PI3K/AKT inhibitors aggravate death receptor-mediated hepatocyte apoptosis and liver injury.

Abstract

The PI3K/AKT signaling pathway is one of the most frequently activated signaling networks in human cancers and has become a valuable target in anticancer therapy. However, accumulating reports suggest that adverse effects such as severe liver injury and inflammation may accompany treatment with pan-PI3K and pan-AKT inhibitors. Our prior work has demonstrated that activation of the PI3K/AKT pathway has a protective role in Fas- or TNFα-induced hepatocytic cell death and liver injury. We postulated that PI3K or AKT inhibitors may exacerbate liver damage via the death factor-mediated hepatocyte apoptosis. In this study we found that several drugs targeting PI3K/AKT either clinically used or in clinical trials sensitized hepatocytes to agonistic anti-Fas antibody- or TNFα-induced apoptosis and significantly shortened the survival of mice in in vivo liver damage models. The PI3K or AKT inhibitors promoted Fas aggregation, inhibited the expression of cellular FLICE-inhibitory protein S and L (FLIPL/S), and enhanced procaspase-8 activation. Conversely, cotreatment with the AKT specific activator SC79 reversed these effects. Taken together, these findings suggest that PI3K or AKT inhibitors may render hepatocytes hypersensitive to Fas- or TNFα-induced apoptosis and liver injury.

• Authors: Wei Liu, Zhen-Tang Jing, Chao-Rong Xue, Shu-Xiang Wu, Wan-Nan Chen, Xin-Jian Lin, Xu Lin
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 381 Pg. 114729 (10 15 2019) ISSN: 1096-0333 [Electronic] United States
• PMID: 31445927 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Aminopyridines
• Antibodies
• CASP8 and FADD-Like Apoptosis Regulating Protein
• CH-11 anti-fas antibody, human
• Imidazoles
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors
• Purines
• Quinazolinones
• TNF protein, human
• Tumor Necrosis Factor-alpha
• Proto-Oncogene Proteins c-akt
• Miransertib
• idelalisib

Topics

• Aminopyridines (toxicity)
• Animals
• Antibodies (toxicity)
• Apoptosis (drug effects)
• CASP8 and FADD-Like Apoptosis Regulating Protein (metabolism)
• Chemical and Drug Induced Liver Injury (metabolism, pathology)
• Hep G2 Cells
• Hepatocytes (drug effects, metabolism)
• Humans
• Imidazoles (toxicity)
• Liver (drug effects, pathology)
• Male
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Phosphoinositide-3 Kinase Inhibitors (toxicity)
• Protein Kinase Inhibitors (toxicity)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors)
• Purines (toxicity)
• Quinazolinones (toxicity)
• Tumor Necrosis Factor-alpha (toxicity)