CC-5079: A Small Molecule with MKP1, Antiangiogenic, and Antitumor Activity

• Published in: The Journal of surgical research Vol. 164; no. 1; pp. 116 - 125
• Main Authors: Vu, Huan N., M.D, Miller, Walter J., D.O, O'Connor, Sarah A., B.S, He, Mei, M.S, Schafer, Peter H., Ph.D, Payvandi, Faribourz, Ph.D, Muller, George W., Ph.D, Stirling, David I, Libutti, Steven K., M.D
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.11.2010; Elsevier
• Subjects: angiogenesis; Angiogenesis Inhibitors - chemistry; Angiogenesis Inhibitors - pharmacology; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Aorta - cytology; Biological and medical sciences; Cell Division - drug effects; Cell Line, Tumor; Cell Movement - drug effects; Chickens; Chorioallantoic Membrane - cytology; Colonic Neoplasms - drug therapy; Colonic Neoplasms - metabolism; Dual Specificity Phosphatase 1 - genetics; Dual Specificity Phosphatase 1 - metabolism; Endothelial Cells - cytology; Endothelial Cells - drug effects; Fibroblasts - cytology; Fibroblasts - drug effects; Gene Expression Regulation, Enzymologic - drug effects; General aspects; Humans; Lymphocytes - cytology; Lymphocytes - drug effects; Medical sciences; Mice; Nitriles - chemistry; Nitriles - pharmacology; Rats; Selcids; small molecule inhibitor; Surgery; Umbilical Veins - cytology; Selcids; angiogenesis; small molecule inhibitor; Antineoplastic agent; Medicine; Angiogenesis; Molecules; Treatment; Surgery; Inhibitor; Neovascularization; Antiangiogenic agent; Biological activity
• ISSN: 0022-4804; 1095-8673
• DOI: 10.1016/j.jss.2009.01.031

Introduction CC-5079, a small molecule inhibitor of tubulin polymerization and phosphodiesterase-4 activity, was evaluated for antiangiogenic and antitumor activities. Materials and Methods First, CC-5079 in vitro activity on human umbilical vein endothelial cells (HUVECs), fibroblasts, and MC38 were evaluated by proliferation, migration, and invasion assays. Second, CC-5079 effect on microvessel formation was evaluated ex vivo by chick chorioallantoic membrane (CAM), rat aortic rings assays, and with directed in vivo angiogenesis assay (DIVAA). Third, CC-5079 antitumor effect was determined in treatment of C57BL/6 mice with MC38 tumors. Finally, CC-5079 modulation of MKP1 in HUVECs, human fibroblast, and MC38 were determined by RNA isolation for qRT-PCR. Results At the 0.1 μM concentration CC-5079 significantly inhibited HUVEC, fibroblast, and MC38 proliferation and migration (all P < 0.001). At the 0.1 μM concentration, CC-5079 also inhibited HUVEC invasion ( P < 0.05) but not fibroblast. In the CAM and rat aortic ring assays, CC-5079 at 0.1 μM inhibited microvessel formation ( P < 0.05). By DIVAA, CC-5079 at 1 mg/kg/d continuous delivered inhibited microvessel formation ( P < 0.05). Intraperitoneal CC-5079 was well tolerated and inhibited the growth of subcutaneous MC38 at 100 mg/kg/d ( P < 0.01). By qRT-PCR, CC-5079 stimulated MKP1 expression in HUVEC and fibroblast. Conclusion CC-5079 demonstrated stimulation of MKP1, antiangiogenic, and antitumor properties.