1. Academic Validation
  2. MgIG exerts therapeutic effects on crizotinib-induced hepatotoxicity by limiting ROS-mediated autophagy and pyroptosis

MgIG exerts therapeutic effects on crizotinib-induced hepatotoxicity by limiting ROS-mediated autophagy and pyroptosis

  • J Cell Mol Med. 2022 Aug;26(16):4492-4505. doi: 10.1111/jcmm.17474.
Min Li 1 Chenxiang Wang 1 Zheng Yu 1 Qin Lan 1 Shaolin Xu 1 Zhongjiang Ye 1 Rongqi Li 1 Lili Ying 2 Xiuhua Zhang 3 Ziye Zhou 3
Affiliations

Affiliations

  • 1 Department of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
  • 2 Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
  • 3 Clinical Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Abstract

Crizotinib (CRIZO) has been widely employed to treat non-small-cell lung Cancer. However, hepatic inflammatory injury is the major toxicity of CRIZO, which limits its clinical application, and the underlying mechanism of CRIZO-induced hepatotoxicity has not been fully explored. Herein, we used cell counting kit-8 assay and flow cytometry to detect CRIZO-induced cytotoxicity on human hepatocytes (HL-7702). CRIZO significantly reduced the survival rate of hepatocytes in a dose-dependent manner. Furthermore, the Reactive Oxygen Species (ROS) assay kit showed that CRIZO treatment strongly increased the level of ROS. In addition, CRIZO treatment caused the appearance of balloon-like bubbles and autophagosomes in HL-7702 cells. Subsequently, Western blotting, quantitative Real-Time PCR and ELISA assays revealed that ROS-mediated Pyroptosis and Autophagy contributed to CRIZO-induced hepatic injury. Based on the role of ROS in CRIZO-induced hepatotoxicity, magnesium isoglycyrrhizinate (MgIG) was used as an intervention drug. MgIG activated the Nrf2/HO-1 signalling pathway and reduced ROS level. Additionally, MgIG suppressed hepatic inflammation by inhibiting NF-κB activity, thereby reducing CRIZO-induced hepatotoxicity. In conclusion, CRIZO promoted Autophagy activation and Pyroptosis via the accumulation of ROS in HL-7702 cells. MgIG exerts therapeutic effects on CRIZO-induced hepatotoxicity by decreasing the level of ROS.

Keywords

autophagy; crizotinib; hepatotoxicity; magnesium isoglycyrrhizinate; pyroptosis; reactive oxygen species.

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