Targeting Inducible Chemotherapy Resistance Mechanisms in Colon Cancer

  • David Ljungman
  • James C. CusackJr.
Part of the Cancer Drug Discovery and Development book series (CDD&D)


Resistance toward chemotherapy remains one of the principle obstacles to the effective treatment of malignancies. As our knowledge of mechanisms involved in cancer biology expands, new molecular targets emerge. This chapter aims to overview the major resistance mechanisms, in order to identify potential targets appropriate for developmental therapeutics. An emphasis on the role of transcription factor NF-κB in colorectal cancer is presented as an example of how targeted therapies may advance from the bench to the bedside.

Key Words

Chemotherapy resistance apoptosis transcription factors NF-κB proteasome inhibition combination chemotherapy 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Kastan MB. Molecular determinants of sensitivity to antitumor agents. Biochim Biophys Acta 1999; 1424(1):R37–R42.PubMedGoogle Scholar
  2. 2.
    Fisher DE. Apoptosis in cancer therapy: crossing the threshold. Cell 1994; 78(4):539–542.PubMedCrossRefGoogle Scholar
  3. 3.
    Schmitt CA, Lowe SW. Apoptosis and therapy. J Pathol 1999; 187(1):127–137.PubMedCrossRefGoogle Scholar
  4. 4.
    Baldini N. Multidrug resistance—a multiplex phenomenon. Nature Med 1997; 3(4):378–380.PubMedCrossRefGoogle Scholar
  5. 5.
    Wang CY, Mayo MW, Baldwin AS Jr. TNF-and cancer therapy-induced apoptosis: potentiation by inhibition of NF-kappaB. Science 1996; 274(5288):784–787.PubMedCrossRefGoogle Scholar
  6. 6.
    Wang CY, et al. Control of inducible chemoresistance: enhanced anti-tumor therapy through increased apoptosis by inhibition of NF-kappaB. Nature Med 1999; 5(4):412–417.PubMedCrossRefGoogle Scholar
  7. 7.
    Beg AA, Baltimore D. An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. Science 1996; 274(5288):782–784.PubMedCrossRefGoogle Scholar
  8. 8.
    Cusack JC Jr, Liu R, Baldwin AS Jr. Inducible chemoresistance to 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothe cin (CPT-11) in colorectal cancer cells and a xenograft model is overcome by inhibition of nuclear factor-kappaB activation. Cancer Res 2000; 60(9):2323–2330.PubMedGoogle Scholar
  9. 9.
    Fulda S, et al. Molecular ordering of apoptosis induced by anticancer drugs in neuroblastoma cells. Cancer Res 1998; 58(19):4453–4460.PubMedGoogle Scholar
  10. 10.
    Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate. Advanced Colorectal Cancer Meta-Analysis Project. J Clin Oncol 1992; 10(6):896–903.Google Scholar
  11. 11.
    Saltz LB, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 2000; 343(13):905–914.PubMedCrossRefGoogle Scholar
  12. 12.
    Douillard JY, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 2000; 355(9209): 1041–1047.PubMedCrossRefGoogle Scholar
  13. 13.
    de Gramont A, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000; 18(16):2938–2947.PubMedGoogle Scholar
  14. 14.
    Tournigand C, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004; 22(2):229–237.PubMedCrossRefGoogle Scholar
  15. 15.
    Vincent M, Labianca R, Harper P. Which 5-fluorouracil regimen?—the great debate. Anticancer Drugs 1999; 10(4):337–354.PubMedCrossRefGoogle Scholar
  16. 16.
    Andre T, Louvet C, de Gramont A. [Colon cancer: what is new in 2004?]. Bull Cancer 2004; 91(1):75–80.PubMedGoogle Scholar
  17. 17.
    Kern A, et al. Nucleotide and transported substrates modulate different steps of the ATPase catalytic cycle of MRP1 multidrug transporter. Biochem J 2004; 380(Pt. 2):549–560.PubMedCrossRefGoogle Scholar
  18. 18.
    Baldini N. Multidrug resistance—a multiplex phenomenon. Nature Med 1997; 3(4):378–380.PubMedCrossRefGoogle Scholar
  19. 19.
    Sikic BI, et al. Modulation and prevention of multidrug resistance by inhibitors of P-glycoprotein. Cancer Chemother Pharmacol 1997; 40(Suppl):S13–S29.PubMedCrossRefGoogle Scholar
  20. 20.
    Maliepaard M, et al. Overexpression of the BCRP/MXR/ABCP gene in a topotecan-selected ovarian tumor cell line. Cancer Res 1999; 59(18):4559–4563.PubMedGoogle Scholar
  21. 21.
