RJ, Broxterman HJ, Scheffer GL, et al. Overexpression of an Mr 110,000 vesicular protein in non-P-glycoprotein-mediated multidrug resistance. Cancer Res. 1993; 53:1475–1479.

    PubMed  CAS  Google Scholar 

  36. Izquierdo MA, Scheffer GL, Flens MJ, et al. Broad distribution of the multidrug resistance-related vault lung resistance protein in normal human tissues and tumors. Am J Pathol 1996; 148:877–887.

    PubMed  CAS  Google Scholar 

  37. Scheffer GL, Schroeijers AB, Izquierdo MA, et al. Lung resistance-related protein/major vault protein and vaults in multidrug-resistant cancer. Curr Opin Oncol 2000; 12:550–556.

    Article  PubMed  CAS  Google Scholar 

  38. Izquierdo MA, Shoemaker RH, Flens MJ, et al. Overlapping phenotypes of multidrug resistance among panels of human cancer-cell lines. Int J Cancer 1996; 65:230–237.

    Article  PubMed  CAS  Google Scholar 

  39. Laurencot CM, Scheffer GL, Scheper RJ, Shoemaker RH. Increased LRP mRNA expression is associated with the MDR phenotype in intrinsically resistant human cancer cell lines. Int J Cancer 1997; 72:1021–1026.

    Article  PubMed  CAS  Google Scholar 

  40. Meschini S, Calcabrini A, Monti E, et al. Intracellular P-glycoprotein expression is associated with the intrinsic multidrug resistance phenotype in human colon adenocarcinoma cells. Int J Cancer 2000; 87:615–628.

    Article  PubMed  CAS  Google Scholar 

  41. Gariboldi MB, Ravizza R, Riganti L, et al. Molecular determinants of intrinsic resistance to doxorubicin in human cancer cell lines. Int J Oncol. 2003; 22:1057–1064.

    PubMed  CAS  Google Scholar 

  42. Harada T, Ogura S, Yamazaki K, et al. Predictive value of expression of P53, Bcl-2 and lung resistance-related protein for response to chemotherapy in non-small celllung cancers. Cancer Sci 2003; 94:394–399.

    Article  PubMed  CAS  Google Scholar 

  43. Siva AC, Raval-Fernandes S, Stephen AG, et al. Up-regulation of vaults may be necessary but not sufficient for multidrug resistance. Int J Cancer 2001; 92:195–202.

    Article  PubMed  CAS  Google Scholar 

  44. Mossink MH, van Zon A, Franzel-Luiten E, et al. Disruption of the murine major vault protein (MVP/ LRP) gene does not induce hypersensitivity to cytostatics. Cancer Res 2002; 62:7298–7304.

    PubMed  CAS  Google Scholar 

  45. Scaffidi C, Fulda S, Srinivasan A, et al. Two CD95 (APO-1/Fas) signaling pathways. EMBO J 1998; 17:1675–1687.

    Article  PubMed  CAS  Google Scholar 

  46. Fulda S, Meyer E, Friesen C, et al. Cell type specific involvement of death receptor and mitochondrial pathways in drug-induced apoptosis. Oncogene 2001; 20:1063–1075.

    Article  PubMed  CAS  Google Scholar 

  47. Igney FH, Krammer PH. Death and anti-death: tumour resistance to apoptosis. Nature Rev Cancer 2002; 2:277–288.

    Article  CAS  Google Scholar 

  48. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100:57–70.

    Article  PubMed  CAS  Google Scholar 

  49. Schmitt CA, Lowe SW. Apoptosis and therapy. J Pathol 1999; 187:127–137.

    Article  PubMed  CAS  Google Scholar 

  50. Johnstone RW, Ruefli AA, Lowe SW. Apoptosis: a linkbetween cancer genetics and chemotherapy. Cell 2002; 108:153–164.

    Article  PubMed  CAS  Google Scholar 

  51. Herr I and Debatin KM. Cellular stress response in apoptosis and cancer therapy. Blood 2001; 98:2603–2614.

    Article  PubMed  CAS  Google Scholar 

  52. Debatin KM. Apoptosis pathways in cancer and cancer therapy. Cancer Immunol Immunother 2004; 53:153–159.

    Article  PubMed  Google Scholar 

  53. Kaufmann SH, Vaux DL. Alterations in the apoptotic machinery and their potential role in anticancer drug resistance. Oncogene 2003; 22:7414–7430.

