Dovitinib, a multiple kinase inhibitor, induces apoptosis and overcomes sorafenib resistance in hepatocellular carcinoma through SHP-1-mediated inhibition of STAT3
Menée in vitro et à l'aide de xénogreffes, cette étude montre que le dovitinib, un inhibiteur de multiples kinases, est susceptible d'induire une apoptose dans les cellules de carcinome hépatocellulaire et dans les cellules résistantes au sorafenib
The multiple kinase inhibitor dovitinib is currently under clinical investigation for hepatocellular carcinoma (HCC). Here, we investigated the mechanistic basis for the effects of dovitinib in HCC. Dovitinib showed significant antitumor activity in HCC cell lines PLC5, Hep3B, Sk-Hep1 and Huh-7. Dovitinib downregulated phospho-STAT3 (p-STAT3) at tyrosine 705 and subsequently reduced the levels of expression of STAT3-related proteins Mcl-1, survivin and cyclin D1 in a time-dependent manner. Ectopic expression of STAT3 abolished the apoptotic effect of dovitinib, indicating that STAT3 is indispensable in mediating the effect of dovitinib in HCC. SHP-1 inhibitor reversed down-regulation of p-STAT3 and apoptosis induced by dovitinib, and silencing of SHP-1 by RNA-interference abolished the effects of dovitinib on p-STAT3, indicating that SHP-1, a protein tyrosine phosphatase, mediates the effects of dovitinib. Notably, dovitinib increased SHP-1 activity in HCC cells. Incubation of dovitinib with pure SHP-1 protein enhanced its phosphatase activity, indicating that dovitinib up-regulates the activity of SHP-1 via direct interactions. In addition, dovitinib induced apoptosis in two sorafenib-resistant cell lines through inhibition of STAT3; and sorafenib-resistant cells showed significant activation of STAT3, suggesting that targeting STAT3 may be a useful approach to overcome drug resistance in HCC. Finally, in vivo, dovitinib significantly suppressed growth of both Huh-7 and PLC5 xenograft tumors and downregulated p-STAT3 by increasing SHP-1 activity. In conclusion, dovitinib induces significant apoptosis in HCC cells and sorafenib-resistant cells via SHP-1-mediated inhibition of STAT3.
http://mct.aacrjournals.org/content/early/2011/12/16/1535-7163.MCT-11-0412.abstract 2011