TRAIL/Apo-2L: mechanisms and clinical applications in cancer

Neoplasia. Nov-Dec 2001;3(6):535-46. doi: 10.1038/sj.neo.7900203.

Abstract

TNF-related apoptosis-inducing ligand (TRAIL/APO-2L) is a member of the TNF family that promotes apoptosis by binding to the transmembrane receptors TRAIL-R1/DR4 and TRAIL-R2/DR5. Its cytotoxic activity is relatively selective to the human tumor cell lines without much effect on the normal cells. Hence, it exerts an antitumor activity without causing toxicity, as apparent by studies with several xenograft models. This review discusses the intracellular mechanisms by which TRAIL induces apoptosis. The major pathway of its action proceeds through the formation of DISC and activation of caspase-8. The apoptotic processes, therefore, follow two signaling pathways, namely the mitochondrial-independent activation of caspase-3, and mitochondrial-dependent apoptosis due to cleavage of BID by caspase-8, the formation of apoptosomes, and activation of caspase-9 and the downstream caspases. Bcl-2 and Bcl-X(L) have no effect on TRAIL-induced apoptosis in lymphoid cells, whereas these genes block or delay apoptosis in nonlymphoid cancer cells. TRAIL participates in cytotoxicity mediated by activated NK cells, monocytes, and some cytotoxic T cells. Hence, TRAIL may prove to be an effective antitumor agent. In addition, it may enhance the effectiveness of treatment with chemotherapeutic drugs and irradiation. Nontagged Apo-2L/TRAIL does not cause hepatotoxicity in monkeys and chimpanzees and in normal human hepatocytes. Thus, nontagged Apo-2L/TRAIL appears to be a promising new candidate for use in the treatment of cancer.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Antineoplastic Agents / toxicity
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins
  • Arabidopsis Proteins*
  • Caspase Inhibitors
  • Caspases / physiology
  • Cytotoxicity, Immunologic
  • Drug Synergism
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Fatty Acid Desaturases / physiology
  • Female
  • Hepatocytes / drug effects
  • Humans
  • Killer Cells, Natural / immunology
  • Liver / drug effects
  • Male
  • Membrane Glycoproteins / pharmacology*
  • Membrane Glycoproteins / therapeutic use
  • Membrane Glycoproteins / toxicity
  • Mice
  • Mitochondria / physiology
  • Models, Biological
  • Monocytes / immunology
  • NF-kappa B / physiology
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / physiology
  • Neoplasms / drug therapy
  • Primates
  • Proto-Oncogene Proteins c-bcl-2 / physiology
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor / drug effects*
  • Receptors, Tumor Necrosis Factor / physiology
  • Safety
  • Signal Transduction / physiology
  • T-Lymphocytes, Cytotoxic / immunology
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / pathology
  • Tumor Necrosis Factor-alpha / pharmacology*
  • Tumor Necrosis Factor-alpha / therapeutic use
  • Tumor Necrosis Factor-alpha / toxicity
  • Xenograft Model Antitumor Assays
  • bcl-X Protein

Substances

  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • Arabidopsis Proteins
  • BCL2L1 protein, human
  • Bcl2l1 protein, mouse
  • Caspase Inhibitors
  • Enzyme Inhibitors
  • Membrane Glycoproteins
  • NF-kappa B
  • Neoplasm Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFRSF10A protein, human
  • TNFRSF10B protein, human
  • TNFSF10 protein, human
  • Tnfrsf10b protein, mouse
  • Tnfsf10 protein, mouse
  • Tumor Necrosis Factor-alpha
  • bcl-X Protein
  • Fatty Acid Desaturases
  • Fad7 protein, Arabidopsis
  • Caspases