    Article  PubMed  CAS  Google Scholar 

  54. Searle J, Lawson TA, Abbott PJ, et al. An electron-microscope study of the mode of cell death induced by cancer-chemotherapeutic agents in populations of proliferating normal and neoplastic cells. J Pathol 1975; 116:129–38.

    Article  PubMed  CAS  Google Scholar 

  55. Wyllie AH, Golstein P. More than one way to go. Proc Natl Acad Sci U S A 2000; 93:11–13.

    Google Scholar 

  56. Stein WD, Bates SE, Fojo T. Intractable cancers: the many faces of multidrug resistance and the many targets it presents for therapeutic attack. Curr Drug Targets 2004; 5:333–346.

    Article  PubMed  CAS  Google Scholar 

  57. Soengas MS, Capodieci P, Polsky D, et al. Inactivation of the apoptosis effector Apaf-1 in malignant melanoma. Nature 2001; 409:207–211.

    Article  PubMed  CAS  Google Scholar 

  58. Soengas MS, Lowe SW. Apoptosis and melanoma chemoresistance. Oncogene 2003; 22:3138–3151.

    Article  PubMed  CAS  Google Scholar 

  59. Debatin KM, Poncet D, Kroemer G. Chemotherapy: targeting the mitochondrial cell death pathway. Oncogene 2002; 21:8786–8803.

    Article  PubMed  CAS  Google Scholar 

  60. Fulda S, Los M, Friesen C, Debatin KM. Chemosensitivity of solid tumor cells in vitro is related to activation of the CD95 system. Int J Cancer 1998; 76:105–114.

    Article  PubMed  CAS  Google Scholar 

  61. Fulda S, Debatin KM. Signaling through death receptors in cancer therapy. Curr Opin Pharmacol 2004; 4:327–332.

    Article  PubMed  CAS  Google Scholar 

  62. Mow BM, Blajeski AL, Chandra J, Kaufmann SH. Apoptosis and the response to anticancer therapy. Curr Opin Oncol 2001; 13:453–462.

    Article  PubMed  CAS  Google Scholar 

  63. Los M, Wesselborg S, Schulze-Osthoff K. The role of caspases in development, immunity, and apoptotic signal transduction: lessons from knockout mice. Immunity 1999; 10:629–639.

    Article  PubMed  CAS  Google Scholar 

  64. Vousden KH, Lu X. Live or let die: the cell’s response to p53. Nature Rev Cancer 2002; 2:594–604.

    Article  CAS  Google Scholar 

  65. Hofseth LJ, Hussain SP, Harris CC. p53: 25 years after its discovery. Trends Pharmacol Sci 2004; 25:177–181.

    Article  PubMed  CAS  Google Scholar 

  66. Sax JK, el-Deiry W. p53 downstream targets and chemosensitivity, Cell Death Differ 2003; 10:413–417.

    Article  PubMed  CAS  Google Scholar 

  67. Friedman JS, Lowe SW. Control of apoptosis by p53. Oncogene 2003; 22:9030–9040.

    Article  CAS  Google Scholar 

  68. Hussain SP, Harris CC. Molecular epidemiology of human cancer: contribution of mutation spectra studies of tumor suppressor genes. Cancer Res 1998; 58:4023–4037.

    PubMed  CAS  Google Scholar 

  69. Lowe SW, Ruley HE, Jacks T, Housman DE. p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 1993; 74:957–967.

    Article  PubMed  CAS  Google Scholar 

  70. Weinstein JN, Myers TG, O’Connor PM, et al. An information-intensive approach to the molecular pharmacology of cancer. Science 1997; 275:343–349.

    Article  PubMed  CAS  Google Scholar 

  71. Bunz F, Hwang PM, Torrance C, et al. Disruption of p53 in human cancer cells alters the responses to therapeutic agents. J Clin Invest. 1999; 104:263–269.

