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Zheng, J. ; Sato, M.* ; Mishima, E. ; Sato, H.* ; Proneth, B. ; Conrad, M.

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

Cell Death Dis. 12:698 (2021)

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	Open Access Gold

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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^-.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords X(c)(-) Cystine Transporter; Plasma-membrane; Death; Inhibition; Resistance; Exchange; Growth

ISSN (print) / ISBN 2041-4889

e-ISSN 2041-4889

Journal Cell Death & Disease

Quellenangaben Volume: 12, Issue: 7, Article Number: 698

Publisher Nature Publishing Group

Publishing Place Campus, 4 Crinan St, London, N1 9xw, England

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Metabolism and Cell Death (MCD)

Grants Deutsche Forschungsgemeinschaft (German Research Foundation)