Abstract
Sorafenib is approved for the treatment of hepatocellular carcinoma (HCC) and advanced renal cell carcinoma (RCC). However, low tumor response and side effects have been widely reported. Therefore, to improve the efficacy of sorafenib, we investigated whether combined treatment with sorafenib and kahweol, the coffee-specific diterpene, has a synergistic effect on apoptotic cell death. Combined treatment with sorafenib and kahweol markedly induced caspase-mediated apoptosis in renal carcinoma Caki cells. Combined treatment with sorafenib and kahweol induced down-regulation of Mcl-1 and c-FLIP expression. We found down-regulation of Mcl-1 and c-FLIP expression was modulated by the ubiquitin-proteasome pathway. Ectopic expression of Mcl-1 inhibited sorafenib plus kahweol-induced apoptosis. Interestingly, combined treatment with sorafenib and kahweol induced apoptotic cell death in c-FLIP overexpressed cells. In addition, combined treatment with sorafenib and kahweol markedly induced apoptosis in human lung carcinoma (A549) and breast carcinoma (MDA-MB-361) cells, but not in human normal mesangial cells and human skin fibroblast cells (HSF). Collectively, our study demonstrates that combined treatment with sorafenib and kahweol induces apoptotic cell death through down-regulation of Mcl-1 expression.
Highlights
Sorafenib, a tyrosine kinase inhibitor, possesses potential inhibitory activity against several receptor tyrosine kinases including vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor-β (PDGFR-β) [1]
These results indicated that combined treatment with sorafenib and kahweol induces caspase-dependent apoptosis and down-regulation of Mcl-1 and c-FLIP expression
Because Mcl-1 protein stability is well known to be regulated by the ubiquitinproteasome pathways [17], we examined whether proteasome inhibitors (MG132 and lactacystin) reverse sorafenib plus kahweol-induced Mcl-1 downregulation
Summary
A tyrosine kinase inhibitor, possesses potential inhibitory activity against several receptor tyrosine kinases including vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor-β (PDGFR-β) [1]. It is an effective chemotherapeutic drug in human hepatocellular, renal, colon and breast cancer [2,3,4,5]. The efficacy of sorafenib is limited, as it improves only survival rate by three months in hepatocellular carcinoma patients [1, 2]. The anti-cancer effect of sorafenib is inhibited by development of multiple drug resistance mechanisms [6]. Combination therapy with other less toxic agents could improve the therapeutic efficacy and reduce the drug resistance of sorafenib
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