    Article  PubMed  CAS  Google Scholar 

  72. Wallace-Brodeur RR, Lowe SW. Clinical implications of p53 mutations. Cell Mol Life Sci 1999; 55:64–75.

    Article  PubMed  CAS  Google Scholar 

  73. Degeorges A, de Roquancourt A, Extra JM, et al. Is p53 a protein that predicts the response to chemotherapy in node negative breast cancer? Breast Cancer Res Treat 1998; 47:47–55.

    Article  PubMed  CAS  Google Scholar 

  74. Hosaka N, Ichikawa Y, Ishikawa T, et al. Correlation of immunohistochemical p53 labeling index with inhibition rate in chemosensitivity test in gastric and colon cancer. Anticancer Res 2001; 21:229–235.

    PubMed  CAS  Google Scholar 

  75. Rozan S, Vincent-Salomon A, Zafrani B, et al. No significant predictive value of c-erbB-2 or p53 expression regarding sensitivity to primary chemotherapy or radiotherapy in breast cancer. Int J Cancer 1998; 79:27–33.

    Article  PubMed  CAS  Google Scholar 

  76. Cote RJ, Esrig D, Groshen S, Jones PA, Skinner DG. p53 and treatment of bladder cancer. Nature 1997; 385:123–125.

    Article  PubMed  CAS  Google Scholar 

  77. Jost CA, Marin MC, Kaelin WJ. p73 is a human p53-related protein that can induce apoptosis. Nature 1997; 389:191–194.

    Article  PubMed  CAS  Google Scholar 

  78. Flores ER, Tsai KY, Crowley D, et al. p63 and p73 are required for p53-dependent apoptosis in response to DNA damage. Nature 2002; 416:560–564.

    Article  PubMed  CAS  Google Scholar 

  79. Irwin MS, Kondo K, Marin MC, et al. Chemosensitivity linked to p73 function. Cancer Cell 2003; 3:403–410.

    Article  PubMed  CAS  Google Scholar 

  80. Zaika AI, Slade N, Erster SH, et al. DeltaNp73, a dominant-negative inhibitor expression interferes with p53-independent apoptotic pathways. J. Exp. Med 2002; 196:765–780.

    Article  PubMed  CAS  Google Scholar 

  81. Cory S, Huang DC, Adams JM. The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene 2003; 22:8590–8607.

    Article  PubMed  CAS  Google Scholar 

  82. Martinou JC, Green DR. Breaking the mitochondrial barrier. Nature Rev Mol Cell Biol 2001; 2:63–67.

    Article  CAS  Google Scholar 

  83. Miyashita T, Reed JC. bcl-2 gene transfer increases relative resistance of S49.1 and WEHI7.2 lymphoid cells to cell death and DNA fragmentation induced by glucocorticoids and multiple chemotherapeutic drugs. Cancer Res 1992; 52:5407–5411.

    PubMed  CAS  Google Scholar 

  84. Bettaieb A, Dubrez-Daloz L, Launay S, et al. Bcl-2 proteins: targets and tools for chemosensitisation of tumor cells. Curr Med Chem Anti-Canc Agents 2003; 3:307–318.

    Article  CAS  Google Scholar 

  85. Reed JC. Dysregulation of apoptosis in cancer. J Clin Oncol 1999; 17:2941–2953.

    PubMed  CAS  Google Scholar 

  86. Violette S, Poulain L, Dussaulx E, et al. Resistance of colon cancer cells to long-term 5-fluorouracil exposure is correlated to the relative level of Bcl-2 and Bcl-XL in addition to Bax and p53 status. Int J Cancer 2002; 98:498–504.

    Article  PubMed  CAS  Google Scholar 

  87. Liu R, Page C, Beidler DR, et al. Overexpression of Bcl-xL promotes chemotherapy resistance of mammary tumors in a syngeneic mouse model. Am J Pathol 1999; 155:1861–1867.

