CC-5079: a small molecule with MKP1, antiangiogenic, and antitumor activity.

Abstract

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.

• Authors: Huan N Vu, Walter J Miller, Sarah A O'Connor, Mei He, Peter H Schafer, Faribourz Payvandi, George W Muller, David I Stirling, Steven K Libutti
• Journal: The Journal of surgical research (J Surg Res) Vol. 164 Issue 1 Pg. 116-25 (Nov 2010) ISSN: 1095-8673 [Electronic] United States
• PMID: 19726061 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Elsevier Inc. All rights reserved.

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents
• CC-5079
• Nitriles
• Dual Specificity Phosphatase 1

Topics

• Angiogenesis Inhibitors (chemistry, pharmacology)
• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Aorta (cytology)
• Cell Division (drug effects)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Chickens
• Chorioallantoic Membrane (cytology)
• Colonic Neoplasms (drug therapy, metabolism)
• Dual Specificity Phosphatase 1 (genetics, metabolism)
• Endothelial Cells (cytology, drug effects)
• Fibroblasts (cytology, drug effects)
• Gene Expression Regulation, Enzymologic (drug effects)
• Humans
• Lymphocytes (cytology, drug effects)
• Mice
• Nitriles (chemistry, pharmacology)
• Rats
• Umbilical Veins (cytology)