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

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.

Targeted Pyroptosis Is a Potential Therapeutic Strategy for Cancer

“…Miltirone, a derivative of phenanthrene-quinone isolated from the root of Salvia miltiorrhiza Bunge, promotes the accumulation of intracellular ROS and induces the GSDME-dependent pyroptosis of HCC [ 158 ]. Likewise, crizotinib (CRIZO) increases ROS in HL-7702 cells to promote pyroptosis and inhibit HCC [ 159 ]. Furthermore, CRIZO induces apoptosis and suppresses the proliferation of HCC cells by inhibiting the phosphorylation of the anaplastic lymphoma kinase (ALK), Akt, and ERK [ 160 ].…”

“…Accumulates the ROS in cancer cells [159] Inhibits the activation of ALK, Akt, and ERK [160] Cannabidiol Regulates the caspase-3/GSDME pathway [161] Arrests the G0/G1 phase in the cell cycle and induces mitochondrial-dependent apoptosis [162] Metformin Promots FOXO3 expression and activates NLRP3 transcription [163] Regulates AMPK/p53/p38/miR-23a/FOXA1 pathway, regulates PI3K/Akt/ mTOR pathway, and downregulates Bcl-2 [164][165][166][167] Curcumin Increases the generation and accumulation of ROS [168] Promotes the P53-dependent apoptosis and inhibits the PI3K/Akt/GSK-3β…”

Successful Retreatment with Crizotinib After Crizotinib-Induced Liver Failure in ALK-Positive Advanced Lung Adenocarcinoma: A Case Report

“… 3 Previous studies have shown that crizotinib activates the oxidative stress response and stimulates hepatocyte mitochondrial apoptosis through reactive oxygen species (ROS) and the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in human hepatocytes 10 and that accumulation of ROS promotes pyroptosis and excessive autophagy. 11 Further studies are needed to clarify the mechanism of crizotinib-induced hepatotoxicity.…”

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

“…GA is widely considered one of the main active substances of licorice and possesses a strong liver protective effect ( Yang et al, 2017 ; Wu et al, 2021b ). Li et al (2022) found that magnesium isoglycyrrhizinate exerts therapeutic effects on crizotinib-induced hepatotoxicity by decreasing the level of ROS. Xu et al (2022) also reported that GA significantly mitigated Sunitinib-induced cardiotoxicity.…”