    PubMed  CAS  Google Scholar 

  88. Bairey O, Zimra Y, Shaklai M, et al. Bcl-2, Bcl-X, Bax, and Bak expression in short-and long-lived patients with diffuse large B-cell lymphomas. Clin Cancer Res 1999; 5:2860–2866.

    PubMed  CAS  Google Scholar 

  89. Aebersold DM, Kollar A, Beer KT, et al. Involvement of the hepatocyte growth factor/scatter factor receptor c-met and of Bcl-xL in the resistance of oropharyngeal cancer to ionizing radiation. Int J Cancer 2001; 96:41–54.

    Article  PubMed  CAS  Google Scholar 

  90. Kohler T, Wurl P, Meye A, et al. High bad and bcl-xL gene expression and combined bad, bcl-xL, bax and bcl-2 mRNA levels: molecular predictors for survival of stage 2 soft tissue sarcoma patients. Anticancer Res 2002; 22:1553–1559.

    PubMed  Google Scholar 

  91. Theodorakis P, Lomonosova E, Chinnadurai G. Critical requirement of BAX for manifestation of apoptosis induced by multiple stimuli in human epithelial cancer cells. Cancer Res 2002; 62:3373–3376.

    PubMed  CAS  Google Scholar 

  92. Zhang L, Yu J, Park BH, Kinzler KW, Vogelstein B. Role of BAX in the apoptotic response to anticancer agents. Science 2000; 290:989–992.

    Article  PubMed  CAS  Google Scholar 

  93. Wei MC, Zong WX, Cheng EH, et al. Proapoptotic BAX and BAK: arequisite gateway to mitochondrial dysfunction and death. Science 2001; 292:727–730.

    Article  PubMed  CAS  Google Scholar 

  94. Rampino N, Yamamoto H, Ionov Y, et al. Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science 1997; 275:967–969.

    Article  PubMed  CAS  Google Scholar 

  95. Pepper C, Hoy T, Bentley P. Elevated Bcl-2/Bax are a consistent feature of apoptosis resistance in B-cell chronic lymphocytic leukaemia and are correlated with in vivo chemoresistance. Leuk Lymphoma 1998; 28:355–361.

    PubMed  CAS  Google Scholar 

  96. Miao J, Chen GG, Chun SY, et al. Bid sensitizes apoptosis induced by chemotherapeutic drugs in hepatocellular carcinoma. Int J Oncol 2004; 25:651–659.

    PubMed  CAS  Google Scholar 

  97. Minko T, Dharap SS, Fabbricatore AT. Enhancing the efficacy of chemotherapeutic drugs by the suppression of antiapoptotic cellular defense. Cancer Detect Prev 2003; 27:193–202.

    Article  PubMed  CAS  Google Scholar 

  98. Villunger A, Michalak EM, Coultas L, et al. p53-and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa. Science 2003; 302:1036–1038.

    Article  PubMed  CAS  Google Scholar 

  99. Degterev A, Boyce M, Yuan J. A decade of caspases. Oncogene 2003; 22:8543–8567.

    Article  PubMed  CAS  Google Scholar 

  100. Kim H, Lee J, Soung Y, Park W, et al. Inactivating mutations of caspase-8 gene in colorectal carcinomas. Gastroenterology 2003; 125:708–715.

    Article  PubMed  CAS  Google Scholar 

  101. Hopkins-Donaldson S, Ziegler A, Kurtz S, et al. Silencing of death receptor and caspase-8 expression in small cell lung carcinoma cell lines and tumors by DNA methylation. Cell Death Differ 2003; 10:356–364.

    Article  PubMed  CAS  Google Scholar 

  102. Fulda S, Kufer MU, Meyer E, et al. Sensitization for death receptor-or drug-induced apoptosis by re-expression of caspase-8 through demethylation or gene transfer. Oncogene 2001; 20:5865–5877.

    Article  PubMed  CAS  Google Scholar 

  103. Beere HM, Green DR. Stress management-heat shock protein-70 and the regulation of apoptosis. Trends Cell Biol 2001; 11:6–10.

    Article  PubMed  CAS  Google Scholar 

  104. Janicke RU, Sprengart ML, Wati MR, Porter AG. Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis. J Biol Chem 1998; 273:9357–9360.

