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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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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 xc-. 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 xc- 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 xc- 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 xc- inhibitors can only be achieved in a fraction of tumor cell lines despite robust expression of SLC7A11, the substrate-specific subunit of system xc-.
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Publication type Article: Journal article
Document type Scientific Article
Keywords X(c)(-) Cystine Transporter; Plasma-membrane; Death; Inhibition; Resistance; Exchange; Growth
ISSN (print) / ISBN 2041-4889
e-ISSN 2041-4889
Quellenangaben Volume: 12, Issue: 7, Pages: , Article Number: 698 Supplement: ,
Publisher Nature Publishing Group
Publishing Place Campus, 4 Crinan St, London, N1 9xw, England
Reviewing status Peer reviewed
Grants Deutsche Forschungsgemeinschaft (German Research Foundation)