Sorafenib acts as a multi-kinase inhibitor, targeting Raf-1 and B-Raf with IC50 values of 6 nM and 22 nM, respectively. Additionally, Sorafenib demonstrates inhibitory effects on VEGFR-2, VEGFR-3, PDGFR-β, Flt-3, and c-KIT, displaying corresponding IC50 values of 90 nM, 20 nM, 57 nM, 59 nM, and 68 nM. Beyond these kinase activities, Sorafenib is capable of inducing autophagy and apoptosis while triggering ferroptosis activation, resulting in its notable antitumor efficacy [1-3].
Sorafenib(5-40μM; 24 h) had a dose-dependent inhibitory effect on HSC-T6 cells viability [4]. Sorafenib(25mM;0-42h) alters the lipid composition in Huh7.5 cells[5].
Sorafenib(2.5, 5, 10 mg/kg; i.p; twice a week for 8 weeks) attenuated liver injury and extracellular matrix (ECM) accumulation in CCl4 -induced fibrotic livers, accompanied by reduction of SLC7A11 and GPX4 proteins[4]. Treatment with erastin and sorafenib(10 mg/kg; i.p; once every other day) alleviated liver fibrosis in mice by inducing hepatic stellate cells(HSCs) ferroptosis in mice[6].The synergism of sorafenib and T cells is mediated via reduced ATF4 expression, causing activation of the IRF7-IL-15 axis in leukemia cells and thereby leading to metabolic reprogramming of leukemia-reactive T cells in humans[7].
索拉非尼Sorafenib是Raf-1和B-Raf的多激酶抑制剂，IC50分别为6 nM和22 nM;Sorafenib对VEGFR-2 VEGFR-3 PDGFR-β Flt-3和c-KIT也有抑制作用，IC50值分别为90 nM、20 nM、57 nM、59 nM和68 nM;索拉非尼能诱导自噬细胞凋亡和激活铁死亡，并具有抗肿瘤活性[1-3]。
索拉非尼(5-40μM; 24 h)对HSC-T6细胞活力有剂量依赖性抑制作用[4]。索拉非尼(25mM;0-42h)改变Huh7.5细胞的脂质组成[5]。
索拉非尼(2.5, 5, 10 mg/kg; i.p; twice a week for 8 weeks)减轻了CCl4诱导的纤维化肝的肝损伤和细胞外基质积累，并伴有SLC7A11和GPX4蛋白的减少[4]。用铁死亡诱导剂erastin和索拉非尼(10 mg/kg; i.p; once every other day)治疗通过诱导小鼠肝星状细胞(HSCs)铁死亡来减轻小鼠肝纤维化[6]。索拉非尼和T细胞的协同作用是通过ATF4表达的降低来介导的，导致白血病细胞中IRF7-IL-15轴的激活，从而导致人类白血病反应性T细胞的代谢重编程[7]。
参考文献:
[1]. Abdelgalil AA, Alkahtani HM, et,al.Sorafenib. Profiles Drug Subst Excip Relat Methodol. 2019;44:239-266. doi: 10.1016/bs.podrm.2018.11.003. Epub 2019 Jan 18. PMID: 31029219.
[2]. Wilhelm SM, Carter C, et,al.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. 2004 Oct 1;64(19):7099-109. doi: 10.1158/0008-5472.CAN-04-1443. PMID: 15466206.
[3]. Xia S, Pan Y, et,al.The microenvironmental and metabolic aspects of sorafenib resistance in hepatocellular carcinoma. EBioMedicine. 2020 Jan;51:102610. doi: 10.1016/j.ebiom.2019.102610. Epub 2020 Jan 6. PMID: 31918403; PMCID: PMC7000339.
[4]. Yuan S, Wei C, et,al. Sorafenib attenuates liver fibrosis by triggering hepatic stellate cell ferroptosis via HIF-1α/SLC7A11 pathway. Cell Prolif. 2022 Jan;55(1):e13158. doi: 10.1111/cpr.13158. Epub 2021 Nov 22. PMID: 34811833; PMCID: PMC8780895.