    Article  PubMed  CAS  Google Scholar 

  105. Salvesen GS, Duckett CS. IAP proteins: blocking the road to death’s door. Nat Rev Mol Cell Biol 2002; 3:401–410.

    Article  PubMed  CAS  Google Scholar 

  106. Krajewska M, Krajewski S, Banares S, et al. Elevated expression of inhibitor of apoptosis proteins in prostate cancer. Clin Cancer Res 2003; 9:4914–4925.

    PubMed  CAS  Google Scholar 

  107. Tamm I, Richter S, Oltersdorf D, et al. High expression levels of X-linked inhibitor of apoptosis protein and survivin correlate with poor overall survival in childhood de novo acute myeloid leukemia. Clin Cancer Res 2004; 10:3737–3744.

    Article  PubMed  CAS  Google Scholar 

  108. Li J, Feng Q, Kim JM, et al. Human ovarian cancer and cisplatin resistance: possible role of inhibitor of apoptosis proteins. Endocrinology 2001; 142:370–380.

    Article  PubMed  CAS  Google Scholar 

  109. Amantana A, London CA, Iversen PL, Devi GR. X-linked inhibitor of apoptosis protein inhibition induces apoptosis and enhances chemotherapy sensitivity in human prostate cancer cells. Mol Cancer Ther 2004; 3:699–707.

    PubMed  CAS  Google Scholar 

  110. Hu Y, Cherton-Horvat G, Dragowska V, et al. Antisense oligonucleotides targeting XIAP induce apoptosis and enhance chemotherapeutic activity against human lung cancer cells in vitro and in vivo. Clin Cancer Res 2003; 9:2826–2836.

    PubMed  CAS  Google Scholar 

  111. Vucic D, Stennicke HR, Pisabarro MT, et al. ML-IAP, a novel inhibitor of apoptosis that is preferentially expressed in human melanomas. Curr Biol 2000; 10:1359–1366.

    Article  PubMed  CAS  Google Scholar 

  112. Vucic D, Deshayes K, Ackerly H, et al. SMAC negatively regulates the anti-apoptotic activity of melanoma inhibitor of apoptosis (ML-IAP). J Biol Chem 2002; 277:12,275–12,279.

    Article  PubMed  CAS  Google Scholar 

  113. Tamm I, Kornblau SM, Segall H, et al. Expression and prognostic significance of IAP-family genes in human cancers and myeloid leukemias. Clin Cancer Res 2000; 6:1796–1803.

    PubMed  CAS  Google Scholar 

  114. Altieri D. The molecular basis and potential role of survivin in cancer diagnosis and therapy. Trends Mol Med 2001; 7:542–547.

    Article  PubMed  CAS  Google Scholar 

  115. Reed JC, Bischoff JR. BIRinging chromosomes through cell division-and survivin the experience. Cell 2000; 102:545–548.

    Article  PubMed  CAS  Google Scholar 

  116. Zaffaroni N, Daidone MG. Survivin expression and resistance to anticancer treatments: perspectives for new therapeutic interventions. Drug Resist Updat 2002; 5:65–72.

    Article  PubMed  CAS  Google Scholar 

  117. Pennati M, Binda M, De Cesare M, et al. Ribozyme-mediated down-regulation of survivin expression sensitizes human melanoma cells to topotecan in vitro and in vivo. Carcinogenesis 2004; 25:1129–1136.

    Article  PubMed  CAS  Google Scholar 

  118. Pennati M, Colella G, Folini M, et al. Ribozyme-mediated attenuation of survivin expression sensitizes human melanoma cells to cisplatin-induced apoptosis. J Clin Invest 2002; 109:285–286.

    Article  PubMed  CAS  Google Scholar 

  119. Fulda S, Debatin KM. Sensitization for anticancer drug-induced apoptosis by the chemopreventive agent resveratrol. Oncogene 2004; 23:6702–6711.

    Article  PubMed  CAS  Google Scholar 

  120. Vivanco I, Sawyers CL.The phosphatidylinositol 3-kinase-AKT pathway in human cancer. Nature Rev Cancer 2002; 2:489–501.