    Sikic BI. New approaches in cancer treatment. Ann Oncol 1999; 10(Suppl 6):149–153.PubMedCrossRefGoogle Scholar
  22. 22.
    Maliepaard M, et al. Circumvention of breast cancer resistance protein (BCRP)-mediated resistance to camptothecins in vitro using non-substrate drugs or the BCRP inhibitor GF120918. Clin Cancer Res 2001; 7(4):935–941.PubMedGoogle Scholar
  23. 23.
    Sinha P, et al. Search for novel proteins involved in the development of chemoresistance in colorectal cancer and fibrosarcoma cells in vitro using two-dimensional electrophoresis, mass spectrometry and microsequencing. Electrophoresis 1999; 20(14):2961–2969.PubMedCrossRefGoogle Scholar
  24. 24.
    Mini E, et al. Marked variation of thymidylate synthase and folylpolyglutamate synthetase gene expression in human colorectal tumors. Oncol Res 1999; 11(9):437–445.PubMedGoogle Scholar
  25. 25.
    Plummer R, et al. A phase I trial of ZD9331, a water-soluble, nonpolyglutamatable, thymidylate synthase inhibitor. Clin Cancer Res 2003; 9(4):1313–1322.PubMedGoogle Scholar
  26. 26.
    Gibbs D, Raynaud CP, Valenti M, Jackman AL. CB300638, an alpha-folate receptor (a-FR) targeted antifolate thymidylate synthase (TS) inhibitor that inhibits TS in human tumour xenografts but not in normal tissues. Proc Am Assoc Cancer Res 2003; 2624a.Google Scholar
  27. 27.
    Townsend DM, Tew KD. The role of glutathione-S-transferase in anti-cancer drug resistance. Oncogene 2003; 22(47):7369–7375.PubMedCrossRefGoogle Scholar
  28. 28.
    Kivisto KT, Kroemer HK, Eichelbaum M. The role of human cytochrome P450 enzymes in the metabolism of anticancer agents: implications for drug interactions. Br J Clin Pharmacol 1995; 40(6):523–530.PubMedGoogle Scholar
  29. 29.
    Ferreira CG, Tolis C, Giaccone G. p53 and chemosensitivity. Ann Oncol 1999; 10(9):1011–1021.PubMedCrossRefGoogle Scholar
  30. 30.
    Yamamoto M, et al. The p53 tumor suppressor gene in anticancer agent-induced apoptosis and chemosensitivity of human gastrointestinal cancer cell lines. Cancer Chemother Pharmacol 1999; 43(1):43–49.PubMedCrossRefGoogle Scholar
  31. 31.
    Zheng M, et al. The influence of the p53 gene on the in vitro chemosensitivity of colorectal cancer cells. J Cancer Res Clin Oncol 1999; 125(6):357–360.PubMedCrossRefGoogle Scholar
  32. 32.
    Fujiwara T, et al. Induction of chemosensitivity in human lung cancer cells in vivo by adenovirus-mediated transfer of the wild-type p53 gene. Cancer Res 1994; 54(9):2287–2291.PubMedGoogle Scholar
  33. 33.
    Spitz FR, et al. In vivo adenovirus-mediated p53 tumor suppressor gene therapy for colorectal cancer. Anticancer Res 1996; 16(6B):3415–3422.PubMedGoogle Scholar
  34. 34.
    Bullock AN, Fersht AR. Rescuing the function of mutant p53. Nature Rev Cancer 2001; 1(1):68–76.CrossRefGoogle Scholar
  35. 35.
    Wang W, Rastinejad F, El-Deiry WS. Restoring p53-dependent tumor suppression. Cancer Biol Ther 2003; 2(4 Suppl 1):S55–S63.PubMedGoogle Scholar
  36. 36.
    Foster BA, et al. Pharmacological rescue of mutant p53 conformation and function. Science 1999; 286(5449):2507–2510.PubMedCrossRefGoogle Scholar
  37. 37.
    Kaufmann SH, Vaux DL. Alterations in the apoptotic machinery and their potential role in anticancer drug resistance. Oncogene 2003; 22(47):7414–7430.PubMedCrossRefGoogle Scholar
  38. 38.
    te Poele RH, et al. DNA damage is able to induce senescence in tumor cells in vitro and in vivo. Cancer Res 2002; 62(6):1876–1883.Google Scholar
  39. 39.
    Schmitt CA, et al. A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell 2002; 109(3):335–346.PubMedCrossRefGoogle Scholar
  40. 40.
    Chang BD, et al. Molecular determinants of terminal growth arrest induced in tumor cells by a chemotherapeutic agent. Proc Natl Acad Sci USA 2002; 99(1):389–394.PubMedCrossRefGoogle Scholar
  41. 41.
