New Study Questions the Safety of Caspase Inhibitors for the Treatment of Liver Disease

Although effective in preventing apoptosis, caspase inhibitors may lead to necrotic cell death, according to a report in The American Journal of Pathology

Philadelphia, PA, September 9, 2016

Many acute and chronic liver diseases, including alcoholic hepatitis, result from apoptotic (programmed) cell death mediated by the enzyme caspase. Caspase inhibitors have therapeutic potential to treat and prevent apoptosis-mediated liver injury, and some are currently in clinical trials. However, a new study published in The American Journal of Pathology raises serious safety concerns regarding the clinical use of caspase inhibitors by demonstrating the occurrence of delayed-onset necrotic, non–caspase-dependent liver cell injury.

“Our data suggest that one should be cautious in treating apoptotic cell death just with caspase inhibitors as, despite their efficacy in preventing apoptosis, these inhibitors may trigger necrotic cell death,” noted Wen-Xing Ding, PhD, Associate Professor, Department of Pharmacology, Toxicology and Therapeutics of The University of Kansas Medical Center (Kansas City). “The failure to protect against endotoxin-induced liver injury raises concerns on the clinical use of caspase inhibitors.”

Liver health and injury depend upon a complex interaction between physiological processes affecting cell survival and death. “A liver cell can die in many different ways, but caspase-dependent apoptosis and caspase-independent necrosis are the predominant cell death pathways that contribute to liver injury,” explained Dr. Ding.

Researchers investigated endotoxin and tumor necrosis factor (TNF)-α–induced cell death in cultured hepatocytes and in mouse livers, similar to certain acute human hepatitis and liver failure. Apoptotic cell death is associated with many human liver diseases such as alcoholic hepatitis and nonalcoholic steatohepatitis (NASH). In this study, the researchers found that blocking apoptosis can trigger alternative necrotic cell death.

Inhibition of caspases by ZVAD switched TNF/ActD-induced apoptosis to necrosis

Inhibition of caspases by ZVAD switched TNF/ActD-induced apoptosis to necrosis.

Apoptotic cell death was caused by TNF-α/actinomycin D (ActD) after 24 hours in primary cultured mouse hepatocytes. Adding the caspase inhibitor ZVAD blocked early apoptotic cell death but revealed the presence of necrotic cell death at 48 hours. Researchers also found that the TNF-ZVAD–induced necrosis was not due to autophagy. More importantly, researchers also confirmed these cell culture findings in an endotoxin-induced liver injury mouse model.  Although blocking caspase protected against endotoxin-induced liver injury at an early time point (six hours), this protection was lost after 24 hours due to the switch of liver cell apoptosis to necrosis.

According to Dr. Ding, “We still don’t know the mechanism underlying caspase inhibitor–induced necrosis of the liver. Nevertheless, our findings raised concerns about the safety of the current ongoing clinical trials using the caspase inhibitors.”

This study provides important insights on the inter-relationship of different types of cell death: apoptosis, necrosis, and autophagy. Apoptosis refers to the death of apoptotic cells that still maintain relative cell membrane integrity without inflammation under physiological and pathological conditions. Apoptosis often occurs during an organism’s growth or development. Necrosis refers to the cell death of necrotic cells characterized by rupture of plasma membranes and release of intracellular contents, which are associated with inflammation. Necrosis often occurs under harsh conditions, severe tissues injury, or organ blood supply failure. Autophagy is a conserved lysosomal degradation pathway that regulates homeostasis of proteins and organelles in hepatocytes and plays a critical role in normal liver physiology and liver diseases. However, under certain conditions, excessive activated autophagy may also cause cell death.

---

Notes for editors
The article is "Caspase inhibition prevents tumor necrosis factor-α–induced apoptosis and promotes necrotic cell death in mouse hepatocytes in vivo and in vitro," by Hong-Min Ni, Mitchell R. McGill, Xiaojuan Chao, Benjamin L. Woolbright, Hartmut Jaeschke and Wen-Xing Ding (doi:10.1016/j.ajpath.2016.06.009). It appears in The American Journal of Pathology, volume 186, issue 10 (2016), published by Elsevier.

Copies of this paper are available to credentialed journalists upon request; please contact Eileen Leahy at +1 732-238-3628 or jdsmedia@elsevier.com. Journalists wishing to interview the authors should contact Wen-Xing Ding at +1 913-588-9813 or wxding@kumc.edu.

This research was supported in part by the NIAAA funds R01 AA020518 (W.X.D.), R01 DK102142 (W.X.D. and H.J.), National Center for Research Resources P20RR021940 (H.J.), the National Institute of General Medical Sciences P20 GM103549 (H.J.), the National Institutes of Environmental Health Sciences T32 ES007079 (M.R.M. and B.L.W.), an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health (P20 GM103418), and an award received in an internal Lied basic science grant program of the KUMC Research Institute, with support from a NIH Clinical and Translational Science Award grant (UL1TR000001, formerly UL1RR033179). The EMRL is supported in part, by NIH COBRE grant 9P20GM104936.

About The American Journal of Pathology
The American Journal of Pathology, official journal of the American Society for Investigative Pathology, seeks to publish high-quality, original papers on the cellular and molecular biology of disease. The editors accept manuscripts that advance basic and translational knowledge of the pathogenesis, classification, diagnosis, and mechanisms of disease, without preference for a specific analytic method. High priority is given to studies on human disease and relevant experimental models using cellular, molecular, animal, biological, chemical, and immunological approaches in conjunction with morphology. The leading global forum for reporting quality original research on cellular and molecular mechanisms of disease, The American Journal of Pathology is the most highly cited journal in Pathology – close to 40,000 cites in 2015 – with an Impact Factor of 4.206 and Eigenfactor of 0.05638 according to the 2015 Journal Citation Reports®, Thomson Reuters, 2016, and an h-index of 228 according to the 2015 SCImago Journal and Country Rank. ajp.amjpathol.org

About Elsevier
Elsevier is a world-leading provider of information solutions that enhance the performance of science, health, and technology professionals, empowering them to make better decisions, deliver better care, and sometimes make groundbreaking discoveries that advance the boundaries of knowledge and human progress. Elsevier provides web-based, digital solutions — among them ScienceDirect, Scopus, Research Intelligence and ClinicalKey— and publishes over 2,500 journals, including The Lancet and Cell, and more than 35,000 book titles, including a number of iconic reference works. Elsevier is part of RELX Group, a world-leading provider of information and analytics for professional and business customers across industries. www.elsevier.com

Media contacts
Eileen Leahy
Elsevier
+1 732-238-3628
jdsmedia@elsevier.com

Dr. Chhavi Chauhan
Scientific Editor, The American Journal of Pathology
+1 301-634-7953
cchauhan@asip.org