AZD6244 and doxorubicin induce growth suppression and apoptosis in mouse models of hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide, with no effective treatment for most individuals who succumb to this neoplasm. We report that treatment of primary HCC cells with the

AZD6244 enhances the anti-tumor activity of sorafenib in ectopic and orthotopic models of human hepatocellular carcinoma (HCC)

“…AZD6244, is an inhibitor of the MEK/ERK signaling pathway [27,28], and sorafenib, an inhibitor of angiogenesis [21]. As predicted, AZD6244 abolished the phosphorylation of ERK at Thr202/Tyr204 (phospho-ERK) and sorafenib inhibited phospho-VEGFR-2 Tyr951 and PDGFR-b Tyr1021 (Fig.…”

Signaling Pathways in Liver Cancer

“…Mutation in the RAS gene has been reported in 10-30% of HCC tumors (Whittaker et al, 2010). The involvement of the ERK pathway in HCC is further confirmed by preclinical studies using the MEK inhibitor, AZD6244, which blocks proliferation and promotes apoptosis in primary HCC cells (Huynh et al, 2007a;Huynh et al, 2007b). AZD6244 also suppresses tumor growth in HCC xenograft model in a dose-dependent manner.…”

“…And tumor growth inhibition after AZD6244 treatment correlates with inactivation of ERK, up-regulation of apoptotic genes such as caspase-3 and 7 and down-regulation of cell cycle regulators such as cyclin D1. It has also been shown that AZD6244 can induce a synergistic effect in tumor suppression when combined with chemotherapeutic agent doxorubicin (Huynh et al, 2007a;Huynh et al, 2007b).…”

The role of signaling pathways in the development and treatment of hepatocellular carcinoma

“…The antitumor activity of AZD6244 correlates with levels of phosphorylated MEK (Huynh et al, 2007b) and one study suggests that AZD6244 may be effectively combined with doxorubicin in patients with HCC (Huynh et al, 2007a). These data suggest that CRAF drugs could also produce antitumor activity in HCC, and a recent report has highlighted the importance of CRAF in HCV viral replication, suggesting that it may also have a role in HCC tumor initiation (Himmelsbach et al, 2009).…”