Lessons from TRAIL-resistance mechanisms in colorectal cancer cells: paving the road to patient-tailored therapy

Drug Resist Updat. 2004 Dec;7(6):345-58. doi: 10.1016/j.drup.2004.11.002. Epub 2005 Jan 8.


Colorectal cancer is one of the leading causes of cancer-related deaths worldwide. Intrinsic, as well as acquired, resistance to chemotherapy remains a major problem in the treatment of this disease. It is, therefore, of great importance to develop new, patient-tailored, treatment strategies for colorectal cancer patients. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) acts through the pro-apoptotic DR4 and DR5 receptors in tumor cells without harming normal cells and will soon be tested in clinical trials as a novel anti-cancer agent. However, not all human colon cancer cell lines are sensitive to TRAIL due to intrinsic or acquired TRAIL-resistance. This review discusses the mechanisms and modulation of TRAIL-resistance in colon cancer cells. Cell sensitivity to TRAIL can be affected by TRAIL-receptor expression at the cell membrane, DR4/DR5 ratio and functionality of TRAIL-receptors. Additional intracellular factors leading to TRAIL-resistance affect the caspase 8/c-FLIP ratio, such as loss of caspase 8 and caspase 10 due to mutations or gene methylation, CARP-dependent degradation of active caspase 8 and changes in caspase 8 or c-FLIP expression levels. Further downstream in the TRAIL apoptotic pathway, Bax mutations, or increased expression of IAP family members, in particularly XIAP and survivin, also cause resistance. Chemotherapeutic drugs, NSAIDs, interferon-gamma and proteasome inhibitors can overcome TRAIL-resistance by acting on TRAIL-receptor expression or changing the expression of pro- or anti-apoptotic proteins.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins
  • Cell Line, Tumor
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • Drug Resistance, Neoplasm*
  • Humans
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Membrane Glycoproteins / pharmacology
  • Receptors, Tumor Necrosis Factor / metabolism
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / pharmacology
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism*
  • Tumor Necrosis Factor-alpha / pharmacology


  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • Membrane Glycoproteins
  • Receptors, Tumor Necrosis Factor
  • Recombinant Proteins
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tumor Necrosis Factor-alpha