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Novel Proteasome Inhibitor PS-341 Inhibits Activation of Nuclear Factor-B, Cell Survival, Tumor Growth, and Angiogenesis in Squamous Cell Carcinoma¹

Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, Maryland 20892 [J. B. S., Z. C., G. D., N. Y., C. C. B., C. V. W.]; Developmental Therapeutics Program, National Cancer Institute, NIH, Rockville, Maryland 20850 [E. S.]; and Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139 [J. A., P. E.]

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

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