Novel Proteasome Inhibitor PS-341 Inhibits Activation of Nuclear Factor-κB, Cell Survival, Tumor Growth, and Angiogenesis in Squamous Cell Carcinoma

Abstract

We have shown that activation of nuclear factor-κB (NF-κB) promotes cell survival and expression of cytokines such as growth-regulated oncogene-α, which can modulate angiogenesis, growth, and metastasis of squamous cell carcinoma (SCC). Activation of NF-κB and cytoprotective genes in cancer may result from signal-induced phosphorylation and proteasome-dependent degradation of inhibitor-κB. In this study, we examined the effects of the novel proteasome inhibitor PS-341 on activation of NF-κB and cell survival, growth, and angiogenesis in murine and human SCC cell lines. PS-341 inhibited activation of NF-κB DNA binding and functional reporter 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 early 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 proangiogenic cytokines growth-regulated oncogene-α and vascular endothelial growth factor by SCC in the range at which PS-341 inhibits NF-κB. We conclude that PS-341 inhibits activation of NF-κB pathway components related to cell survival, tumor growth, and angiogenesis in SCC.