    Brown JM, Wouters BG. Apoptosis, p53, and tumor cell sensitivity to anticancer agents. Cancer Res 1999; 59(7):1391–1399.PubMedGoogle Scholar
  42. 42.
    Leist M, Jaattela M. Four deaths and a funeral: from caspases to alternative mechanisms. Nature Rev Mol Cell Biol 2001; 2(8):589–598.CrossRefGoogle Scholar
  43. 43.
    Kaufmann SH, Gores GJ. Apoptosis in cancer: cause and cure. Bioessays 2000; 22(11):1007–1017.PubMedCrossRefGoogle Scholar
  44. 44.
    Johnstone RW, Ruefli AA, Lowe SW. Apoptosis: a link between cancer genetics and chemotherapy. Cell 2002; 108(2):153–164.PubMedCrossRefGoogle Scholar
  45. 45.
    Violette S, et al. Resistance of colon cancer cells to long-term 5-fluorouracil exposure is correlated to the relative level of Bcl-2 and Bcl-X(L) in addition to Bax and p53 status. Int J Cancer 2002; 98(4): 498–504.PubMedCrossRefGoogle Scholar
  46. 46.
    Oliver L, et al. Resistance to apoptosis is increased during metastatic dissemination of colon cancer. Clin Exp Metastasis 2002; 19(2):175–180.PubMedCrossRefGoogle Scholar
  47. 47.
    Thornberry NA, Lazebnik Y. Caspases: enemies within. Science 1998; 281(5381):1312–1316.PubMedCrossRefGoogle Scholar
  48. 48.
    Ashkenazi A, Dixit VM. Death receptors: signaling and modulation. Science 1998; 281(5381): 1305–1308.PubMedCrossRefGoogle Scholar
  49. 49.
    Budihardjo I, et al. Biochemical pathways of caspase activation during apoptosis. Annu Rev Cell Dev Biol 1999; 15:269–290.PubMedCrossRefGoogle Scholar
  50. 50.
    Wang X. The expanding role of mitochondria in apoptosis. Genes Dev 2001; 15(22):2922–2933.PubMedGoogle Scholar
  51. 51.
    Acehan D, et al. Three-dimensional structure of the apoptosome: implications for assembly, procaspase-9 binding, and activation. Mol Cell 2002; 9(2):423–432.PubMedCrossRefGoogle Scholar
  52. 52.
    Cheng EH, et al. BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX-and BAK-mediated mitochondrial apoptosis. Mol Cell 2001; 8(3):705–711.PubMedCrossRefGoogle Scholar
  53. 53.
    Ozoren N, El-Deiry WS. Defining characteristics of Types I and II apoptotic cells in response to TRAIL. Neoplasia 2002; 4(6):551–557.PubMedCrossRefGoogle Scholar
  54. 54.
    Barnhart BC, Alappat EC, Peter ME. The CD95 type I/type II model. Semin Immunol 2003; 15(3): 185–193.PubMedCrossRefGoogle Scholar
  55. 55.
    Ravagnan L, Roumier T, Kroemer G. Mitochondria, the killer organelles and their weapons. J Cell Physiol 2002; 192(2):131–137.PubMedCrossRefGoogle Scholar
  56. 56.
    Srinivasula SM, et al. Molecular determinants of the caspase-promoting activity of Smac/DIABLO and its role in the death receptor pathway. J Biol Chem 2000; 275(46):36,152–36,157.PubMedCrossRefGoogle Scholar
  57. 57.
    Martins LM, et al. The serine protease Omi/HtrA2 regulates apoptosis by binding XIAP through a reaper-like motif. J Biol Chem 2002; 277(1):439–444.PubMedCrossRefGoogle Scholar
  58. 58.
    Jansen B, et al. bcl-2 antisense therapy chemosensitizes human melanoma in SCID mice. Nature Med 1998; 4(2):232–234.PubMedCrossRefGoogle Scholar
  59. 59.
    Waters JS, et al. Phase I clinical and pharmacokinetic study of bcl-2 antisense oligonucleotide therapy in patients with non-Hodgkin’s lymphoma. J Clin Oncol 2000; 18(9):1812–1823.PubMedGoogle Scholar
  60. 60.
    Jansen B, et al. Chemosensitisation of malignant melanoma by BCL2 antisense therapy. Lancet 2000; 356(9243):1728–1733.PubMedCrossRefGoogle Scholar
  61. 61.
    Taylor JK, et al. Induction of endogenous Bcl-xS through the control of Bcl-x pre-mRNA splicing by antisense oligonucleotides. Nature Biotechnol 1999; 17(11):1097–1100.CrossRefGoogle Scholar
  62. 62.
