Sorafenib fails to trigger ferroptosis across a wide range of cancer cell lines

• Published in: Cell death & disease Vol. 12; no. 7; p. 698
• Main Authors: Zheng, Jiashuo, Sato, Mami, Mishima, Eikan, Sato, Hideyo, Proneth, Bettina, Conrad, Marcus
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.07.2021; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/109; 13/44; 631/80/82; 631/92/613; 82/80; Antibodies; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell death; Enzyme inhibitors; Ferroptosis; Genetic engineering; Hepatocellular carcinoma; Immunology; Kidney cancer; Kinases; Life Sciences; Protein kinase inhibitors; Renal cell carcinoma; Sulfasalazine; Targeted cancer therapy; Tumor cell lines; Tumor cells
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-021-03998-w

Sorafenib, a protein kinase inhibitor approved for the treatment of hepatocellular carcinoma and advanced renal cell carcinoma, has been repeatedly reported to induce ferroptosis by possibly involving inhibition of the cystine/glutamate antiporter, known as system x c − . Using a combination of well-defined genetically engineered tumor cell lines and canonical small molecule ferroptosis inhibitors, we now provide unequivocal evidence that sorafenib does not induce ferroptosis in a series of tumor cell lines unlike the cognate system x c − inhibitors sulfasalazine and erastin. We further show that only a subset of tumor cells dies by ferroptosis upon sulfasalazine and erastin treatment, implying that certain cell lines appear to be resistant to system x c − inhibition, while others undergo ferroptosis-independent cell death. From these findings, we conclude that sorafenib does not qualify as a bona fide ferroptosis inducer and that ferroptosis induced by system x c − inhibitors can only be achieved in a fraction of tumor cell lines despite robust expression of SLC7A11, the substrate-specific subunit of system x c − .