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

• Published in: Cancer research (Chicago, Ill.) Vol. 66; no. 2; pp. 951 - 959
• Main Authors: ZHANG, Ling-Hua, LEI WU, BARTLETT, J. Blake, SCHAFER, Peter H, PAWANDI, Faribourz, RAYMON, Heather K, CHEN, Roger S, CORRAL, Laura, SHIRLEY, Michael A, NARLA, Rama Krishna, GAMEZ, Jim, MULLER, George W, STIRLING, David I
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-01-2006
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Cell Cycle - drug effects; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; General aspects; Humans; Medical sciences; Mice; Neoplasms - pathology; Nitriles - pharmacology; Pharmacology. Drug treatments; Transplantation, Heterologous; Tubulin - metabolism; Tubulin Modulators - pharmacology; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha - biosynthesis; Tumors; Antineoplastic agent; Synthetic product; Tubulin; Cytokine; Polymerization; Inhibitor; Mechanism of action; Antimitotic; Biological activity; Tumor necrosis factor α; Research and development
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-05-2083

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.