    Grossman D, et al. Inhibition of melanoma tumor growth in vivo by survivin targeting. Proc Natl Acad Sci USA 2001; 98(2):635–640.PubMedCrossRefGoogle Scholar
  63. 63.
    Zamore PD. RNA interference: listening to the sound of silence. Nature Struct Biol 2001; 8(9): 746–750.PubMedCrossRefGoogle Scholar
  64. 64.
    McManus MT, Sharp PA. Gene silencing in mammals by small interfering RNAs. Nature Rev Genet 2002; 3(10):737–747.CrossRefGoogle Scholar
  65. 65.
    Crnkovic-Mertens I, Hoppe-Seyler F, Butz K. Induction of apoptosis in tumor cells by siRNA-mediated silencing of the livin/ML-IAP/KIAP gene. Oncogene 2003; 22(51):8330–8336.PubMedCrossRefGoogle Scholar
  66. 66.
    Guo F, et al. Ectopic overexpression of second mitochondria-derived activator of caspases (Smac/DIABLO) or cotreatment with N-terminus of Smac/DIABLO peptide potentiates epothilone B derivative-(BMS 247550) and Apo-2L/TRAIL-induced apoptosis. Blood 2002; 99(9):3419–3426.PubMedCrossRefGoogle Scholar
  67. 67.
    Fulda S, et al. Smac agonists sensitize for Apo2L/TRAIL-or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo. Nature Med 2002; 8(8):808–815.PubMedGoogle Scholar
  68. 68.
    Arnt CR, et al. Synthetic Smac/DIABLO peptides enhance the effects of chemotherapeutic agents by binding XIAP and cIAP1 in situ. J Biol Chem 2002; 277(46):44,236–44,243. Epub 2002 Sep 5.PubMedCrossRefGoogle Scholar
  69. 69.
    Darnell JE Jr. Transcription factors as targets for cancer therapy. Nature Rev Cancer 2002; 2(10):740–749.CrossRefGoogle Scholar
  70. 70.
    Brivanlou AH, Darnell JE Jr. Signal transduction and the control of gene expression. Science 2002; 295(5556):813–818.PubMedCrossRefGoogle Scholar
  71. 71.
    Gibbs JB. Mechanism-based target identification and drug discovery in cancer research. Science 2000; 287(5460):1969–1973.PubMedCrossRefGoogle Scholar
  72. 72.
    Tilley WD, et al. Hormones and cancer: new insights, new challenges. Trends Endocrinol Metab 2001; 12(5):186–188.PubMedCrossRefGoogle Scholar
  73. 73.
    Barnes PJ. Anti-inflammatory actions of glucocorticoids: molecular mechanisms. Clin Sci (Lond) 1998; 94(6):557–572.Google Scholar
  74. 74.
    Stark GR, et al. How cells respond to interferons. Annu Rev Biochem 1998; 67:227–264.PubMedCrossRefGoogle Scholar
  75. 75.
    Levy DE, Darnell JE Jr. Stats: transcriptional control and biological impact. Nature Rev Mol Cell Biol 2002; 3(9):651–662.CrossRefGoogle Scholar
  76. 76.
    Starr R, Hilton DJ. Negative regulation of the JAK/STAT pathway. Bioessays 1999; 21(1):47–52.PubMedCrossRefGoogle Scholar
  77. 77.
    Shuai K. Modulation of STAT signaling by STAT-interacting proteins. Oncogene 2000; 19(21): 2638–2644.PubMedCrossRefGoogle Scholar
  78. 78.
    Bowman T, et al. STATs in oncogenesis. Oncogene 2000; 19(21):2474–2488.PubMedCrossRefGoogle Scholar
  79. 79.
    Lacronique V, et al. Transforming properties of chimeric TEL-JAK proteins in Ba/F3 cells. Blood 2000; 95(6):2076–2083.PubMedGoogle Scholar
  80. 80.
    Lacronique V, et al. A TEL-JAK2 fusion protein with constitutive kinase activity in human leukemia. Science 1997; 278(5341):1309–1312.PubMedCrossRefGoogle Scholar
  81. 81.
    Song JI, Grandis JR. STAT signaling in head and neck cancer. Oncogene 2000; 19(21):2489–2495.PubMedCrossRefGoogle Scholar
  82. 82.
    Catlett-Falcone R, et al. Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity 1999; 10(1):105–115.PubMedCrossRefGoogle Scholar
  83. 83.
    Cantley LC. The phosphoinositide 3-kinase pathway. Science 2002; 296(5573):1655–1657.PubMedCrossRefGoogle Scholar
  84. 84.
    Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nature Rev Cancer 2002; 2(7):489–501.CrossRefGoogle Scholar
  85. 85.
    Hayakawa J, et al. Inhibition of BAD phosphorylation either at serine 112 via extracellular signal-regulated protein kinase cascade or at serine 136 via Akt cascade sensitizes human ovarian cancer cells to cisplatin. Cancer Res 2000; 60(21):5988–5994.PubMedGoogle Scholar
  86. 86.
    Park SY, Seol DW. Regulation of Akt by EGF-R inhibitors, a possible mechanism of EGF-R inhibitor-enhanced TRAIL-induced apoptosis. Biochem Biophys Res Commun 2002; 295(2):515–518.PubMedCrossRefGoogle Scholar
  87. 87.
    Neshat MS, et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci USA 2001; 98(18):10,314–10,319.PubMedCrossRefGoogle Scholar
  88. 88.
    Guba M, et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nature Med 2002; 8(2):128–135.PubMedCrossRefGoogle Scholar
  89. 89.
    Barish GD, Williams BO. In: Gutkind JS, ed. Signaling networks and cell cycle control: the molecular basis of cancer and other diseases. Humana, Totowa, NJ, 2000:53–82.CrossRefGoogle Scholar
  90. 90.
    Taipale J, Beachy PA. The Hedgehog and Wnt signalling pathways in cancer. Nature 2001; 411(6835): 349–354.PubMedCrossRefGoogle Scholar
  91. 91.
    van Gijn ME, et al. The wnt-frizzled cascade in cardiovascular disease. Cardiovasc Res 2002; 55(1):16–24.PubMedCrossRefGoogle Scholar
  92. 92.
    Wong CM, Fan ST, Ng IO. beta-Catenin mutation and overexpression in hepatocellular carcinoma: clinicopathologic and prognostic significance. Cancer 2001; 92(1):136–145.PubMedCrossRefGoogle Scholar
  93. 93.
    Kramps T, et al. Wnt/wingless signaling requires BCL9/legless-mediated recruitment of pygopus to the nuclear beta-catenin-TCF complex. Cell 2002; 109(1):47–60.PubMedCrossRefGoogle Scholar
  94. 94.
    Barker N, Clevers H. Catenins, Wnt signaling and cancer. Bioessays 2000; 22(11):961–965.PubMedCrossRefGoogle Scholar
  95. 95.
    Karin M, Lin A. NF-kappaB at the crossroads of life and death. Nature Immunol 2002; 3(3): 221–227.CrossRefGoogle Scholar
  96. 96.
    Wang CY, Mayo MW, Baldwin AS Jr. TNF-and cancer therapy-induced apoptosis: potentiation by inhibition of NF-kappaB. Science 1996; 274(5288):784–787.PubMedCrossRefGoogle Scholar
  97. 97.
    Wang CY, et al. NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science 1998; 281(5383):1680–1683.PubMedCrossRefGoogle Scholar
  98. 98.
    Hsu H, et al. TNF-dependent recruitment of the protein kinase RIP to the TNF receptor-1 signaling complex. Immunity 1996; 4(4):387–396.PubMedCrossRefGoogle Scholar
  99. 99.
    Hsu H, Xiong J, Goeddel DV. The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation. Cell 1995; 81(4):495–504.PubMedCrossRefGoogle Scholar
  100. 100.
    Santana P, et al. Acid sphingomyelinase-deficient human lymphoblasts and mice are defective in radiation-induced apoptosis. Cell 1996; 86(2):189–199.PubMedCrossRefGoogle Scholar
  101. 101.
    Tartaglia LA, Goeddel DV. Two TNF receptors. Immunol Today 1992; 13(5):151–153.PubMedCrossRefGoogle Scholar
  102. 102.
    Ryan KM, et al. Role of NF-kappaB in p53-mediated programmed cell death. Nature 2000; 404(6780): 892–897.PubMedCrossRefGoogle Scholar
  103. 103.
    Cusack JC, Liu R, Baldwin AS. NF-kappa B and chemoresistance: potentiation of cancer drugs via inhibition of NF-kappa B. Drug Resist Update 1999; 2(4):271–273.CrossRefGoogle Scholar
  104. 104.
    Spencer E, Jiang J, Chen ZJ.Signal-induced ubiquitination of IkappaBalpha by the F-box protein Slimb/beta-TrCP. Genes Dev 1999; 13(3):284–294.PubMedGoogle Scholar
  105. 105.
    Baldwin AS. Control of oncogenesis and cancer therapy resistance by the transcription factor NF-kappaB. J Clin Invest 2001; 107(3):241–246.PubMedCrossRefGoogle Scholar
  106. 106.
