The Synthetic Compound Cc-5079 is a Potent Inhibitor of Tubulin Polymerization and Tumor Necrosis Factor-alpha Production with Antitumor Activity.
From: Division of Immunotherapeutics, Celgene Corp., 86 Morris Avenue, Summit, NJ 07901, USA. Lzhang@celgene.com
Cancer research
- Publish Date: Jan 2006
- ISSN: 0008-5472
- Volume: 66
- Issue: 2
- Pages: 951-9
- Medium: Print
- Language: English
- Citation (JAMA): Zhang Ling-Hua, Wu Lei, Raymon Heather K, et al. The Synthetic Compound Cc-5079 is a Potent Inhibitor of Tubulin Polymerization and Tumor Necrosis Factor-alpha Production with Antitumor Activity.. Cancer Res. Jan 2006;66:951-9
Abstract
We have found that the synthetic compound CC-5079 potently inhibits cancer cell growth in vitro and in vivo by a novel combination of molecular mechanisms. CC-5079 inhibits proliferation of cancer cell lines from various organs and tissues at nanomolar concentrations. Its IC(50) value ranges from 4.1 to 50 nmol/L. The effect of CC-5079 on cell growth is associated with cell cycle arrest in G(2)-M phase, increased phosphorylation of G(2)-M checkpoint proteins, and apoptosis. CC-5079 prevents polymerization of purified tubulin in a concentration-dependent manner in vitro and depolymerizes microtubules in cultured cancer cells. In competitive binding assays, CC-5079 competes with [(3)H]colchicine for binding to tubulin; however, it does not compete with [(3)H]paclitaxel (Taxol) or [(3)H]vinblastine. Our data indicate that CC-5079 inhibits cancer cell growth with a mechanism of action similar to that of other tubulin inhibitors. However, CC-5079 remains active against multidrug-resistant cancer cells unlike other tubulin-interacting drugs, such as Taxol and colchicine. Interestingly, CC-5079 also inhibits tumor necrosis factor-alpha (TNF-alpha) secretion from lipopolysaccharide-stimulated human peripheral blood mononuclear cells (IC(50), 270 nmol/L). This inhibitory effect on TNF-alpha production is related to its inhibition of phosphodiesterase type 4 enzymatic activity. Moreover, in a mouse xenograft model using HCT-116 human colorectal tumor cells, CC-5079 significantly inhibits tumor growth in vivo. In conclusion, our data indicate that CC-5079 represents a new chemotype with novel mechanisms of action and that it has the potential to be developed for neoplastic and inflammatory disease therapy.
Mesh Headings (Keywords): Animals, Cell Cycle, Cell Proliferation, Dose-Response Relationship, Drug, Humans, Mice, Neoplasms, Nitriles, Transplantation, Heterologous, Tubulin, Tubulin Modulators, Tumor Cells, Cultured, Tumor Necrosis Factor-alpha
Check for Full Text / PubMed Unique Identifier (PMID): 16424030
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