This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Özören, N. Articles by El-Deiry, W. S. Search for Related Content PubMed PubMed Citation Articles by Özören, N. Articles by El-Deiry, W. S.

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

Laboratory of Molecular Oncology and Cell Cycle Regulation [N. Ö., K. K., T. F. B., D. T. D., W. S. E-D.], Howard Hughes Medical Institute [D. T. D., W. S. E-D.], Departments of Medicine [K. K., W. S. E-D.], Molecular and Cellular Engineering [A. D. M.], Genetics [W. S. E-D.], Pharmacology [W. S. E-D.], Cancer Center [W. S. E-D.], and Institute for Human Gene Therapy [A. D. M., W. S. E-D.], University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

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.

This article has been cited by other articles:

				B. Loureiro, A. M. Brad, and P. J. Hansen Heat shock and tumor necrosis factor-{alpha} induce apoptosis in bovine preimplantation embryos through a caspase-9-dependent mechanism Reproduction, June 1, 2007; 133(6): 1129 - 1137. [Abstract] [Full Text] [PDF]

				A. W. Tolcher, M. Mita, N. J. Meropol, M. von Mehren, A. Patnaik, K. Padavic, M. Hill, T. Mays, T. McCoy, N. L. Fox, et al. Phase I Pharmacokinetic and Biologic Correlative Study of Mapatumumab, a Fully Human Monoclonal Antibody With Agonist Activity to Tumor Necrosis Factor Related Apoptosis-Inducing Ligand Receptor-1 J. Clin. Oncol., April 10, 2007; 25(11): 1390 - 1396. [Abstract] [Full Text] [PDF]

				M. Bagnoli, E. Balladore, E. Luison, P. Alberti, F. Raspagliesi, B. Marcomini, S. Canevari, and D. Mezzanzanica Sensitization of p53-mutated epithelial ovarian cancer to CD95-mediated apoptosis is synergistically induced by cisplatin pretreatment Mol. Cancer Ther., February 1, 2007; 6(2): 762 - 772. [Abstract] [Full Text] [PDF]

				A. K. Samraj, E. Keil, N. Ueffing, K. Schulze-Osthoff, and I. Schmitz Loss of Caspase-9 Provides Genetic Evidence for the Type I/II Concept of CD95-mediated Apoptosis J. Biol. Chem., October 6, 2006; 281(40): 29652 - 29659. [Abstract] [Full Text] [PDF]

				Z. Liu, H. Li, M. Derouet, A. Berezkin, T. Sasazuki, S. Shirasawa, and K. Rosen Oncogenic Ras Inhibits Anoikis of Intestinal Epithelial Cells by Preventing the Release of a Mitochondrial Pro-apoptotic Protein Omi/HtrA2 into the Cytoplasm J. Biol. Chem., May 26, 2006; 281(21): 14738 - 14747. [Abstract] [Full Text] [PDF]

				S. Yui, T. Saeki, R. Kanamoto, and K. Iwami Characteristics of Apoptosis in HCT116 Colon Cancer Cells Induced by Deoxycholic Acid J. Biochem., August 1, 2005; 138(2): 151 - 157. [Abstract] [Full Text] [PDF]

				Y.-Y. Wu, Y.-C. Chang, T.-L. Hsu, S.-L. Hsieh, and M.-Z. Lai Sensitization of Cells to TRAIL-induced Apoptosis by Decoy Receptor 3 J. Biol. Chem., October 15, 2004; 279(42): 44211 - 44218. [Abstract] [Full Text] [PDF]

				M. S. Ricci, Z. Jin, M. Dews, D. Yu, A. Thomas-Tikhonenko, D. T. Dicker, and W. S. El-Deiry Direct Repression of FLIP Expression by c-myc Is a Major Determinant of TRAIL Sensitivity Mol. Cell. Biol., October 1, 2004; 24(19): 8541 - 8555. [Abstract] [Full Text] [PDF]

				S.-H. Kim, K. Kim, J. G. Kwagh, D. T. Dicker, M. Herlyn, A. K. Rustgi, Y. Chen, and W. S. El-Deiry Death Induction by Recombinant Native TRAIL and Its Prevention by a Caspase 9 Inhibitor in Primary Human Esophageal Epithelial Cells J. Biol. Chem., September 17, 2004; 279(38): 40044 - 40052. [Abstract] [Full Text] [PDF]

				G. Kuznetsov, M. J. Towle, H. Cheng, T. Kawamura, K. TenDyke, D. Liu, Y. Kishi, M. J. Yu, and B. A. Littlefield Induction of Morphological and Biochemical Apoptosis following Prolonged Mitotic Blockage by Halichondrin B Macrocyclic Ketone Analog E7389 Cancer Res., August 15, 2004; 64(16): 5760 - 5766. [Abstract] [Full Text] [PDF]