    Soengas MS, Lowe SW. Apoptosis and melanoma chemoresistance. Oncogene 2003; 22(20):3138–3151.PubMedCrossRefGoogle Scholar
  107. 107.
    Tam WF, Wang W, Sen R. Cell-specific association and shuttling of IkappaBalpha provides a mechanism for nuclear NF-kappaB in B lymphocytes. Mol Cell Biol 2001; 21(14):4837–4846.PubMedCrossRefGoogle Scholar
  108. 108.
    Song HY, Rothe M, Goeddel DV. The tumor necrosis factor-inducible zinc finger protein A20 interacts with TRAF1/TRAF2 and inhibits NF-kappaB activation. Proc Natl Acad Sci USA 1996; 93(13):6721–6725.PubMedCrossRefGoogle Scholar
  109. 109.
    Micheau O, Tschopp J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 2003; 114(2):181–190.PubMedCrossRefGoogle Scholar
  110. 110.
    Joyce D, et al. Integration of Rac-dependent regulation of cyclin D1 transcription through a nuclear factor-kappaB-dependent pathway. J Biol Chem 1999; 274(36):25,245–25,249.PubMedCrossRefGoogle Scholar
  111. 111.
    Wadgaonkar R, et al. CREB-binding protein is a nuclear integrator of nuclear factor-kappaB and p53 signaling. J Biol Chem 1999; 274(4):1879–1882.PubMedCrossRefGoogle Scholar
  112. 112.
    Tergaonkar V, et al. p53 stabilization is decreased upon NFkappaB activation: a role for NfkappaB in acquisition of resistance to chemotherapy. Cancer Cell 2002; 1(5):493–503.PubMedCrossRefGoogle Scholar
  113. 113.
    Bentires-Alj M, et al. Inhibition of the NF-kappa B transcription factor increases Bax expression in cancer cell lines. Oncogene 2001; 20(22):2805–2813.PubMedCrossRefGoogle Scholar
  114. 114.
    Bottero V, et al. Ikappa b-alpha, the NF-kappa B inhibitory subunit, interacts with ANT, the mitochondrial ATP/ADP translocator. J Biol Chem 2001; 276(24):21,317–21,324.PubMedCrossRefGoogle Scholar
  115. 115.
    Cogswell PC, et al. NF-kappa B and I kappa B alpha are found in the mitochondria. Evidence for regulation of mitochondrial gene expression by NF-kappa B. J Biol Chem 2003; 278(5):2963–2968.PubMedCrossRefGoogle Scholar
  116. 116.
    Rayet B, Gelinas C. Aberrant rel/nfkb genes and activity in human cancer. Oncogene 1999; 18(49): 6938–6947.PubMedCrossRefGoogle Scholar
  117. 117.
    Maxwell SA, Mukhopadhyay T. A novel NF-kappa B p65 spliced transcript lacking exons 6 and 7 in a non-small cell lung carcinoma cell line. Gene 1995; 166(2):339–340.PubMedCrossRefGoogle Scholar
  118. 118.
    Visconti R, et al. Expression of the neoplastic phenotype by human thyroid carcinoma cell lines requires NFkappaB p65 protein expression. Oncogene 1997; 15(16):1987–1994.PubMedCrossRefGoogle Scholar
  119. 119.
    Mathew S, et al. Chromosomal localization of genes encoding the transcription factors, c-rel, Nf-kappa Bp50, NF-kappa Bp65, and lyt-10 by fluorescence in situ hybridization. Oncogene 1993; 8(1):191–193.PubMedGoogle Scholar
  120. 120.
    Bours V, et al. The NF-kappa B transcription factor and cancer: high expression of NF-kappa B-and I kappa B-related proteins in tumor cell lines. Biochem Pharmacol 1994; 47(1):145–149.PubMedCrossRefGoogle Scholar
  121. 121.
    Cabannes E, et al. Mutations in the IkBa gene in Hodgkin’s disease suggest a tumour suppressor role for IkappaBalpha. Oncogene 1999; 18(20):3063–3070.PubMedCrossRefGoogle Scholar
  122. 122.
    Chen C, Edelstein LC, Gelinas C. The Rel/NF-kappaB family directly activates expression of the apoptosis inhibitor Bcl-x(L). Mol Cell Biol 2000; 20(8):2687–2695.PubMedCrossRefGoogle Scholar
  123. 123.
    Ni H, et al. Analysis of expression of nuclear factor kappa B (NF-kappa B) in multiple myeloma: downregulation of NF-kappa B induces apoptosis. Br J Haematol 2001; 115(2):279–286.PubMedCrossRefGoogle Scholar
  124. 124.
