Sorafenib Blocks the RAF/MEK/ERK Pathway, Inhibits Tumor Angiogenesis, and Induces Tumor Cell Apoptosis in Hepatocellular Carcinoma Model PLC/PRF/5

Abstract

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 signalingdependent and signaling-independent mechanisms).

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“…In the first 5 min after H 2 O 2 injection, the cell morphology was indistinguishable from that of healthy cells, indicating there was no obvious apoptosis. At 30 min, a few cells were observed to start severing attachments to other cells and the extracellular matrix, and to rounded up (Figure 6d), indicating that a few of the cells were dying 49, 50. At 60 min, a large number of cells with morphological signs of death appeared (Figure 7e).…”

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“…Indeed, Antoun et al 12 reported that muscle loss was specifically exacerbated by sorafenib (Sor) treatment and described it as an adverse effect of the drug related to asthenia, fatigue, and physical disability. Sorafenib is a multikinase inhibitor that showed efficacy against a wide variety of tumours in pre‐clinical models13; it inhibits cell proliferation by targeting the Raf/MEK/ERK signalling pathways and exerts an anti‐angiogenic effect by inhibition of tumour angiogenesis through vascular endothelial growth factor receptor (VEGFR) and platelet‐derived growth factor receptor (PDGFR) 14, 15. It is already approved in humans for the treatment of advanced hepatocellular carcinoma16 and advanced renal cell carcinoma 17.…”

Tetrandrine induces apoptosis by activating reactive oxygen species and repressing Akt activity in human hepatocellular carcinoma

“…[5][6][7] Radix Stephaniae tetrandrae is a key ingredient of traditional Chinese medicine that has been broadly used for thousands of years in China to treat patients with arthritis, hypertension, inflammation and even silicosis. Studies have demonstrated that tetrandrine could block Ca 2þ channels 7,8 and possessed immunosuppressive property, 9 free radical scavenging effects 10 and even antiproliferative feature.…”