				S. Wang and W. S. El-Deiry Requirement of p53 targets in chemosensitization of colonic carcinoma to death ligand therapy PNAS, December 9, 2003; 100(25): 15095 - 15100. [Abstract] [Full Text] [PDF]

				D. J. Buchsbaum, T. Zhou, W. E. Grizzle, P. G. Oliver, C. J. Hammond, S. Zhang, M. Carpenter, and A. F. LoBuglio Antitumor Efficacy of TRA-8 Anti-DR5 Monoclonal Antibody Alone or in Combination with Chemotherapy and/or Radiation Therapy in a Human Breast Cancer Model Clin. Cancer Res., September 1, 2003; 9(10): 3731 - 3741. [Abstract] [Full Text] [PDF]

				S. Armeanu, U. M. Lauer, I. Smirnow, M. Schenk, T. S. Weiss, M. Gregor, and M. Bitzer Adenoviral Gene Transfer of Tumor Necrosis Factor-related Apoptosis-Inducing Ligand Overcomes an Impaired Response of Hepatoma Cells but Causes Severe Apoptosis in Primary Human Hepatocytes Cancer Res., May 15, 2003; 63(10): 2369 - 2372. [Abstract] [Full Text] [PDF]

				W. Yu, B. G. Sanders, and K. Kline RRR-{alpha}-Tocopheryl Succinate-induced Apoptosis of Human Breast Cancer Cells Involves Bax Translocation to Mitochondria Cancer Res., May 15, 2003; 63(10): 2483 - 2491. [Abstract] [Full Text] [PDF]

				D.-M. Kim, S.-Y. Koo, K. Jeon, M. H. Kim, J. Lee, C. Y. Hong, and S. Jeong Rapid Induction of Apoptosis by Combination of Flavopiridol and Tumor Necrosis Factor (TNF)-{alpha} or TNF-related Apoptosis-inducing Ligand in Human Cancer Cell Lines Cancer Res., February 1, 2003; 63(3): 621 - 626. [Abstract] [Full Text] [PDF]

				H. Klonowski-Stumpe, R. Fischer, R. Reinehr, R. Luthen, and D. Haussinger Apoptosis in activated rat pancreatic stellate cells Am J Physiol Gastrointest Liver Physiol, September 1, 2002; 283(3): G819 - G826. [Abstract] [Full Text] [PDF]

				I. Y. Kim, D. H. Seong, B.-C. Kim, D. K. Lee, A. T. Remaley, F. Leach, R. A. Morton, and S.-J. Kim Raloxifene, a Selective Estrogen Receptor Modulator, Induces Apoptosis in Androgen-responsive Human Prostate Cancer Cell Line LNCaP through an Androgen-independent Pathway Cancer Res., July 1, 2002; 62(13): 3649 - 3653. [Abstract] [Full Text] [PDF]

				C. Kumar-Sinha, S. Varambally, A. Sreekumar, and A. M. Chinnaiyan Molecular Cross-talk between the TRAIL and Interferon Signaling Pathways J. Biol. Chem., January 4, 2002; 277(1): 575 - 585. [Abstract] [Full Text]

				P. Secchiero, A. Gonelli, C. Celeghini, P. Mirandola, L. Guidotti, G. Visani, S. Capitani, and G. Zauli Activation of the nitric oxide synthase pathway represents a key component of tumor necrosis factor-related apoptosis-inducing ligand-mediated cytotoxicity on hematologic malignancies Blood, October 1, 2001; 98(7): 2220 - 2228. [Abstract] [Full Text] [PDF]

				L. Qiao, E. Studer, K. Leach, R. McKinstry, S. Gupta, R. Decker, R. Kukreja, K. Valerie, P. Nagarkatti, W. E. Deiry, et al. Deoxycholic Acid (DCA) Causes Ligand-independent Activation of Epidermal Growth Factor Receptor (EGFR) and FAS Receptor in Primary Hepatocytes: Inhibition of EGFR/Mitogen-activated Protein Kinase-Signaling Module Enhances DCA-induced Apoptosis Mol. Biol. Cell, September 1, 2001; 12(9): 2629 - 2645. [Abstract] [Full Text] [PDF]

				T. F. Burns and W. S. El-Deiry Identification of Inhibitors of TRAIL-induced Death (ITIDs) in the TRAIL-sensitive Colon Carcinoma Cell Line SW480 Using a Genetic Approach J. Biol. Chem., October 5, 2001; 276(41): 37879 - 37886. [Abstract] [Full Text] [PDF]