[5]. Liu G, Kuang S, et,al.Sorafenib kills liver cancer cells by disrupting SCD1-mediated synthesis of monounsaturated fatty acids via the ATP-AMPK-mTOR-SREBP1 signaling pathway. FASEB J. 2019 Sep;33(9):10089-10103. doi: 10.1096/fj.201802619RR. Epub 2019 Jun 14. PMID: 31199678.
[6]. Zhang Z, Guo M, et,al. RNA-binding protein ZFP36/TTP protects against ferroptosis by regulating autophagy signaling pathway in hepatic stellate cells. Autophagy. 2020 Aug;16(8):1482-1505. doi: 10.1080/15548627.2019.1687985. Epub 2019 Nov 11. PMID: 31679460; PMCID: PMC7469536.
[7]. Mathew NR, Baumgartner F,et,al. Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells. Nat Med. 2018 Mar;24(3):282-291. doi: 10.1038/nm.4484. Epub 2018 Feb 12. Erratum in: Nat Med. 2018 Apr 10;24(4):526. PMID: 29431743; PMCID: PMC6029618.
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In vitro Kinase Assays with Recombinant Raf-1, BRAF, V599E BRAF, MEK-1, and ERK1[1]: |
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Preparation method |
Test compound inhibition against various RAF kinase isoforms, sorafenib was added to a mixture of Raf-1 (80 ng), wt BRAF, or V599E BRAF (80 ng) with MEK-1 (1 μg) in assay buffer [20 mmol/L Tris (pH 8.2), 100 mmol/L NaCl, 5 mmol/L MgCl2, and 0.15% β-mercaptoethanol] at a final concentration of 1% DMSO. The RAF kinase assay (final volume of 50 μL) was initiated by adding 25 μL of 10 μmol/L γ-[33P]ATP (400 Ci/mol) and incubated at 32℃ for 25 minutes. Phosphorylated MEK-1 was harvested by filtration onto a phosphocellulose mat, and 1% phosphoric acid was used to wash away unbound radioactivity. After drying by microwave heating, a β-plate counter was used to quantify filter-bound radioactivity. |
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Applications |
Sorafenib inhibited Raf-1 with IC50 of 6nM; Sorafenib inhibited B-Raf activity of wild type and V599E mutant with IC50 of 22 nM and 38 nM, respectively; Sorafenib has no activity against ERK-1, MEK-1. |
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Cell experiment [2]: |
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Cell lines |
HSC-T6 cells |
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Preparation method |
Cells were seeded into 96-well plates. When the cell density reached 70%, different concentrations of sorafenib were added, and equal amounts of DMSO without drug were exposed to the control group for 24 h. |
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Reaction Conditions |
5-40μM; 24 h |
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Applications |
HSC-T6 cell viability was dose-dependently inhibited by sorafenib at concentrations ranging from 5 to 40 μM. |
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Animal experiment [2]: |
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Animal models |
Male C57BL/6 mice (6-8 weeks) |
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Preparation method |
Mice were randomly divided into five groups (n=6 per group) including the vehicle group, CCl4-treated group, CCl4 + sorafenib (2.5, 5, 10 mg/kg)-treated groups. The groups treated with CCl4, CCl4 + sorafenib were subjected intraperitoneal injections of olive oil with 10% CCl4 for 8 weeks to induce liver fibrosis. The vehicle group was subjected intraperitoneal injections of the same dose of olive oil. After 4 weeks, each mouse in the groups treated with CCl4 + sorafenib was orally administered sorafenib daily. The vehicle group and the CCl4-treated group were orally administered the same dose of saline daily. |
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Dosage form |
2.5, 5, 10 mg/kg; i.p; twice a week for 8 weeks |
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Applications |
Sorafenib attenuated liver injury and ECM accumulation in CCl4 -induced fibrotic livers. |
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参考文献: [1]. Wilhelm SM, Carter C, et,al. 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. 2004 Oct 1;64(19):7099-109. doi: 10.1158/0008-5472.CAN-04-1443. PMID: 15466206. [2]. Yuan S, Wei C, et,al.Sorafenib attenuates liver fibrosis by triggering hepatic stellate cell ferroptosis via HIF-1α/SLC7A11 pathway. Cell Prolif. 2022 Jan;55(1):e13158. doi: 10.1111/cpr.13158. Epub 2021 Nov 22. PMID: 34811833; PMCID: PMC8780895. |
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