CCR 20th Anniversary Commentary: Preclinical Study of Proteasome Inhibitor Bortezomib in Head and Neck Cancer
| Autor: | J B, Sunwoo, Z, Chen, G, Dong, N, Yeh, C, Crowl Bancroft, E, Sausville, J, Adams, P, Elliott, C, Van Waes |
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| Rok vydání: | 2015 |
| Předmět: |
Oncology
Proteasome Endopeptidase Complex Cancer Research medicine.medical_specialty Cell Survival Gene Expression Antineoplastic Agents Mice SCID medicine.disease_cause Article Bortezomib Mice Multienzyme Complexes Internal medicine Tumor Cells Cultured medicine Animals Humans In patient Mice Inbred BALB C Neovascularization Pathologic business.industry Head and neck cancer NF-kappa B Cancer Neoplasms Experimental NFKB1 medicine.disease Boronic Acids Xenograft Model Antitumor Assays Clinical trial Cysteine Endopeptidases Disease Models Animal Treatment Outcome Pyrazines Immunology Carcinoma Squamous Cell Proteasome inhibitor Blood Vessels Cytokines business Carcinogenesis Cell Division Neoplasm Transplantation medicine.drug |
| Zdroj: | Clinical Cancer Research. 21:942-943 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-14-2550 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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