The synthetic compound CC-5079 is a potent inhibitor of tubulin polymerization and tumor necrosis factor-alpha production with antitumor activity.

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.

• Authors: Ling-Hua Zhang, Lei Wu, Heather K Raymon, Roger S Chen, Laura Corral, Michael A Shirley, Rama Krishna Narla, Jim Gamez, George W Muller, David I Stirling, J Blake Bartlett, Peter H Schafer, Faribourz Payvandi
• Journal: Cancer research (Cancer Res) Vol. 66 Issue 2 Pg. 951-9 (Jan 15 2006) ISSN: 0008-5472 [Print] United States
• PMID: 16424030 (Publication Type: Journal Article)

Chemical References

• CC-5079
• Nitriles
• Tubulin
• Tubulin Modulators
• Tumor Necrosis Factor-alpha

Topics

• Animals
• Cell Cycle (drug effects)
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Humans
• Mice
• Neoplasms (pathology)
• Nitriles (pharmacology)
• Transplantation, Heterologous
• Tubulin (metabolism)
• Tubulin Modulators (pharmacology)
• Tumor Cells, Cultured
• Tumor Necrosis Factor-alpha (biosynthesis)