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The caspase 9 inhibitor Z-LEHD-FMK protects human liver cells while permitting death of cancer cells exposed to tumor necrosis factor-related apoptosis-inducing ligand.
Cancer Res. 2000 Nov 15; 60(22):6259-65.CR

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis of transformed and cancer cells but not of most normal cells. Recent studies have revealed an unforeseen toxicity of TRAIL toward normal human hepatocytes, thereby bringing into question the safety of systemic administration of TRAIL in humans with cancer. We found that SW480 colon adenocarcinoma, or H460 non-small cell lung cancer cell lines, which are sensitive to TRAIL, were not protected by the caspase 9 inhibitor Z-LEHD-FMK from TRAIL-induced apoptosis. However, a human colon cancer cell line HCT116 and a human embryonic kidney cell line 293, which are sensitive to TRAIL, were protected by Z-LEHD-FMK from TRAIL-mediated death. Both HCT116 and SW480 cells were protected from TRAIL by the caspase 8 inhibitor Z-IETD-FMK, dominant-negative FADD and cellular FLIP-s and interestingly both cell lines displayed caspase 9 cleavage to a similar extent after TRAIL exposure. We confirmed that normal human liver cells are sensitive to TRAIL. Moreover, we found that normal human liver cells could be protected from TRAIL-induced apoptosis by simultaneous exposure to Z-LEHD-FMK. A similar brief exposure to TRAIL plus Z-LEHD-FMK inhibited colony growth of SW480 but not HCT116 cells. Because some cancer cell lines are not protected from TRAIL-mediated killing by Z-LEHD-FMK, we believe that a brief period of caspase 9 inhibition during TRAIL administration may widen the therapeutic window and allow cancer cell killing while protecting normal liver cells. This strategy could be further developed in the effort to advance TRAIL into clinical trials.

Authors+Show Affiliations

Laboratory of Molecular Oncology and Cell Cycle Regulation, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

11103780

Citation

Ozoren, N, et al. "The Caspase 9 Inhibitor Z-LEHD-FMK Protects Human Liver Cells While Permitting Death of Cancer Cells Exposed to Tumor Necrosis Factor-related Apoptosis-inducing Ligand." Cancer Research, vol. 60, no. 22, 2000, pp. 6259-65.
Ozoren N, Kim K, Burns TF, et al. The caspase 9 inhibitor Z-LEHD-FMK protects human liver cells while permitting death of cancer cells exposed to tumor necrosis factor-related apoptosis-inducing ligand. Cancer Res. 2000;60(22):6259-65.
Ozoren, N., Kim, K., Burns, T. F., Dicker, D. T., Moscioni, A. D., & El-Deiry, W. S. (2000). The caspase 9 inhibitor Z-LEHD-FMK protects human liver cells while permitting death of cancer cells exposed to tumor necrosis factor-related apoptosis-inducing ligand. Cancer Research, 60(22), 6259-65.
Ozoren N, et al. The Caspase 9 Inhibitor Z-LEHD-FMK Protects Human Liver Cells While Permitting Death of Cancer Cells Exposed to Tumor Necrosis Factor-related Apoptosis-inducing Ligand. Cancer Res. 2000 Nov 15;60(22):6259-65. PubMed PMID: 11103780.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The caspase 9 inhibitor Z-LEHD-FMK protects human liver cells while permitting death of cancer cells exposed to tumor necrosis factor-related apoptosis-inducing ligand. AU - Ozoren,N, AU - Kim,K, AU - Burns,T F, AU - Dicker,D T, AU - Moscioni,A D, AU - El-Deiry,W S, PY - 2000/12/5/pubmed PY - 2001/2/28/medline PY - 2000/12/5/entrez SP - 6259 EP - 65 JF - Cancer research JO - Cancer Res VL - 60 IS - 22 N2 - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis of transformed and cancer cells but not of most normal cells. Recent studies have revealed an unforeseen toxicity of TRAIL toward normal human hepatocytes, thereby bringing into question the safety of systemic administration of TRAIL in humans with cancer. We found that SW480 colon adenocarcinoma, or H460 non-small cell lung cancer cell lines, which are sensitive to TRAIL, were not protected by the caspase 9 inhibitor Z-LEHD-FMK from TRAIL-induced apoptosis. However, a human colon cancer cell line HCT116 and a human embryonic kidney cell line 293, which are sensitive to TRAIL, were protected by Z-LEHD-FMK from TRAIL-mediated death. Both HCT116 and SW480 cells were protected from TRAIL by the caspase 8 inhibitor Z-IETD-FMK, dominant-negative FADD and cellular FLIP-s and interestingly both cell lines displayed caspase 9 cleavage to a similar extent after TRAIL exposure. We confirmed that normal human liver cells are sensitive to TRAIL. Moreover, we found that normal human liver cells could be protected from TRAIL-induced apoptosis by simultaneous exposure to Z-LEHD-FMK. A similar brief exposure to TRAIL plus Z-LEHD-FMK inhibited colony growth of SW480 but not HCT116 cells. Because some cancer cell lines are not protected from TRAIL-mediated killing by Z-LEHD-FMK, we believe that a brief period of caspase 9 inhibition during TRAIL administration may widen the therapeutic window and allow cancer cell killing while protecting normal liver cells. This strategy could be further developed in the effort to advance TRAIL into clinical trials. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/11103780/The_caspase_9_inhibitor_Z_LEHD_FMK_protects_human_liver_cells_while_permitting_death_of_cancer_cells_exposed_to_tumor_necrosis_factor_related_apoptosis_inducing_ligand_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=11103780 DB - PRIME DP - Unbound Medicine ER -