Molecular mechanisms of sorafenib action in liver cancer cells

Abstract

Sorafenib, a multikinase inhibitor, recently received FDA approval for the treatment of advanced hepatocellular carcinoma (HCC). However, as the clinical application of sorafenib evolves, there is increasing interest in defining the mechanisms underlying its anti-tumor activity. Considering that this specific inhibitor could target unexpected molecules depending on the biologic context, a precise understanding of its mechanism of action could be critical to maximize its treatment efficacy, while minimizing adverse effects. Two human HCC cell lines (HepG2 and Huh7), carrying different biological and genetic characteristics, were used in this study to examine the intracellular events leading to sorafenib-induced HCC cell-growth inhibition. Sorafenib inhibited cell growth in both cell lines in a dose- and time-dependent manner and significantly altered expression levels of 826 and 2011 transcripts in HepG2 and Huh7 cells, respectively. Genes functionally involved in angiogenesis, apoptosis, transcription regulation, signal transduction, protein biosynthesis and modification were predominantly upregulated, while genes implicated in cell cycle control, DNA replication recombination and repair, cell adhesion, metabolism and transport were mainly downregulated upon treatment. However, each sorafenib-treated HCC cell line displayed specificity in the expression and activity of crucial factors involved in hepatocarcinogenesis. The altered expression of some of these genes was confirmed by semiquantitative and quantitative RT-PCR and by western blotting. Many novel genes emerged from our transcriptomics analysis that had not previously been reported to be effected by sorafenib. Further functional analyses may determine whether these genes can serve as potential molecular targets for more effective anti-HCC strategies.

Cyclin E1 Inhibition can Overcome Sorafenib Resistance in Hepatocellular Carcinoma Cells Through Mcl-1 Suppression

“…Results from our study and other investigators support Mcl-1 as a key mediator of cell survival and drug resistance in hepatocellular carcinoma (5,6,27,28). Mcl-1 may be suppressed by sorafenib through downregulation of E2F1, which also suppress cyclin E1 expression in hepatocellular carcinoma cells.…”

“…Sorafenib can suppress several key cell-cycle regulators, including E2F1, cyclin D, cyclin E1, and CDKs, which may contribute to its antitumor efficacy (5,6,(20)(21)(22). We determined cyclin E1 expression in hepatocellular carcinoma cells was associated with sensitivity to sorafenib (20).…”

“…Sorafenib has been found to exert many "offtarget effects" that may contribute to its antitumor efficacy, in addition to the inhibition of Raf kinase signaling and tumor angiogenesis (3,4). Multiple mediators in the apoptosis regulatory pathways, including Mcl-1 and survivin, may regulate the antitumor efficacy of sorafenib in cancer cells (5)(6)(7). Identifying these pathways and molecules will greatly contribute to design strategies for overcoming sorafenib resistance (8).…”

Lipid nanocarriers containing sorafenib inhibit colonies formation in human hepatocarcinoma cells

“…Most patients show disease recurrence that rapidly progresses to the advanced stages with vascular invasion and multiple intrahepatic metastases (Liu et al, 2006). Therapeutic options in advanced stage have been quite limited so far, until the discovery of new therapeutic agents that target the molecular pathways involved in hepatocarcinogenesis Bondì et al, 2014;Finn, 2013;Cervello et al, 2012a;Giannitrapani et al, 2014).…”

A Randomized Phase II Open-Label Multi-Institution Study of the Combination of Bevacizumab and Erlotinib Compared to Sorafenib in the First-Line Treatment of Patients with Advanced Hepatocellular Carcinoma

“…The anticancer activity of S results from a dual inhibitory effect on angiogenesis and tumor cell proliferation [38, 39]. S is currently the only first-line systemic therapy approved for the treatment of patients with advanced HCC based on results from the pivotal SHARP trial [5]; thus, additional effective and tolerable treatment options are needed for these patients.…”