Apoptosis induced in normal human hepatocytes by tumor necrosis factor-related apoptosis-inducing ligand.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been reported to induce apoptosis in various tumor cells but not in nontransformed, normal cells. Preclinical studies in mice and nonhuman primates have shown that administration of TRAIL can induce apoptosis in human tumors, but that no cytotoxicity to normal organs or tissues is found. The susceptibility of tumor cells to TRAIL and an apparent lack of activity in normal cells has lead to a proposal to use TRAIL in cancer therapy. Here, we assessed the sensitivity of hepatocytes from rat, mouse, rhesus monkey and human livers to TRAIL-induced apoptosis. TRAIL induced apoptosis in normal human hepatocytes in culture but not in hepatocytes isolated from the other species. Human hepatocytes showed characteristic features of apoptosis, including cytoplasmic shrinkage, the activation of caspases and DNA fragmentation. Apoptosis and cell death in human hepatocytes was massive and rapid, occurring in more than 60% of the cells exposed to TRAIL within 10 hours. These results indicate that there are species differences in sensitivity to TRAIL, and that substantial liver toxicity might result if TRAIL were used in human cancer therapy.
Jo
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Department of Pathology, School of Medicine, 200 Lothrop St. BST S-450, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Kim
T H
TH
Seol
D W
DW
Esplen
J E
JE
Dorko
K
K
Billiar
T R
TR
Strom
S C
SC
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D008253:Macaca mulatta; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D051379:Mice; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D018124:Receptors, Tumor Necrosis Factor / Q000302:isolation & purification; D013045:Species Specificity; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; C505655:Tnfsf10 protein, rat; D014409:Tumor Necrosis Factor-alpha