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

Abstract

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

• Authors: J B Sunwoo, Z Chen, G Dong, N Yeh, C Crowl Bancroft, E Sausville, J Adams, P Elliott, C Van Waes
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 7 Issue 5 Pg. 1419-28 (May 2001) ISSN: 1078-0432 [Print] United States
• PMID: 11350913 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Boronic Acids
• Cytokines
• Multienzyme Complexes
• NF-kappa B
• Pyrazines
• Bortezomib
• Cysteine Endopeptidases
• Proteasome Endopeptidase Complex

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Blood Vessels (drug effects)
• Boronic Acids (pharmacology, therapeutic use)
• Bortezomib
• Carcinoma, Squamous Cell
• Cell Division (drug effects)
• Cell Survival (drug effects)
• Cysteine Endopeptidases
• Cytokines (biosynthesis)
• Disease Models, Animal
• Gene Expression (drug effects)
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, SCID
• Multienzyme Complexes (antagonists & inhibitors)
• NF-kappa B (antagonists & inhibitors, metabolism)
• Neoplasm Transplantation
• Neoplasms, Experimental (drug therapy)
• Neovascularization, Pathologic (metabolism)
• Proteasome Endopeptidase Complex
• Pyrazines (pharmacology, therapeutic use)
• Treatment Outcome
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays