Preoperative chemotherapy with irinotecan is associated with the development of chemotherapy-associated steatohepatitis (CASH). Epidemiological studies have shown that irinotecan-treated obese patients have a higher risk to develop CASH and subsequent related mortality. However, the underlying mechanisms of these aggravated effects of irinotecan in hepatic steatosis are still unknown.
The aim of this study was to establish an in vitro model of irinotecan-induced CASH in normal and steatotic hepatocytes and to unravel the molecular mechanisms of this phenomenon.
Methods and Results: Initially, we determined the dose-range in which neither irinotecan nor free fatty acid (FFA) treatment affected the viability primary human hepatocytes or human hepatoma cells. In this dose-range irinotecan (up to 50µM) and FFA (up to 0.2 mM) dose-dependently induced cellular lipid accumulation as assessed by oil-red O staining and analysis of cellular triglyceride levels. Moreover, irinotecan as well as FFA induced beta-oxidation, formation of reactive oxygen species (ROS), ERK-activation and the expression of pro-inflammatory genes (IL-8 and ICAM-1). Interestingly, all these pathological factors were further synergistically induced by costimulation with irinotecan and FFA.
Conclusion: Our novel in vitro model allows the investigation of isolated or joint effects of irinotecan and FFA on hepatocellular lipid metabolisms and inflammatory signaling. Our present findings indicate oxidative stress and ERK-activation as critical mechanisms of irinotecan-induced CASH. Noteworthy, pathological irinotecan effects became synergistically accentuated in steatotic hepatocytes, which may explain the higher frequency and the severity of CASH in obese patients.
