Sorafenib Inhibits Hypoxia-Inducible Factor-1α Synthesis: Implications for Antiangiogenic Activity in Hepatocellular Carcinoma

Abstract

Purpose: The overexpression of hypoxia-inducible factor 1a (HIF-1a) is a common finding in hepatocellular carcinoma (HCC), and it leads to angiogenesis and poor prognosis. Sorafenib, a multikinase inhibitor, has shown significant improvement in survival in patients with advanced HCC in clinical trials. However, the mechanisms that account for the antiangiogenic efficiency of sorafenib have not been fully elucidated. The present study aims to explore the effect of sorafenib on HIF-1a expression and activation in HCC cells and xenografts.Experimental Design: HCC cells and xenografts were treated with sorafenib or vehicles. Western blotting and quantitative PCR array were used to determine protein and mRNA expression, respectively. HIF-1a activity, de novo protein synthesis, and VEGF secretions were determined using assay kits.Results: Sorafenib dose dependently decreased the hypoxia-induced accumulation and activation of HIF1a protein. Further analysis revealed that such reduction of HIF-1a was associated with the inhibition of HIF-1a protein synthesis rather than the promotion of HIF-1a protein degradation or the reduction of HIF1a mRNA. Moreover, the phosphorylation levels of mTOR, extracellular signal-regulated kinase (ERK), p70S6K, RP-S6, 4E-BP1, and eIF4E were significantly suppressed by sorafenib. In vivo studies further confirmed the inhibitory effect of sorafenib on the expression of HIF-1a and VEGF proteins, leading to a decrease in tumor vascularization and growth of the xenografts.Conclusions: Sorafenib-mediated inhibition of HIF-1a synthesis is associated with previously undefined pathways in which mTOR/p70S6K/4E-BP1 and ERK phosphorylation are downregulated. Our preclinical data expand our understanding of sorafenib's antiangiogenic mechanism of action by inhibiting HIF-1a and VEGF protein expression. Clin Cancer Res; 18(20); 5662-71. Ó2012 AACR.

Pre-clinical activity of PR-104 as monotherapy and in combination with sorafenib in hepatocellular carcinoma

“…6D), even though that finding has been reported in other studies. 28,29 Sorafenib did inhibit ERK phosphorylation in PLC/PRF/5 cells in vitro (Fig. 6E), as previously reported.…”

“…We also examined whether sorafenib could inhibit ERK phosphorylation in PLC/ PRF/5 cells in vitro. Consistent with previous reports, 28,29 we found a »50% inhibition of pERK/ERK ratios by band densitometry after a 2 h incubation with 10 mM sorafenib (Fig. 6E).…”

“…6E), as previously reported. 28,29 Sorafenib has been shown to inhibit a wide range of receptor tyrosine kinases and activate aspects of the unfolded protein response in other cell line models, 33 any of these phenomena might contribute to the observed synergy between PR-104 and sorafenib. Indeed, sorafenib treatment resulted in increased sensitivity of PLC/PRF/5 cells in vitro to PR-104A under anoxic conditions and reduced sensitivity under aerobic conditions (Fig.…”

Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma

“…We have previously demonstrated that targeting hypoxia-inducible pathways enhanced the antitumor activity of doxorubicin in HCC [4,31] . Although sorafenib downregulates the synthesis of hypoxia-inducible factor (HIF)-1α in HCC cells in vitro and in vivo [32] , the correlation of sorafenib resistance and hypoxic microenvironment is attractive because the antiangiogenic activity of sorafenib is speculated to lead to tumor starvation and subsequent tumor hypoxia [33] . A recent study [34] has shown that sorafenib-resistant HCC tissues had higher expression of HIF-1α than sorafenibsensitive and pre-treated HCC tissues.…”

Chapter 8. Polymeric Nanoparticles and Cancer: Lessons Learnt from CRLX101

“…Studies also showed that sorafenib had inhibitory effects on HIF-1 activity. 101,102 Temsirolimus (CCI-779, Torisel s ; Pfizer) is an mTOR inhibitor that is approved for RCC. Temsirolimus also inhibited HIF-1a in human lung cancer cell lines under hypoxic conditions.…”