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  2. Bim- and Bax-mediated mitochondrial pathway dominates abivertinib-induced apoptosis and ferroptosis

Bim- and Bax-mediated mitochondrial pathway dominates abivertinib-induced apoptosis and ferroptosis

  • Free Radic Biol Med. 2022 Feb 20;180:198-209. doi: 10.1016/j.freeradbiomed.2022.01.013.
Qiling Tang 1 Hongce Chen 1 Zihao Mai 1 Han Sun 1 LingJun Xu 2 Guihao Wu 2 Zhuang Tu 1 Xuecheng Cheng 1 Xiaoping Wang 3 Tongsheng Chen 4
Affiliations

Affiliations

  • 1 MOE Key Laboratory of Laser Life Science & Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China.
  • 2 Department of Pain Management, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, China.
  • 3 Department of Pain Management, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, China. Electronic address: txp2938@jnu.edu.cn.
  • 4 MOE Key Laboratory of Laser Life Science & Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China; SCNU Qingyuan Institute of Science and Technology Innovation Co., Ltd., South China Normal University, Qingyuan, 511500, China. Electronic address: chentsh@scnu.edu.cn.
Abstract

Abivertinib (AC) is a novel epidermal growth factor receptor tyrosine kinase inhibitor with highly efficient antitumor activity. Here, we report the capacity of AC to induce both Reactive Oxygen Species (ROS)-dependent Apoptosis and Ferroptosis in tumor cells. Our data showed that AC induced iron- and ROS-dependent cytotoxicity in MCF7, HeLa, and A549 cell lines. Flow cytometry analyses showed that AC increased ferrous ions and ROS and induced Ferroptosis in MCF-7 cells. This was confirmed by the findings that AC not only decreased solute carrier family 7 member 11 (SLC7A11) and Glutathione Peroxidase 4 (GPX4) expression but also induced iron- and ROS-dependent aggrandized lipid ROS accumulation and plasma membrane damage. Meanwhile, AC induced nuclear condensation and increased ROS-dependent phosphatidylserine (PS) eversion, Caspase-3 activation, and cleaved-PARP expression, suggesting that AC also induced ROS-dependent Apoptosis. In addition, mitochondrial depletion significantly inhibited AC-induced cytotoxicity, including Ferroptosis and Apoptosis, indicating the key role of mitochondria in AC-induced Ferroptosis and Apoptosis. Moreover, knockout of Bim or Bax not only remarkably inhibited AC-induced Apoptosis, but also markedly inhibited AC-triggered downregulation of SLC711 and GPX4, accumulation of lipid ROS, and damage to the plasma membrane. This suggests that Bim and Bax act upstream of SLC7A11 and GPX4 to mediate AC-induced Ferroptosis. Collectively, AC induces Ferroptosis and Apoptosis, in which the Bim- and Bax-mediated mitochondrial pathways play a dominant role.

Keywords

Abivertinib; Apoptosis; Bax; Bim; Ferroptosis; Mitochondria.

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