Role of Erastin in Ferroptosis-Induced Cell Death in Human Cancer Cells

2024 | Vol-1 | Issue-1 | Date of Submission: 25 October 2024 | Date of Publication: 5 November 2024

Abstract

Erastin (ER) mediates ferroptosis through a variety of mechanisms, including the cystine-glutamate transport receptor (system XC?), the voltage-dependent anion channel (VDAC), and p53. Ferroptosis is characterized by accumulation of reactive oxygen species (ROS) within the cell, leading to an iron-dependent oxidative stress-mediated cell death. ER also enhances the sensitivity of chemotherapy and radiotherapy, suggesting a promising future in cancer therapy. Our recent studies showed that NCX4040, a nitric oxide donor, is cytotoxic to human tumors, including ovarian and colon cells. We investigated ferroptosis-dependent mechanism(s) of cytotoxicity of NCX4040 in HT-29 and K-RAS mutant HCT116 colon cell lines. We found that NCX4040 generated ROS in CRC cells without any depletion of cellular GSH. Combinations of NCX4040 with ER significantly enhanced CRC death. In contrast, Ferrostatin-1, an inhibitor of ferroptosis, significantly inhibited NCX404-induced cell death. Treatment of CRC cells with NCX4040 resulted in induction of lipid peroxidation in a dose- and time-dependent manner. NCX4040 treatment induced several genes related to ferroptosis (e.g., CHAC1, GPX4 and NOX4) in both cell lines. Metabolomic studies also indicated significant increases in both lipid and energy metabolism following the drug treatment in HT-29 and HCT116 cells. These observations strongly suggest that NCX4040 causes ferroptosis-mediated cell death of CRC cells. Furthermore, combinations of NCX4040 and ER may contribute significantly for the treatment of CRC, including those that are difficult to treat due to the presence of Ras mutation in the clinic. Roles of Erastin in human ovarian tumor cell death is also currently being investigated and results will be presented.