Human normal hepatocytes are susceptible to apoptosis signal mediated by both TRAIL-R1 and TRAIL-R2

Mori, Eiji; Thomas, M.E.; Motoki, Kazuhiro; Nakazawa, Kumiko; Tahara, Tomoyuki; Tomizuka, Kazuma; Ishida, Isao; Kataoka, Satoshi

doi:10.1038/sj.cdd.4401331

Cited by 73 publications

(82 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This finding is in line with recent reports demonstrating strong apoptosis induction and caspase activation in PHHs after treatment with TRAIL, agonistic TRAIL-R antibodies, or expressed adenoviral TRAIL. [40][41][42][43] Our findings in isolated PHHs are also in accordance with the observation that, in addition to hepatocytes, other isolated primary human cells, such as prostate and thyroid epithelial cells, microvascular endothelial cells, keratinocytes and brain cells, 19,[44][45][46] might be susceptible to TRAIL. Thus, the toxic effects of TRAIL observed are obviously not restricted solely to cultured PHHs.…”

Section: Discussionsupporting

confidence: 78%

Increased hepatotoxicity of tumor necrosis factor-related apoptosis-inducing ligand in diseased human liver

Fischer²,

et al. 2007

View full text Add to dashboard Cite

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. Conclusion: 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.

show abstract

Section: Discussionsupporting

confidence: 78%

Increased hepatotoxicity of tumor necrosis factor-related apoptosis-inducing ligand in diseased human liver

Fischer²,

et al. 2007

View full text Add to dashboard Cite

show abstract

“…Some recombinant versions of TRAIL with exogenous tags and agonistic mAbs against DR4 or DR5 have been reported to be cytotoxic to normal human hepatocytes, raising the concern of their application as anticancer agents (12,35). To determine whether AY4 induces hepatocellular toxicity in vitro, we treated normal human hepatocytes that have been reported to express DR5 and DR4 on the cell surface (12,35) with various concentrations of AY4 and, for comparison, also with TRAIL.…”

Section: Ay4 Alone Induces Cell Death Of Various Cancer Cells But Is mentioning

confidence: 99%

“…To determine whether AY4 induces hepatocellular toxicity in vitro, we treated normal human hepatocytes that have been reported to express DR5 and DR4 on the cell surface (12,35) with various concentrations of AY4 and, for comparison, also with TRAIL. During 24-hour incubation, AY4 treatment exhibited very low levels of cytotoxicity with <10% of hepatocytes killed in the presence of 10 μg/mL AY4, which was similar to that of 0.5 μg/mL TRAIL treatment (∼12% cell death; Fig.…”

Section: Ay4 Alone Induces Cell Death Of Various Cancer Cells But Is mentioning

confidence: 99%

A novel agonistic antibody to human death receptor 4 induces apoptotic cell death in various tumor cells without cytotoxicity in hepatocytes

Sung

Park²,

Lee³

et al. 2009

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

The proapoptotic tumor necrosis factor-related apoptosis inducing ligand (TRAIL) receptors death receptor (DR) 4 and DR5 are attractive targets to develop the receptorspecific agonistic monoclonal antibodies (mAb) as anticancer agents because of their tumor-selective cell death-inducing activity. Here, we report a novel agonistic mAb, AY4, raised against human DR4 in mice. ELISA analysis revealed that AY4 specifically bound to DR4 without competition with TRAIL for the binding. Despite distinct binding regions of AY4 on DR4 from those of TRAIL, AY4 as a single agent induced caspase-dependent apoptotic cell death of several tumor types through the extrinsic and/or intrinsic pathways without substantial cytotoxicity to normal human hepatocytes. Further, the AY4-sensitive cells followed the same cell death characteristics classified as type I and type II cells by the response to TRAIL, suggesting that the cell death profiles in responses to DR4 and/or DR5 stimulation are determined by the downstream signaling of the receptor rather than the kind of receptor. Noticeably, AY4 efficiently induced cell death of Jurkat cells, which have been reported to be resistant to other anti-DR4 agonistic mAbs, most likely due to the unique epitope property of AY4. In vivo administration of AY4 significantly inhibited tumor growth of human non-small cell lung carcinoma preestablished in athymic nude mice. Conclusively, our results provide further insight into the DR4-mediated cell death signaling and potential use of AY4 mAb as an anticancer therapeutic agent, particularly for

show abstract

“…As early as 1999, intracranial experiments suggested that locally administered TRAIL may be efficacious in malignant gliomas (18). Systemic TRAIL administration may not be feasible because of potential toxicity, but this has been debated as different preparations of recombinant TRAIL have differential hepatocyte toxicity (4,(19)(20)(21). This potential limitation led to the development of pro-apoptotic monoclonal antibodies against individual death receptors (22-29), including TRA-8, which binds to DR5 (4).…”

Section: Discussionmentioning

confidence: 99%

Enhancement of Glioma Radiotherapy and Chemotherapy Response With Targeted Antibody Therapy Against Death Receptor 5

Fiveash

Gillespie

Oliver

et al. 2008

International Journal of Radiation Oncology*Biology*Physics

View full text Add to dashboard Cite

Purpose-TRA-8 is an agonistic mouse monoclonal antibody that binds to TRAIL death receptor 5 (DR5) which induces apoptosis in cancer cells through a caspase-8 dependent mechanism. We investigated the ability of TRA-8 to augment radiation therapy (RT) and chemotherapy response of human glioma cells in vitro and in vivo.Methods and Materials-In vitro cytotoxicity of TRA-8 and temozolomide (Tmz) or RT was examined using ATP dependent viability and clonogenic survival assays with 5 glioma cell lines. DR5 expression was determined by flow cytometry. In vivo studies included subcutaneous and intracranial xenograft models testing various combination treatments, including RT, Tmz, and TRA-8.Results-TRA-8 combined with Tmz or RT produced enhanced cytotoxicity against 5 glioma cell lines compared to individual agents. DR5 upregulation occurred in response to RT. Complete tumor regressions in subcutaneous experiments were most common in animals that received combination therapy with TRA-8/Tmz/RT. TRA-8 enhanced tumor growth delay in combination with RT or Tmz. TRA-8 alone had limited activity against intracranial tumors, whereas median survival of mice treated with TRA-8/Tmz/RT was significantly greater than control or TRA-8 alone treated mice. Median survival of mice treated with TRA-8/Tmz/RT or chemoradiation only was significantly greater than control or TRA-8 treated mice. A trend towards improved survival was observed comparing TRA-8/ Tmz/RT treated animals vs. Tmz/RT.Conclusions-These preliminary findings support the hypothesis that TRA-8 will augment RT and chemotherapy response in gliomas. A humanized version of TRA-8 is being evaluated in a Phase II clinical trial.

show abstract

Human normal hepatocytes are susceptible to apoptosis signal mediated by both TRAIL-R1 and TRAIL-R2

Cited by 73 publications

References 20 publications

Increased hepatotoxicity of tumor necrosis factor-related apoptosis-inducing ligand in diseased human liver

Increased hepatotoxicity of tumor necrosis factor-related apoptosis-inducing ligand in diseased human liver

A novel agonistic antibody to human death receptor 4 induces apoptotic cell death in various tumor cells without cytotoxicity in hepatocytes

Enhancement of Glioma Radiotherapy and Chemotherapy Response With Targeted Antibody Therapy Against Death Receptor 5

Contact Info

Product

Resources

About