Induction of Anti-Proliferative and Apoptotic Effects of Sorafenib Using miR-27a Inhibitor in Hepatocellular Carcinoma Cell Lines (original) (raw)
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Bentham Science
Angiogenesis and signaling through the RAS/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 carcinoma (HCC). Sorafenib (Nexavar), a novel bi-aryl urea BAY 43-9006, is an orally administered multikinase inhibitor with activity against RAS/RAF kinases multikinase inhibitor with activity against RAFkinases and several receptor tyrosine kinases, including vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), FLT3, Ret, and c-Kit. It is involved in angiogenic pathway and cell proliferation. Sorafenib has demonstrated potent anti-tumor activity in in vitro studies, preclinical xenograft models of different tumor types and human clinical trials. This review summarizes the history of sorafenib from its discovery by the medicinal chemistry approach through to clinical development and ongoing trials on the combination between sorafenib and trans-arterial chemoembolization (TACE) in HCC patients.
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MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression through post-transcriptional interactions with mRNA. MiRNAs have recently considered as key regulators of various cancers including liver cancer. Sorafenib is one of the antitumor drugs for the treatment of advanced hepatocellular carcinoma. It acts as a multikinase inhibitor suppressing cell proliferation and angiogenesis. This study tries to investigate a potential microRNA-based mechanism of action of the drug by studying the effect of sorafenib on miR-23a and miR-24 levels in HCC cell lines HepG2 /Huh7 and revealing the possible drug mechanism against these oncogenic miRNAS in this study cell viability of cultured HepG2 /Huh7 after treatment with sorafenib were evaluated using Sulphorhodamine-B (SRB) assay, cell cycle and apoptosis estimated by flow cytometry assay. The caspase-3 level was determined using the ELISA assay. Moreover, miR-23a and miR-24 expressions levels analyzed by qPCR. Finally, TGF-β le...
Critical appraisal of the role of sorafenib in the management of hepatocellular carcinoma
Hepatic Medicine: Evidence and Research, 2010
Sorafenib is an oral multiple kinase inhibitor that blocks Raf, vascular endothelial growth factor receptor, and platelet-derived growth factor receptor. It has been approved in the US and Europe for the treatment of advanced hepatocellular carcinoma (HCC). Sorafenib has demonstrated a 44% increase in survival for advanced HCC patients, compared with best supportive care alone. We have reviewed the pharmacology, pivotal studies, and safety data for this agent. Sorafenib is the first systemic drug demonstrating a significant survival benefit, and is the standard of care for patients with advanced HCC for whom no potential curative option is available.
Effects of miR-193a and sorafenib on hepatocellular carcinoma cells
Molecular Cancer, 2013
Background: Hepatocellular carcinoma (HCC) is a challenging malignancy of global importance, it is the third most common cause of cancer-related mortality worldwide. In the last years the multikinase inhibitor sorafenib has been used for advanced HCC, but some patients do not benefit from this therapy; thus, novel therapeutic options based on molecular approaches are urgently needed. microRNAs are short non coding RNAs involved in several physiological and pathological conditions including HCC and increasing evidence describes miRs as good tools for the molecular targeted therapies in HCC. The purpose of this study was to identify novel approaches to sensitize the HCC cells to sorafenib by microRNAs targeting urokinase-type plasminogen activator (uPA). Methods: The miR-193a was validated as negative regulator of urokinase-type plasminogen activator (uPA) in 2 HCC undifferentiated cell lines by transient transfection of miR and anti-miR molecules. The molecular interaction between miR-193a and uPA mRNA target was verified by luciferase reporter assay. The miR-193a expression level was evaluated by stem-loop real time PCR in tumoral tissues from 39 HCC patients. The HCC cells were co-treated with sorafenib and miR-193a and the effects on cellular proliferation, apoptosis were tested. The effect of sorafenib on c-met expression levels was assessed by western blotting.
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Background: Sorafenib constitutes a suitable treatment alternative for patients with advanced hepatocellular carcinoma (HCC) in whom atezolizumab + bevacizumab therapy is contraindicated. The aim of the study was the identification of a miRNA signature in liquid biopsy related to sorafenib response. Methods: miRNAs were profiled in hepatoblastoma HepG2 cells and tested in animal models, extracellular vesicles (EVs), and plasma from HCC patients. Results: Sorafenib altered the expression of 11 miRNAs in HepG2 cells. miR-200c-3p and miR-27a-3p exerted an anti-tumoral activity by decreasing cell migration and invasion, whereas miR-122-5p, miR-148b-3p, miR-194-5p, miR-222-5p, and miR-512-3p exerted pro-tumoral properties by increasing cell proliferation, migration, or invasion, or decreasing apoptosis. Sorafenib induced a change in EVs population with an increased number of larger EVs, and promoted an accumulation of miR-27a-3p, miR-122-5p, miR-148b-3p, miR-193b-3p, miR-194-5p, miR-200c...
Sorafenib response in hepatocellular carcinoma: MicroRNAs as tuning forks
Hepatology research : the official journal of the Japan Society of Hepatology, 2018
Hepatocellular carcinoma (HCC) is the primary liver malignancy that contributes towards the second most common cause of cancer-related mortality. The targeted chemotherapeutic agent, sorafenib, is known to show a statistically significant but limited overall survival advantage in advanced HCC. However, the individual patient response towards sorafenib varies drastically, with most experiencing stable disease and few with partial response; complete response is very rare. Progressive disease despite the treatment is also evident in many patients, indicating drug resistance. These varied responses have been linked with the modulation of several intracellular signaling pathways. Notably, the regulation of these pathways through diverse operating biomolecules, including microRNAs (miRNAs), is the focus of recent studies. MicroRNAs are tiny, non-coding RNA molecules that regulate the expression of several target genes. In addition, miRNAs are known to play a role in the progression of HCC...
Safety and efficacy of sorafenib in the treatment of hepatocellular carcinoma
OncoTargets and Therapy, 2009
Hepatocellular carcinoma (HCC) is frequently diagnosed in the setting of chronic liver disease and cirrhosis. The median survival after diagnosis is dismal. The treatment options that may offer cure are either resection or liver transplantation. Unfortunately most patients are not eligible for either treatment modality at diagnosis because of advanced stage and underlying liver dysfunction. Until recently, there was no effective systemic therapy for patients with advanced HCC. Sorafenib, an oral multikinase inhibitor of the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor and Raf, has shown antitumor activity in patients with advanced HCC in phase III trials. Although objective response is not common, sorafenib promotes disease stabilization and improves overall survival. Sorafenib is well tolerated with a favorable toxicity profile. In this article we review the efficacy and safety data for sorafenib in patients with advanced HCC.