Chemotherapeutic agents augment TRAIL-induced apoptosis in human hepatocellular carcinoma cell lines

Hepatology. 2000 Sep;32(3):482-90. doi: 10.1053/jhep.2000.16266.


TNF-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in various transformed cell lines but not in almost-normal tissues. It is regulated by 2 death receptors, TRAIL receptor 1 (TRAIL-R1) and TRAIL-R2, and 2 decoy receptors, TRAIL-R3 and TRAIL-R4. We investigated the expression of TRAIL-R- and TRAIL-induced apoptosis in human hepatocellular carcinomas (HCCs). TRAIL-R1, -R2, and -R4 were expressed in 6 HCC cell lines examined, but TRAIL-R3 was expressed in only 2 of the 6 cell lines. In addition, immunohistochemical results revealed a high and prevalent expression of TRAIL-R1 and -R2 in human HCC tissues. Despite the expression of TRAIL-R1 and -R2, all 6 HCC cell lines showed resistance to TRAIL-induced apoptosis with no relation to nuclear factor kappa B (NF-kappaB) levels induced by TRAIL. TRAIL-induced death signal was inhibited with both decreased caspase-8 and caspase-3 activity. However, TRAIL induced significant apoptosis in the presence of a subtoxic level of actinomycin D, indicating that the TRAIL-induced apoptotic pathway is in place in these cell lines. In addition, we found that treatment with conventional chemotherapeutic agents, doxorubicin and camptothecin, dramatically augmented TRAIL-induced cytotoxicity in most of the HCC cell lines. Actinomycin D and camptothecin almost completely suppressed NF-kappaB induction by TRAIL, whereas doxorubicin had little effect. These results indicate that TRAIL, in combination with chemotherapeutic agents, may have therapeutic potential in the treatment of human HCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibiotics, Antineoplastic / pharmacology
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins
  • Camptothecin / pharmacology*
  • Carcinoma, Hepatocellular / pathology
  • Carcinoma, Hepatocellular / physiopathology*
  • Dactinomycin / pharmacology
  • Doxorubicin / pharmacology*
  • Humans
  • Liver Neoplasms / pathology
  • Liver Neoplasms / physiopathology*
  • Membrane Glycoproteins / pharmacology*
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism
  • Receptors, Tumor Necrosis Factor / metabolism
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / pharmacology*


  • Antibiotics, Antineoplastic
  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • Membrane Glycoproteins
  • NF-kappa B
  • Receptors, Tumor Necrosis Factor
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tumor Necrosis Factor-alpha
  • Dactinomycin
  • Doxorubicin
  • Camptothecin