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Sunitinib induced hepatotoxicity in L02 cells via ROS-MAPKs signaling pathway

Ting-Li Tang1, Yan Yang1, Lin Guo1

  • 1Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China.

Frontiers in Pharmacology
|November 17, 2022
PubMed

Insights

Sunitinib causes liver damage by triggering apoptosis and autophagy via ROS/MAPKs signaling. Glycyrrhetinic acid (GA) protects against this hepatotoxicity by inhibiting these pathways.

Area of Science:

  • Hepatology
  • Pharmacology
  • Molecular Biology

Background:

  • Sunitinib, a tyrosine kinase inhibitor, shows anticancer efficacy but poses a risk of fatal hepatotoxicity.
  • Understanding the mechanisms of Sunitinib-induced liver injury is crucial for patient safety.

Purpose of the Study:

  • To investigate the mechanism underlying Sunitinib-induced hepatotoxicity.
  • To evaluate the protective potential of glycyrrhetinic acid (GA) against Sunitinib-induced liver damage.

Main Methods:

  • Assessed Sunitinib's effects on human normal hepatocytes (L02 cells), including cell viability and liver enzyme release (ALT, AST, LDH).
  • Utilized chloroquine (CQ) and Z-VAD-FMK to characterize cell death pathways (apoptosis and autophagy).
  • Investigated the role of reactive oxygen species (ROS) and mitogen-activated protein kinases (MAPKs) signaling, using inhibitors like SP600125 and SB203580, and N-acetylcysteine (NAC).

Main Results:

  • Sunitinib significantly reduced L02 cell survival, increased liver enzymes, and induced apoptosis and autophagy.
  • Sunitinib exposure led to excessive ROS generation, activating the MAPKs pathway.
  • Inhibiting JNK and p38 kinases blocked Sunitinib-induced apoptosis and autophagy, respectively.
  • ROS inhibition with NAC ameliorated Sunitinib's effects on MAPKs.
  • GA treatment alleviated Sunitinib-induced cell damage by inhibiting apoptosis and autophagy.

Conclusions:

  • The ROS/MAPKs signaling pathway is implicated in Sunitinib-induced hepatotoxicity.
  • Glycyrrhetinic acid (GA) demonstrates a protective effect against Sunitinib-induced liver injury, suggesting its potential as a preventive strategy.
Keywords:
MAPKSunitinibapoptosisautophagyglycyrrhetinic acidhepatotoxicityoxidative stress

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