CC-5079: a small molecule with MKP1, antiangiogenic, and antitumor activity.
BACKGROUND
CC-5079, a small molecule inhibitor of tubulin polymerization and phosphodiesterase-4 activity, was evaluated for antiangiogenic and antitumor activities.


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.


CONCLUSIONS
CC-5079 demonstrated stimulation of MKP1, antiangiogenic, and antitumor properties.
Vu
Huan N
HN
Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA. HNVU@VCU.EDU
Miller
Walter J
WJ
O'Connor
Sarah A
SA
He
Mei
M
Schafer
Peter H
PH
Payvandi
Faribourz
F
Muller
George W
GW
Stirling
David I
DI
Libutti
Steven K
SK
D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001011:Aorta / Q000166:cytology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002645:Chickens; D049033:Chorioallantoic Membrane / Q000166:cytology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects; D051379:Mice; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D014471:Umbilical Veins / Q000166:cytology
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; C507747:CC-5079; D009570:Nitriles; D054638:Dual Specificity Phosphatase 1