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

Toxicol Appl Pharmacol. 2019 Oct 15:381:114729. doi: 10.1016/j.taap.2019.114729. Epub 2019 Aug 22.

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.

Keywords: AKT inhibition; Death receptor; Hepatocytic apoptosis; Liver injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopyridines / toxicity
  • Animals
  • Antibodies / toxicity
  • Apoptosis / drug effects*
  • CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism
  • Chemical and Drug Induced Liver Injury* / metabolism
  • Chemical and Drug Induced Liver Injury* / pathology
  • Hep G2 Cells
  • Hepatocytes / drug effects*
  • Hepatocytes / metabolism
  • Humans
  • Imidazoles / toxicity
  • Liver / drug effects
  • Liver / 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

Substances

  • 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