Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Cancer research (Chicago, Ill.), 2006-01, Vol.66 (2), p.951-959

Ort / Verlag

Philadelphia, PA: American Association for Cancer Research

Erscheinungsjahr

2006

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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.