[2] In HCC, the mitogen-activated protein kinase (MAPK) pathway is often constitutively active, which leads to overexpression of genes that promote cell proliferation. Apoptosis is often prevented by overproduction of the survival factor Mcl-1. Angiogenesis, mediated by the receptor selleck products tyrosine kinases in the vascular endothelial growth factor receptor (VEGFR)

and platelet-derived growth factor receptor (PDGFR) families, ensures that the tumor receives adequate nutrients and oxygen. The standard therapy for HCC is removal of the tumor by surgery. This treatment is indicated if liver function is well-preserved and there is only one tumor.[3] Five-year survival rates for these patients can range 89–93%.[3] Unfortunately, HCC is often detected too late for surgery to be effective. Other options include liver transplantation and percutaneous treatments.[3] However, there are limited donor livers available, and percutaneous treatments can only be used on patients with early unresectable HCC.[3] Most patients with liver cancer are diagnosed with advanced HCC, which limits their treatment options see more to the oral chemotherapeutic agent, sorafenib (Nexavar; Bayer HealthCare Pharmaceuticals, Montville, NJ, USA). Sorafenib is indicated for HCC patients in Child–Pugh class A and B, but it may not be safe or effective for those in Child–Pugh class C.[4,

5] Sorafenib has been shown to increase the mean survival time by approximately 3 months,[6] but it usually cannot put patients into remission. In this review, we discuss the discovery, molecular mechanisms, clinical trials, resistance mechanisms, autophagy induction and combined treatments of sorafenib. SORAFENIB IS A bi-aryl urea. Its chemical name is N-(3-trifluoromethyl-4-chlorophenyl)-N′-(4-[2-methylcarbamoyl pyridin-4-yl] oxyphenyl) urea. Sorafenib was developed by Bayer and Onyx in 1995.[7, 8] The path MTMR9 to development had begun in the 1980s, when oncogenes were discovered. Many oncogenes affect the growth factors, growth factor receptor kinases or non-receptor tyrosine kinases of

the MAPK pathway. Because Raf1 (also known as c-Raf) is the first member of this pathway, efforts were focused on this molecule. When overexpressed, Raf1 prolongs cell survival and can lead to many types of cancers, even in the absence of oncogenic mutations. A study conducted by Kasid et al. found that disrupting the Raf1 gene hinders the growth of human breast, ovarian and lung tumor xenographs in athymic mice, confirming Raf as a suitable anticancer target.[9] After the scintillation proximity assay for high-throughput screening of MAPK pathway inhibitors had been developed by McDonald et al.,[10] Bayer and Onyx were ready to screen molecules for Raf inhibition. They tested over 200 000 compounds, eventually finding that the promising 3-thienyl urea 1 had a Raf1 half maximal inhibitory concentration (IC50) of 17 μM.