Epothilone D, a microtubule-stabilizing compound, inhibits neointimal hyperplasia after rat carotid artery injury by cell cycle arrest via regulation of G1-checkpoint proteins.
Epothilone D (Epo-D) is a paclitaxel-like microtubule-stabilizing agent that was isolated from the myxobacterium Sorangium cellulosum. Although Epo-D can inhibit proliferation in multiple tumor cell lines, the effect of Epo-D on neointimal hyperplasia after angioplasty has not been reported. The aim of the present study was to investigate the effects of Epo-D on neointimal hyperplasia using an in vivo rat carotid artery injury model. We demonstrated that local Epo-D treatment significantly reduced neointimal hyperplasia after in vivo rat carotid artery injury, and Epo-D potently inhibited DNA synthesis, cell cycle progression and cell proliferation after FBS- and PDGF-BB-stimulation; PDGF-BB has been identified as the most potent growth factor for stimulating the proliferation of activated rat aortic smooth muscle cells (RASMCs). To clarify the specific effects of Epo-D on cell cycle machinery, we examined its effects on cyclin-dependent kinase (CDK)2, CDK4, cyclin E, p27, and retinoblastoma (Rb) proteins as cell cycle-related proteins in cellular lysates from PDGF-BB-stimulated RASMCs. Epo-D treatment significantly decreased the level of CDK2 protein, but did not change the levels of CDK4 and cyclin E proteins. Furthermore, Epo-D inhibited the phosphorylation of Rb, a key regulator of the G1 to S phase transition in the cell cycle. These findings suggest that Epo-D may regulate the cell cycle G1-checkpoint proteins as its major molecular mechanism for inhibiting neointimal hyperplasia after in vivo rat carotid artery injury.
Kim
Tack-Joong
TJ
College of Pharmacy, Research Center for Bioresource and Health, Chungbuk National University, 12 Gaesin-Dong, Heungduk-Gu, Cheongju 361-763, Republic of Korea.
Lim
Yong
Y
Kim
Dong-Woon
DW
Kwon
Jin-Sook
JS
Son
Ju-Hee
JH
Jin
Yong-Ri
YR
Son
Dong Ju
DJ
Jung
Jae-Chul
JC
Avery
Mitchell A
MA
Hong
Jin Tae
JT
Yun
Yeo-Pyo
YP
D000818:Animals; D000077214:Becaplermin; D020212:Carotid Artery Injuries / Q000188:drug therapy* / Q000473:pathology; D051357:Cyclin-Dependent Kinase 2 / Q000032:analysis; D051358:Cyclin-Dependent Kinase 4 / Q000032:analysis; D034261:Epothilones / Q000494:pharmacology*; D016193:G1 Phase / Q000187:drug effects*; D006965:Hyperplasia; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000473:pathology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013936:Thymidine / Q000378:metabolism; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology
D034261:Epothilones; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; C495892:Cdk2 protein, rat; C495903:Cdk4 protein, rat; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; C114026:desoxyepothilone B; D013936:Thymidine