    Hideshima T, et al. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res 2001; 61(7):3071–3076.PubMedGoogle Scholar
  125. 125.
    Ogata A, et al. IL-6 triggers cell growth via the Ras-dependent mitogen-activated protein kinase cascade. J Immunol 1997; 159(5):2212–2221.PubMedGoogle Scholar
  126. 126.
    Chauhan D, et al. Dexamethasone induces apoptosis of multiple myeloma cells in a JNK/SAP kinase independent mechanism. Oncogene 1997; 15(7):837–843.PubMedCrossRefGoogle Scholar
  127. 127.
    Palombella VJ, et al. Role of the proteasome and NF-kappaB in streptococcal cell wall-induced polyarthritis. Proc Natl Acad Sci USA 1998; 95(26):15,671–15,676.PubMedCrossRefGoogle Scholar
  128. 128.
    Wang W, et al. The nuclear factor-kappa B RelA transcription factor is constitutively activated in human pancreatic adenocarcinoma cells. Clin Cancer Res 1999; 5(1):119–127.PubMedGoogle Scholar
  129. 129.
    Nakshatri H, et al. Constitutive activation of NF-kappaB during progression of breast cancer to hormone-independent growth. Mol Cell Biol 1997; 17(7):3629–3639.PubMedGoogle Scholar
  130. 130.
    Sovak MA, et al. Aberrant nuclear factor-kappaB/Rel expression and the pathogenesis of breast cancer. J Clin Invest 1997; 100(12):2952–2960.PubMedGoogle Scholar
  131. 131.
    Palayoor ST, et al. Constitutive activation of IkappaB kinase alpha and NF-kappaB in prostate cancer cells is inhibited by ibuprofen. Oncogene 1999; 18(51):7389–7394.PubMedCrossRefGoogle Scholar
  132. 132.
    Patel NM, et al. Paclitaxel sensitivity of breast cancer cells with constitutively active NF-kappaB is enhanced by IkappaBalpha super-repressor and parthenolide. Oncogene 2000; 19(36):4159–4169.PubMedCrossRefGoogle Scholar
  133. 133.
    Lind DS, et al. Nuclear factor-kappa B is upregulated in colorectal cancer. Surgery 2001; 130(2): 363–369.PubMedCrossRefGoogle Scholar
  134. 134.
    Mukhopadhyay T, Roth JA, Maxwell SA. Altered expression of the p50 subunit of the NF-kappa B transcription factor complex in non-small cell lung carcinoma. Oncogene 1995; 11(5):999–1003.PubMedGoogle Scholar
  135. 135.
    Reuning U, et al. Inhibition of NF-kappa B-Rel A expression by antisense oligodeoxynucleotides suppresses synthesis of urokinase-type plasminogen activator (uPA) but not its inhibitor PAI-1. Nucleic Acids Res 1995; 23(19):3887–3893.PubMedCrossRefGoogle Scholar
  136. 136.
    Grundker C, et al. Luteinizing hormone-releasing hormone induces nuclear factor kappaB-activation and inhibits apoptosis in ovarian cancer cells. J Clin Endocrinol Metab 2000; 85(10):3815–3820.PubMedCrossRefGoogle Scholar
  137. 136a.
    Wang CY, Cusack JC Jr, Liu R, Baldwin AS Jr. Control of inducible chemoresistance: enhanced anti-tumor therapy through increased apoptosis by inhibition of NF-kappaB. Nature Med 1999; 5(4): 412–417.PubMedCrossRefGoogle Scholar
  138. 137.
    Duffey DC, et al. Expression of a dominant-negative mutant inhibitor-kappaBalpha of nuclear factor-kappaB in human head and neck squamous cell carcinoma inhibits survival, proinflammatory cytokine expression, and tumor growth in vivo. Cancer Res 1999; 59(14):3468–3474.PubMedGoogle Scholar
  139. 138.
    Cusack JC Jr, et al. Enhanced chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications for systemic nuclear factor-kappaB inhibition. Cancer Res 2001; 61(9):3535–3540.PubMedGoogle Scholar
  140. 139.
    Russo SM, et al. Enhancement of radiosensitivity by proteasome inhibition: implications for a role of NF-kappaB. Int J Radiat Oncol Biol Phys 2001; 50(1):183–193.PubMedCrossRefGoogle Scholar
  141. 140.
    An B, et al. Novel dipeptidyl proteasome inhibitors overcome Bcl-2 protective function and selectively accumulate the cyclin-dependent kinase inhibitor p27 and induce apoptosis in transformed, but not normal, human fibroblasts. Cell Death Differ 1998; 5(12):1062–1075.PubMedCrossRefGoogle Scholar
  142. 141.
