Sorafenib

Sorafenib is a multi-kinase inhibitor that inhibits Raf-1 and B-RAF (IC₅₀s = 6 and 22 µM, respectively), as well as the receptor tyrosine kinases VEGFR2, VEGFR3, PDGFRβ, FLT3, and c-Kit (IC₅₀s = 90, 15, 20, 57, and 58 nM, respectively).^1,2 It is selective for these kinases over 12 other kinases, including ERK1, MEK1, EGFR, and HER2 (IC₅₀s = >10 µM for all).² Sorafenib inhibits proliferation of PLC/PRF/5 and HepG2 cells (IC₅₀s = 6.3 and 4.5 µM, respectively) and induces apoptosis in these cells.³ It completely inhibits tumor growth in a PLC/PRF/5 mouse xenograft model when administered at a dose of 30 mg/kg and reduces basic FGF-induced angiogenesis in a Matrigel^™ assay in vivo.^3,4 Sorafenib (10 µM) induces ferroptotic cell death in HT-1080 fibrosarcoma cells, an effect that can be blocked by the ferroptosis inhibitors ferrostatin-1 (Item No. 17729), deferoxamine (Item No. 14595), and β-mercaptoethanol, but does not induce ferroptosis in a variety of other cancer cell lines.^5,6 It inhibits glutamate release by the system x_c^- cystine/glutamate transporter in HT-1080 cells when used at concentrations ranging from 2.5 to 10 µM, decreases glutathione levels, and increases lipid peroxidation.⁵ Sorafenib also inhibits replication of hepatitis C virus (HCV) in Huh7.5 cells (IC₅₀ = 7.2 µM).⁷ Formulations containing sorafenib have been used in the treatment of hepatocellular, renal cell, and thyroid carcinomas.

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1. Lyons, J.F., Wilhelm, S., Hibner, B., et al. Discovery of a novel Raf kinase inhibitor. Endocr. Relat. Cancer 8(3), 219-225 (2001).

2. Wilhelm, S.M., Carter, C., and Tang, L. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 64(19), 7099-7109 (2004).

3. Liu, L., Cao, Y., Chen, C., et al. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res. 66(24), 11851-11858 (2006).

4. Murphy, D.A., Makonnen, S., Lassoued, W., et al. Inhibition of tumor endothelial ERK activation, angiogenesis, and tumor growth by sorafenib (BAY43-9006). Am. J. Pathol. 169(5), 1875-1885 (2006).

5. Dixon, S.J., Patel, D.N., Welsch, M., et al. Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. Elife 3, e02523 (2014).

6. Zheng, J., Sato, M., Mishima, E., et al. Sorafenib fails to trigger ferroptosis across a wide range of cancer cell lines. Cell Death Dis. 12(7), 698 (2021).

7. Himmelsbach, K., Sauter, D., Baumert, T.F., et al. New aspects of an anti-tumour drug: Sorafenib efficiently inhibits HCV replication. Gut 58(12), 1644-1653 (2009).

Alavi, M.V. Tau phosphorylation and OPA1 proteolysis are unrelated events: Implications for Alzheimer’s Disease. Biochim. Biophys. Acta Mol. Cell Res. 1868(12), 119116 (2021).