2. Academic Validation
  3. Sorafenib fails to trigger ferroptosis across a wide range of cancer cell lines

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

  • Cell Death Dis. 2021 Jul 13;12(7):698. doi: 10.1038/s41419-021-03998-w.
Jiashuo Zheng 1,  Mami Sato 2 3,  Eikan Mishima 1,  Hideyo Sato 2,  Bettina Proneth 1,  Marcus Conrad 4 5
Affiliations

Affiliations

  • 1 Helmholtz Zentrum München, Institute of Metabolism and Cell Death, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.
  • 2 Laboratory of Biochemistry and Molecular Biology, Department of Medical Technology, Faculty of Medicine, Niigata University, Niigata, Japan.
  • 3 Sakeology Center, Niigata University, 8050 Ikarashi 2-no-cho, Nishi-ku Niigata, 950-2181, Japan.
  • 4 Helmholtz Zentrum München, Institute of Metabolism and Cell Death, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany. marcus.conrad@helmholtz-muenchen.de.
  • 5 Pirogov National Research Medical University, Laboratory of Experimental Oncology, Ostrovityanova 1, Moscow, 117997, Russia. marcus.conrad@helmholtz-muenchen.de.
PMID: 34257282 DOI: 10.1038/s41419-021-03998-w
Abstract

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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