Anticancer effects of Cryptotanshinone against lung cancer cells through ferroptosis

Abstract

Lung cancer is considered as one of the most commonly diagnosed malignancies disturbing public health with high rate of mortality worldwide. Cryptotanshinone (CTN), a natural chinese quinoid diterpene isolated from the roots of a herb Salvia miltiorrhiza, has been shown to have anti-tumor properties by inducing apoptosis. CTN inhibits lung cancer invasion, lung tumorigenesis and proliferation of cancer cells. Here, we report a novel mode of death other than apoptosis induced by CTN. We showed that CNT induces caspase-dependent death as well as non-apoptotic ROS-mediated death. Cell survival assay showed the short-term effects of CTN on cell survival of cancer cells. To better understand the CTN-induced mode of death, lung cancer cells titrated with CTN and caspase activity, ROS generation and lipid peroxidation was measured. The EC50 for ROS generation and lipid peroxidation was massively lower than that of caspase activation. CTN-treated cells showed higher iron load and reduced GPx4 activity. In addition, Cytoglobin was upregulated and ferroportin was downregulated in response to CTN. We also showed that CTN induced the iron-dependent lipid peroxidation by blocking the transferrin receptors using anti-TfR antibody. Caspase-3 inhibitor, QVD-OPh, failed to prevent CTN-induced death in lung cancer cell lines. All our data suggests that CTN induces primarily ferroptosis in lung cancer cells although caspase-dependent cell death also explains ̴20% of the death.

Keywords

• Ferroptosis
• Caspase-dependent death
• Lung cancer
• Cryptotanshinone
• ROS generation