Increased hepatotoxicity of tumor necrosis factor-related apoptosis-inducing ligand in diseased human liver.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in tumor cells but not in most normal cells and has therefore been proposed as a promising antitumor agent. Recent experiments suggested that isolated primary human hepatocytes but not monkey liver cells are susceptible to certain TRAIL agonists, raising concerns about the use of TRAIL in cancer treatment. Whether TRAIL indeed exerts hepatotoxicity in vivo and how this is influenced by chemotherapeutic drugs or liver disease are completely unknown. Employing different forms of recombinant TRAIL, we found that the cytokine can induce proapoptotic caspase activity in isolated human hepatocytes. However in marked contrast, these different TRAIL preparations induced little or no cytotoxicity when incubated with tissue explants of fresh healthy liver, an experimental model that may more faithfully mimic the in vivo situation. In healthy liver, TRAIL induced apoptosis only when combined with histone deacetylase inhibitors. Strikingly, however, TRAIL alone triggered massive apoptosis accompanied by caspase activation in tissue explants from patients with liver steatosis or hepatitis C viral infection. This enhanced sensitivity of diseased liver was associated with an increased expression of TRAIL receptors and up-regulation of proapoptotic Bcl-2 proteins.


CONCLUSIONS
These results suggest that clinical trials should be performed with great caution when TRAIL is combined with chemotherapy or administered to patients with inflammatory liver diseases.
Volkmann
Xandra
X
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
Fischer
Ute
U
Bahr
Matthias J
MJ
Ott
Michael
M
Lehner
Frank
F
Macfarlane
Marion
M
Cohen
Gerald M
GM
Manns
Michael P
MP
Schulze-Osthoff
Klaus
K
Bantel
Heike
H
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000819:agonists / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism*; D004347:Drug Interactions; D064420:Drug-Related Side Effects and Adverse Reactions; D053222:Fas Ligand Protein / Q000494:pharmacology; D005234:Fatty Liver / Q000378:metabolism; D005260:Female; D019698:Hepatitis C, Chronic / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D011994:Recombinant Proteins / Q000819:agonists / Q000633:toxicity; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists / Q000633:toxicity*
D000970:Antineoplastic Agents; D053222:Fas Ligand Protein; D056572:Histone Deacetylase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D020169:Caspases