At pharmacologically relevant concentrations, dovitinib did not affect HCC cells. Other groups have reported that dovitinib concentra tions lower than 1 umolL are sufficient to inhibit RTK signaling. In cellular assays, Andrew and collea gues found that dovitinib inhibited FGFR signaling protein inhibitor in BaFs cells lines of myeloproliferative syndrome with IC50 values of 0. 090. 15 umolL, consistent with our studies on endothelial cells. Finally, both clinical and preclinical pharmacodynamic studies showed that pharmacologically Inhibitors,Modulators,Libraries and clinically relevant plasma concen trations of dovitinib are 0. 010. 3 umolL. A recent study using a high concentration of dovitinib reported that anchorage independent growth and FGF induced motility Inhibitors,Modulators,Libraries of HCC cells was inhibited.

Unfortunately, this study did not evaluate the effect of dovitinib on endothelial cells, and the con centration used was much higher than a pharmacologic Inhibitors,Modulators,Libraries ally relevant dose. In our study, dovitinib at 0. 1 umolL did not affect the viability or proliferation of HCC cell lines in vitro. In contrast, it did inhibit endothelial cell proliferation and motility at concentrations that also inhibited VEGFR and FGFR signaling in these cells. Stud ies of HCC xenografts treated with pharmacologically relevant concentrations of dovitinib showed more effect on the inhibition of tumor angiogenesis in vivo than on proliferation or apoptosis. Taken together, these data in dicate that dovitinib acts preferentially to target tumor vasculature rather than cancer cells in the treatment of HCC.

Some previous studies have reported that high expres sion of the angiogenic factors VEGF, basic FGF, and platelet derived growth factor receptor are detected in Inhibitors,Modulators,Libraries patients with HCC, suggesting that VEGFR, FGFR, and PDGFR are likely targets Inhibitors,Modulators,Libraries of dovitinib. Our analysis of HCC and endothelial cell lines found that, of the known dovitinib sensitive RTKs, only PDGFR B was expressed by SMMC7721 and MHCC 97H cells, where VEGFR 2 and FGFR 1 were highly expressed by endothelial cells. Although high PDGFR B expression has been correlated with HCC progression, our in vitro studies showed that dovitinib inhibition of PDGFR signaling was not suffi cient to inhibit the proliferation of HCC cells. Thus, PDGFR signaling in HCC cells is likely through redundant growth signaling pathways.

In contrast, dovitinib inhibited the phosphorylation of VEGFR 2 and FGFR 1 in endothe lial cells at similar concentrations, indicating the import ant role of VEGFR selleck chemical Imatinib and FGFR signaling in the proliferation of endothelial cells. The endothelial cells recruited to the tumor tissue are not only related to blood perfusion of the tumor, but they are also believed to be involved in the cancerstromal cell interaction favoring tumor growth. However, some believe that normal endothelial cells may be the barrier to hematogenous metastasis.