Autophagy impairment and ERK and p38 activation are central mediators of irinotecan-induced steatohepatitis

Treatment with irinotecan is associated with the development of chemotherapy-associated steatohepatitis (CASH), which significantly increases the risk of perioperative morbidity and mortality.

The aim of this study was to unravel the molecular mechanisms of this phenomenon.

Methods: Mechanisms of irinotecan induced steatohepatitis were studied in primary human hepatocytes in vitro, irinotecan treated mice and liver specimens from irinotecan-treated patients.

Results: Irinotecan dose-dependently induced accumulation of free fatty acids and triglycerides, formation of reactive oxygen species (ROS), pro-inflammatory gene expression as well as activation of MAPK ERK and p38 in hepatocytes. Moreover, irinotecan treatment significantly inhibited ATG7 and VSP34 expression accompanied by lower LC3II/I ratio and increased p62 protein levels indicative of reduced autophagy. ROS-scavengers and ERK-inhibition almost completely abrogated irinotecan-induced inflammatory gene expression but had only a slight effect on lipid accumulation. However, p38 inhibition diminished irinotecan effects on autophagy and steatosis. Also in mice irinotecan treatment (50 mg/kg) induced significant hepatic steatosis and inflammation accompanied by MAPK-activation and reduced authophagy. This was confirmed in livers samples of irinotecan-treated patients, which revealed a significant induction of ERK- and p38-activation and a marked reduction of markers of autophagy in comparison to normal liver tissue. Of note, pretreatment with multi-tyrosine kinase inhibitor sorafenib inhibited the irinotecan induced inflammatory response in hepatocytes in vitro as well as in irinotecan treated mice.

Conclusion: ERK and p38 activation are critical mediators of irinotecan-induced steatohepatitis. (Pre)treatment with sorafenib appears as therapeutic option for prevention of CASH.

Corresponding author: Hellerbrand, Claus

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