    Masdehors P, et al. Ubiquitin-proteasome system and increased sensitivity of B-CLL lymphocytes to apoptotic death activation. Leuk Lymphoma 2000; 38(5–6):499–504.PubMedGoogle Scholar
  143. 142.
    Delic J, et al. The proteasome inhibitor lactacystin induces apoptosis and sensitizes chemo-and radio-resistant human chronic lymphocytic leukaemia lymphocytes to TNF-alpha-initiated apoptosis. Br J Cancer 1998; 77(7): 1103–1107.PubMedGoogle Scholar
  144. 143.
    LeBlanc R, et al. Proteasome inhibitor PS-341 inhibits human myeloma cell growth in vivo and prolongs survival in a murine model. Cancer Res 2002; 62(17):4996–5000.PubMedGoogle Scholar
  145. 144.
    Richardson PG, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 2003; 348(26):2609–2617.PubMedCrossRefGoogle Scholar
  146. 145.
    Desai SD, et al. Ubiquitin-dependent destruction of topoisomerase I is stimulated by the antitumor drug camptothecin. J Biol Chem 1997; 272(39):24,159–24,164.PubMedCrossRefGoogle Scholar
  147. 146.
    Cusack JC Jr. Overcoming antiapoptotic responses to promote chemosensitivity in metastatic colorectal cancer to the liver. Ann Surg Oncol 2003; 10(8):852–862.PubMedCrossRefGoogle Scholar
  148. 147.
    Maki CG, Huibregtse JM, Howley PM. In vivo ubiquitination and proteasome-mediated degradation of p53(1). Cancer Res 1996; 56(11):2649–2654.PubMedGoogle Scholar
  149. 148.
    Cayrol C, Ducommun B. Interaction with cyclin-dependent kinases and PCNA modulates proteasome-dependent degradation of p21. Oncogene 1998; 17(19):2437–2444.PubMedCrossRefGoogle Scholar
  150. 149.
    Pagano M, et al. Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science 1995; 269(5224):682–685.PubMedCrossRefGoogle Scholar
  151. 150.
    Chadebech P, et al. Phosphorylation and proteasome-dependent degradation of Bcl-2 in mitotic-arrested cells after microtubule damage. Biochem Biophys Res Commun 1999; 262(3):823–827.PubMedCrossRefGoogle Scholar
  152. 151.
    Salvat C, et al. Differential directing of c-Fos and c-Jun proteins to the proteasome in serum-stimulated mouse embryo fibroblasts. Oncogene 1998; 17(3):327–337.PubMedCrossRefGoogle Scholar
  153. 152.
    Clurman BE, et al. Turnover of cyclin E by the ubiquitin-proteasome pathway is regulated by cdk2 binding and cyclin phosphorylation. Genes Dev 1996; 10(16):1979–1990.PubMedCrossRefGoogle Scholar
  154. 153.
    Diehl JA, Zindy F, Sherr CJ. Inhibition of cyclin D1 phosphorylation on threonine-286 prevents its rapid degradation via the ubiquitin-proteasome pathway. Genes Dev 1997; 11(8):957–972.PubMedCrossRefGoogle Scholar
  155. 154.
    Sudakin V, et al. The cyclosome, a large complex containing cyclin-selective ubiquitin ligase activity, targets cyclins for destruction at the end of mitosis. Mol Biol Cell 1995; 6(2):185–197.PubMedGoogle Scholar
  156. 155.
    Buschmann T, et al. SUMO-1 modification of Mdm2 prevents its self-ubiquitination and increases Mdm2 ability to ubiquitinate p53. Cell 2000; 101(7):753–762.PubMedCrossRefGoogle Scholar
  157. 156.
    Dietrich C, et al. p53-dependent cell cycle arrest induced by N-acetyl-L-leucinyl-L-leucinyl-L-norleucinal in platelet-derived growth factor-stimulated human fibroblasts. Proc Natl Acad Sci USA 1996; 93(20): 10,815–10,819.PubMedCrossRefGoogle Scholar
  158. 157.
    Adams J, et al. Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 1999; 59(11):2615–2622.PubMedGoogle Scholar
  159. 158.
    Bold RJ, Virudachalam S, McConkey DJ. Chemosensitization of pancreatic cancer by inhibition of the 26S proteasome. J Surg Res 2001; 100(1):11–17.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2005

Authors and Affiliations

  • David Ljungman
    • 1
  • James C. CusackJr.
    • 1
  1. 1.Division of Surgical OncologyMassachusetts General HospitalBoston

Personalised recommendations