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

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

Research output: Contribution to journalArticle

6 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)116-125
Number of pages10
JournalJournal of Surgical Research
Volume164
Issue number1
DOIs
StatePublished - Nov 1 2010

Keywords

  • Selcids
  • angiogenesis
  • small molecule inhibitor

ASJC Scopus subject areas

  • Surgery

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    Vu, H. N., Miller, W. J., O'Connor, S. A., He, M., Schafer, P. H., Payvandi, F., Muller, G. W., Stirling, D. I., & Libutti, S. K. (2010). CC-5079: A small molecule with MKP1, antiangiogenic, and antitumor activity. Journal of Surgical Research, 164(1), 116-125. https://doi.org/10.1016/j.jss.2009.01.031