    Article  CAS  Google Scholar 

  121. Nakashio A, Fujita N, Rokudai S, et al. Prevention of phosphatidylinositol 3′-kinase-Akt survival signaling pathway during topotecan-induced apoptosis. Cancer Res 2000; 60:5303–5309.

    PubMed  CAS  Google Scholar 

  122. Saga Y, Mizukami H, Suzuki M, et al. Overexpression of PTEN increases sensitivity to SN-38, an active metabolite of the topoisomerase I inhibitor irinotecan, in ovarian cancer cells. Clin Cancer Res 2002; 8:1248–1252.

    PubMed  CAS  Google Scholar 

  123. Huang H, Cheville JC, Pan Y, et al. PTEN induces chemosensitivity in PTEN-mutated prostate cancer cells by suppression of Bcl-2 expression. J Biol Chem 2001; 276:38830–38836.

    Article  PubMed  CAS  Google Scholar 

  124. Zhao Y, You H, Yang Y, et al. Distinctive regulation and function of PI3K/Akt and MAPKs in doxo-rubicin-induced apoptosis of human lung adenocarcinoma cells. J Cell Biochem 2004; 91:621–632.

    Article  PubMed  CAS  Google Scholar 

  125. Martelli AM, Tazzari PL, Tabellini G, et al. A new selective AKT pharmacological inhibitor reduces resistance to chemotherapeutic drugs, TRAIL, all-trans-retinoic acid, and ionizing radiation of human leukemia cells. Leukemia 2003; 17:1794–1805.

    Article  PubMed  CAS  Google Scholar 

  126. Mayo MW, Baldwin AS. The transcription factor NF-?B: control of oncogenesis and cancer therapy resistance. BiochimBiophys Acta 2000; 1470:M55–M62.

    CAS  Google Scholar 

  127. Wang CY, Mayo MW, Baldwin AS Jr. TNF-a and cancer therapy-induced apoptosis: potentiation by inhibition of NF-?B. Science 1996; 274:784–787.

    Article  PubMed  CAS  Google Scholar 

  128. Panwalkar A, Verstovsek S, Giles F. Nuclear factor-?B modulation as a therapeutic approach in hematologic malignancies. Cancer 2004; 100:1578–1589.

    Article  PubMed  CAS  Google Scholar 

  129. Mitsiades N, Mitsiades CS, Richardson PG, et al. The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood 2003; 101:2377–2380.

    Article  PubMed  CAS  Google Scholar 

  130. Dong QG, Sclabas GM, Fujioka S, et al. The function of multiple I?B: NF-?B complexes in the resistance of cancer cells to Taxol-induced apoptosis. Oncogene 2002; 21:6510–6509.

    Article  PubMed  CAS  Google Scholar 

  131. Fojo T, Bates S. Strategies for reversing drug resistance. Oncogene 2003; 22:7512–7523.

    Article  PubMed  CAS  Google Scholar 

  132. Pakunlu RI, Wang Y, Tsao W, et al. Enhancement of the efficacy of chemotherapy for lung cancer by simultaneous suppression of multidrug resistance and antiapoptotic cellular defense: novel multicom-ponent delivery system. Cancer Res 2004; 64:6214–6224.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Section of Pharmacology, Department of Structural and Functional Biology, University of Insubria, Varese, Italy

    Elena Monti PhD

Authors
  1. Elena Monti PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Genzyme Corporation, Framingham, MA

    Beverly A. Teicher PhD

Rights and permissions

Reprints and permissions

Copyright information

© 2006 Humana Press Inc., Totowa, NJ

About this chapter

Cite this chapter

Monti, E. (2006). Molecular Determinants of Intrinsic Multidrug Resistance in Cancer Cells and Tumors. In: Teicher, B.A. (eds) Cancer Drug Resistance. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-59745-035-5_14

Download citation

  • DOI: https://doi.org/10.1007/978-1-59745-035-5_14

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-530-9

  • Online ISBN: 978-1-59745-035-5

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation