2. Academic Validation
  3. Crizotinib induces pulmonary toxicity by blocking autophagy flux in alveolar epithelial cells

Crizotinib induces pulmonary toxicity by blocking autophagy flux in alveolar epithelial cells

  • Biochem Pharmacol. 2023 Sep:215:115636. doi: 10.1016/j.bcp.2023.115636.
Yuanteng Zhang 1,  Zizheng Gao 2,  Zezheng Pan 2,  Huangxi Fu 2,  Feng Jiang 2,  Hao Yan 2,  Bo Yang 3,  Qiaojun He 4,  Peihua Luo 5,  Zhifei Xu 6,  Xiaochun Yang 7
Affiliations

Affiliations

  • 1 Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China; Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China.
  • 2 Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China.
  • 3 Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China.
  • 4 Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou 310018, Zhejiang, China; Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang, China.
  • 5 Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China; Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 6 Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China. Electronic address: [email protected].
  • 7 Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China. Electronic address: [email protected].
PMID: 37290598 DOI: 10.1016/j.bcp.2023.115636
Abstract

Crizotinib is the first-line drug for advanced non-small cell lung Cancer with the abnormal expression of anaplastic lymphoma kinase gene. Severe, life-threatening, or fatal interstitial lung disease/pneumonia has been reported in patients treated with crizotinib. The clinical benefit of crizotinib is limited by its pulmonary toxicity, but the underlying mechanisms have not been adequately studied, and protective strategies are relatively scarce. Here, we established an in vivo mouse model in which crizotinib was continuously administered to C57BL/6 at 100 mg/kg/day for 6 weeks and verified that crizotinib induced interstitial lung disease in vivo, which was consistent with the clinical observations. We further treated BEAS-2B and TC-1 cells, the alveolar epithelial cell lines, with crizotinib and found the increased Apoptosis rate. We proved that crizotinib-blocked autophagic flux caused Apoptosis of the alveolar epithelial cells and then promoted the recruitment of immune cells, suggesting that limited Autophagy activity was the key reason for pulmonary injury and inflammation caused by crizotinib. Subsequently, we found that metformin could reduce the macrophage recruitment and pulmonary fibrosis by recovering the Autophagy flux, thereby ameliorating impaired lung function caused by crizotinib. In conclusion, our study revealed the mechanism of crizotinib-induced Apoptosis of alveolar epithelial cells and activation of inflammation during the onset of pulmonary toxicity and provided a promising therapeutic strategy for the treatment of crizotinib-induced pulmonary toxicity.

Keywords

Apoptosis; Autophagy; Crizotinib; Metformin; Pulmonary toxicity.

Figures
Products