Novel proteasome inhibitor PS-341 inhibits activation of nuclear factor-kappa B, cell survival, tumor growth, and angiogenesis in squamous cell carcinoma

We have shown that activation of nuclear factor-kappaB (NF-kappaB) promotes cell survival and expression of cytokines such as growth-regulated oncogen e-alpha, which can modulate angiogenesis, growth, and metastasis of squamou s cell carcinoma (SCC), Activation of NF-kappaB and cytoprotective genes in cancer may result from signal-induced phosphorylation and proteasome-depen dent degradation of inhibitor-kappaB, In this study, we examined the effect s of the novel proteasome inhibitor PS-341 on activation of NF-kappaB and c ell survival, growth, and angiogenesis in murine and human SCC cell lines. PS-341 inhibited activation of NF-kappaB DNA binding and functional reporte r activity at concentrations between 10(-8) and 10(-7) M. Cytotoxicity was observed at 10(-7) M in four murine and two human SCC lines, and followed e arly cleavage of poly(ADP-ribose) polymerase, a marker of caspase-mediated apoptosis. In vivo, PS-341 inhibited growth of murine and human SCC in mice at doses of 1-2 mg/kg given three times weekly, and dose-limiting toxicity was encountered at 2 mg/kg, Tumor growth inhibition was associated with a marked decrease in vessel density. PS-341 inhibited expression of the proan giogenic cytokines growth-regulated oncogene-cu and vascular endothelial gr owth factor by SCC in the range at which PS-341 inhibits NF-kappaB, We conc lude that PS-341 inhibits activation of NF-kappaB pathway components relate d to cell survival, tumor growth, and angiogenesis in SCC.