Cisplatin synergizes with PRLX93936 to induce ferroptosis in non-small cell lung cancer cells

Ferroptosis is a newly identified type of regulated cell death that is affected by lipid peroxidation and reactive oxygen species (ROS). In the current study, we showed that cisplatin and PRLX93936, an analog of erastin that has been tested in clinical trials, demonstrated synergistic effects against non-small cell lung cancer (NSCLC) cells. Cotreatment with cisplatin and PRLX93936 induced ferroptosis, as evidenced by the upregulation of ROS, lipid peroxidation and Fe2+. Further investigation revealed that cotreatment with cisplatin and PRLX93936 inhibited GPX4 and that overexpression of GPX4 prevented cell death. Moreover, the Nrf2/Keap1 pathway also regulated the sensitivity to cisplatin and PRLX93936 in NSCLC cells. Nrf2 silencing increased this sensitivity while inhibition of Keap1 attenuated it. Overall, our data reveal a new effective treatment for NSCLC by synergizing cisplatin and PRLX93936 to induce ferroptosis. (c) 2021 Elsevier Inc. All rights reserved.

Automated summary

Synergistic induction of ferroptosis by cisplatin and PRLX93936 is a promising new therapeutic strategy for non-small cell lung cancer (NSCLC), involving upregulation of ROS, lipid peroxidation, Fe2+, inhibition of GPX4, and modulation of the Nrf2/Keap1 pathway.