Premium
Role of sorafenib in the treatment of advanced hepatocellular carcinoma: An update
Author(s) -
Gauthier Angela,
Ho Mitchell
Publication year - 2013
Publication title -
hepatology research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.123
H-Index - 75
eISSN - 1872-034X
pISSN - 1386-6346
DOI - 10.1111/j.1872-034x.2012.01113.x
Subject(s) - sorafenib , hepatocellular carcinoma , medicine , angiogenesis , autophagy , cancer research , pharmacology , vascular endothelial growth factor , oncology , apoptosis , kinase , drug resistance , vegf receptors , biology , biochemistry , microbiology and biotechnology
Sorafenib is the first and only p.o. administrated drug currently approved to treat advanced hepatocellular carcinoma ( HCC ). However, concerns have been raised about sorafenib therapy, including acquired drug resistance. This review provides an overview of sorafenib in the treatment of HCC on the basis of data obtained in the laboratory and in clinical studies. Three underlying mechanisms have been found to support sorafenib therapy. First, sorafenib blocks HCC cell proliferation by inhibiting BR af and R af1/c‐ R af serine/threonine kinase phosphorylation in the mitogen‐activated protein kinase pathway. Second, sorafenib induces apoptosis by reducing el F 4 E phosphorylation and downregulating M cl‐1 levels in tumor cells. Third, sorafenib prevents tumor‐associated angiogenesis by inactivating vascular endothelial growth factor receptors ( VEGFR ‐2 and ‐3) and the platelet‐derived growth factor receptor‐β. Clinical trials have demonstrated the effectiveness and relative safety of sorafenib, and thus the drug is used in unresectable HCC . However, many patients may develop acquired resistance to sorafenib, so their response to sorafenib is eventually lost. Sorafenib may induce autophagy, which leads to apoptosis. However, autophagy can also cause drug resistance. Many studies have combined sorafenib with other treatments in an effort to increase its effects, reduce the necessary dose or overcome resistance. It is urgent to study the mechanisms underlying how sorafenib interacts with cellular molecules and other drugs to increase its efficacy and reduce resistance in HCC patients.