Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5.

By Li Liu, Yichen Cao, Charles Chen, Xiaomei Zhang, Angela Mcnabola, D. Wilkie, S. Wilhelm, M. Lynch, Christopher A. Carter. Cancer Research, 2006

1,498 citations recorded by the source corpus.

Angiogenesis and signaling through the RAF/mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK cascade have been reported to play important roles in the development of hepatocellular carcinomas (HCC). Sorafenib (BAY 43-9006, Nexavar) is a multikinase inhibitor with activity against Raf kinase and several receptor tyrosine kinases, including vascular endothelial growth factor receptor 2 (VEGFR2), platelet-derived growth factor receptor (PDGFR), FLT3, Ret, and c-Kit. In this study, we investigated the in vitro effects of sorafenib on PLC/PRF/5 and HepG2 HCC cells and the in vivo antitumor efficacy and mechanism of action on PLC/PRF/5 human tumor xenografts in severe combined immunodeficient mice. Sorafenib inhibited the phosphorylation of MEK and ERK and down-regulated cyclin D1 levels in these two cell lines. Sorafenib also reduced the phosphorylation level of eIF4E and down-regulated the antiapoptotic protein Mcl-1 in a MEK/ERK-independent manner. Consistent with the effects on both MEK/ERK-dependent and MEK/ERK-independent signaling pathways, sorafenib inhibited proliferation and induced apoptosis in both HCC cell lines. In the PLC/PRF/5 xenograft model, sorafenib tosylate dosed at 10 mg/kg inhibited tumor growth by 49%. At 30 mg/kg, sorafenib tosylate produced complete tumor growth inhibition. A dose of 100 mg/kg produced partial tumor regressions in 50% of the mice. In mechanism of action studies, sorafenib inhibited the phosphorylation of both ERK and eIF4E, reduced the microvessel area (assessed by CD34 immunohistochemistry), and induced tumor cell apoptosis (assessed by terminal deoxynucleotidyl transferase-mediated nick end labeling) in PLC/PRF/5 tumor xenografts. These results suggest that the antitumor activity of sorafenib in HCC models may be attributed to inhibition of tumor angiogenesis (VEGFR and PDGFR) and direct effects on tumor cell proliferation/survival (Raf kinase signaling-dependent and signaling-independent mechanisms).

Subfields: Hepatology, Molecular Biology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/3c8a6e718202056d4a7685cad58d92ddfdfecbee

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Citations in the corpus

Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling (2008, background): “Although a correlation has been shown in several tumor cell lines between the induction of apoptosis by sorafenib and the inhibition of eIF4E phosphorylation and decrease of Mcl-1 protein level (39), there remains a temporal and potency disconnect between the inhibition of eIF4E phosphorylation, whi”
Current Strategy for Staging and Treatment: The BCLC Update and Future Prospects (2010, methodology): “This agent is an oral tyrosine kinase inhibitor that blocks the Raf/MEK/ ERK pathway and the receptor for VEGFR 2 and PDGFR-b.121,122 After showing activity in experimental models and potential delayed tumor progression rate in a large phase 2 study,123 it was tested in a phase III, multicenter, ran”
Identification of miRNomes in human liver and hepatocellular carcinoma reveals miR-199a/b-3p as therapeutic target for hepatocellular carcinoma. (2011, background): “These data confirm that the antitumor effect of miR-199a/b-3p is mediated by inhibiting its target PAK4. miR-199a/b-3p Inhibits PAK4/Raf/MEK/ERK Pathway in HCC PAK4 was known to directly phosphorylate and activate Raf1 (Cammarano et al., 2005), and signaling through the Raf/MEK/ ERK cascade is well ”
Sorafenib or placebo plus TACE with doxorubicin-eluting beads for intermediate stage HCC: The SPACE trial. (2016, background): “Sorafenib is a multikinase inhibitor [22–24] shown in two large, double-blind, randomized, placebo-controlled phase III clinical trials to significantly improve OS and time-to-tumor progression (TTP) in patients with advanced HCC [25,26].”
The Development of the Concept of Ferroptosis (2018, neutral): “part caspase-independent [160,161], this drug was shown to trigger classic apoptosis in some cells [162].”
Curcumin: A review of anti-cancer properties and therapeutic activity in head and neck squamous cell carcinoma (2011, background): “Sorafenib is a multikinase inhibitor targeting the MAP kinase pathway (RAF/MEK/ERK) as well as several other receptor tyrosine kinases including VEGFR, PDGFR, FLT3, Ret and c-kit [213].”
Mechanisms of ferroptosis (2016, background): “However, the effects of this compound are clearly pleiotropic: in some cell lines sorafenib triggers apoptosis [37], and even in cell lines where ferroptosis is observed at low doses of sorafenib, apoptosis or some other form of cell death is observed at higher doses [28].”