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Zhang X, Frank AC, Gille CM, et al. Altered regulation of extrinsic apoptosis pathway in HCV-infected HCC cells enhances susceptibility to mapatumumab-induced apoptosis. Hepatol Res. 2009;39(12):1178-89doi: 10.1111/j.1872-034X.2009.00568.x.
Zhang, X., Frank, A. C., Gille, C. M., Daucher, M., Kabat, J., Becker, S., Lempicki, R. A., Cortez, K. J., Polis, M. A., Subramanian, G. M., & Kottilil, S. (2009). Altered regulation of extrinsic apoptosis pathway in HCV-infected HCC cells enhances susceptibility to mapatumumab-induced apoptosis. Hepatology research : the official journal of the Japan Society of Hepatology, 39(12), 1178-89. https://doi.org/10.1111/j.1872-034X.2009.00568.x
Zhang, Xiaozhen, et al. "Altered regulation of extrinsic apoptosis pathway in HCV-infected HCC cells enhances susceptibility to mapatumumab-induced apoptosis." Hepatology research : the official journal of the Japan Society of Hepatology vol. 39,12 (2009): 1178-89. doi: https://doi.org/10.1111/j.1872-034X.2009.00568.x
Zhang X, Frank AC, Gille CM, Daucher M, Kabat J, Becker S, Lempicki RA, Cortez KJ, Polis MA, Subramanian GM, Kottilil S. Altered regulation of extrinsic apoptosis pathway in HCV-infected HCC cells enhances susceptibility to mapatumumab-induced apoptosis. Hepatol Res. 2009 Dec;39(12):1178-89. doi: 10.1111/j.1872-034X.2009.00568.x. Epub 2009 Sep 25. PMID: 19788693; PMCID: PMC7886285.
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Hepatol Res. 2009 Dec;39(12):1178-89. doi: 10.1111/j.1872-034X.2009.00568.x. Epub 2009 Sep 25.

Altered regulation of extrinsic apoptosis pathway in HCV-infected HCC cells enhances susceptibility to mapatumumab-induced apoptosis.

Hepatology research : the official journal of the Japan Society of Hepatology

Xiaozhen Zhang, Astrid C Frank, Christine M Gille, Marybeth Daucher, Juraj Kabat, Steven Becker, Richard A Lempicki, Karoll J Cortez, Michael A Polis, G Mani Subramanian, Shyam Kottilil

Affiliations

  1. LIR, NIAID, NIH, DHHS, Bethesda, USA.

PMID: 19788693 PMCID: PMC7886285 DOI: 10.1111/j.1872-034X.2009.00568.x

Abstract

BACKGROUND: Hepatitis C virus (HCV)-infected patients, including those co-infected with human immunodeficiency virus (HIV), are at increased risk of developing hepatocellular carcinoma (HCC). We evaluated the ability of agonistic human monoclonal antibodies to tumor necrosis factor-related apoptosis inducing ligand (TRAIL) receptors, mapatumumab and lexatumumab, respectively, to induce TRAIL-receptor mediated apoptosis (TRMA) in HCC (HCV-infected and -uninfected) cells and in peripheral blood cells (HIV-infected and -uninfected).

METHODS: Susceptibility to antibody-mediated TRMA was measured by caspase 3/7 activity and by confocal microscopy. Surface expression of receptors on HCV-uninfected and -infected Huh7.5 cells was measured by flow cytometry and confocal microscopy. Inhibitor of Apoptosis Protein (IAP) RNA levels were quantified by RT-PCR. DNA Microarray was performed using RNA isolated from Huh7.5 cells (HCV-infected and uninfected) using Affymetrix U133A chips.

RESULTS: Mapatumumab preferentially induces TRMA of HCV-infected Huh7.5 cells by binding to TRAIL-R1. Higher basal expression of TRAIL-R2 compared to that of TRAIL-R1 on HCV-uninfected Huh7.5 cells were observed. Lexatumumab induces TRMA of both HCV-infected and -uninfected cells by binding to TRAIL-R2. IFN-alpha has minimal effect on mapatumumab- and lexatumumab-induced TRMA. HCV infection of Huh7.5 cells up-regulates TRAIL-R1 expression and X-linked Inhibitor of apoptosis protein and survivin gene expression. Neither antibody had a pro-apoptotic effect on PBMCs from patients with HIV infection ex vivo.

CONCLUSION: Both mapatumumab and lexatumumab are excellent candidates for therapy of HCC. HCV infection of Huh7.5 cells selectively up-regulates TRAIL-R1 receptor, associated with increased susceptibility to mapatumumab-mediated TRMA. HCV infection up-regulated IAP genes, offering promise for future combination therapy using TRAIL agonists and IAP inhibitors.

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