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- W1584896875 abstract "AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA4404 Novel therapeutic strategies are needed to improve long-term survival of patients with neuroblastoma. Because expansive tumor growth is dependent on an adequate supply of oxygen, therapeutic regimens with direct activity against tumor cells as well as the associated vasculature and the will likely provide the greatest clinical benefit. Small-molecule inhibitors sunitinb, which has activity against VEGFR-1,2,3, PDGFR, Kit, RET, and sorafenib, which inhibits VEGFR-2,3, PDGFR, RET, and Kit have been shown to restrict tumor angiogenesis in multiple tumor models. We investigated whether these receptor tyrosine kinase inhibitors (RTKIs) have direct effects against neuroblastoma cells. We evaluated 7 neuroblastoma cell lines for expression of receptor tyrosine kinases. While neuroblastoma cell lines were heterogeneous in the expression of VEGFR-1, cKit, and RET, the majority of tumor cells expressed PDGFR-α and PDGFR-β. In vitro cell viability studies revealed that sunitinib and sorafenib have direct anti-tumor cell activity with IC50s below 1μM and 10μM respectively. In contrast, the majority of neuroblastoma cell lines were resistant to imatinib with IC50 values above 10μM. Flow cytometry was utilized to evaluate the effect of sunitinib and sorafenib on cell cycle progression and apoptosis on three neuroblastoma cell lines, SH-EP, CHP-134, and SK-N-AS. Both sunitinib and sorafenib effectively decreased the number of cycling cells, whereas only sunitinib induced apoptosis in all cell lines tested. Additionally, sunitinib significantly inhibited VEGFB-mediated migration of SK-N-AS cells while sorafenib did not, suggesting that the effect of sunitinib on cell migration is mediated through inhibition of VEGFR-1. Recently, RTKs such as VEGFR-1 have been shown to be part of a hypoxia-driven autocrine loop involving HIF-1α. To determine the effect of RTKIs on tumor cell response to hypoxia, neuroblastoma cells were incubated in hypoxic conditions with or without sunitinib or sorafinib, and HIF-1α expression was evaluated. Our results indicate that sunitinib and sorafenib diminish hypoxia-induced elevation of HIF-1α. Moreover, sunitinib and sorafenib significantly reduced hypoxia-induced VEGF expression in SY5Y neuroblastoma cells. These findings suggest that these agents may exert antiangiogenic effects by blockade of VEGF signaling as well as by inhibition of hypoxia-induced upregulation of proangiogenic factors in tumors." @default.
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- W1584896875 date "2007-05-01" @default.
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- W1584896875 title "Sunitinib and sorafenib exert direct effects on neuroblastoma cells and inhibit hypoxia-induced increases in HIF-1α and VEGF" @default.
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