e16114 Sorafenib, vorinostat and the combination were examined in 34 RCC and NSCLC cell lines. In growth assays, sorafenib at 8 μM resulted in synergy with multiple vorinostat doses, whereas no synergy was seen with lower doses. Changes in phospho-ERK and AKT were not predictive of growth inhibition, whereas frequent inhibition of cyclin D1 and upregulation of p21Waf1 was observed. To anticipate resistance mechanisms to the anti-angiogenic effects of sorafenib, we studied the expression of 13 angiogenic factors in 10 selected lines. At baseline, bFGF, VEGF and IL-8 were highly expressed in RCCs, whereas Gro-α, VEGF, and IL-8 predominated in NSCLCs. Multiple angiogenic factors were upregulated by sorafenib and vorinostat, especially VEGF, IL-6, CTGF, EDN1, PDGFβ, and IL-8. Importantly, sorafenib at 8 μM, but not lower doses, induced ER stress in these cell lines and thapsigargin or tunicamycin treatment recapitulated many, but not all, of the observed angiogenic gene responses to sorafenib. In fact, CHOP induction by sorafenib plus vorinostat was the only parameter, other than growth inhibition, that changed in a synergistic manner. In summary, sorafenib plus vorinostat potently inhibits the in vitro growth of RCC and NSCLC cell lines. Upregulation of multiple angiogenic genes, in part by an ER-stress mechanism, may contribute to acquired resistance in vivo. No significant financial relationships to disclose.
Correction: In vitro vascularization of tissue engineered constructs by non-viral delivery of pro-angiogenic genes
