An exochelin of Mycobacterium tuberculosis reversibly arrests growth of human vascular smooth muscle cells in vitro.
Proliferation of vascular smooth muscle cells (VSMC) is characteristic of restenosis following balloon angioplasty. We show here that a low concentration of a novel iron chelator, desferri-exochelin 772SM, reversibly arrests the growth of human VSMC in vitro, specifically in G(0)/G(1) and S phases. The lipophilic desferri-exochelin is effective more rapidly and at a 10-fold lower concentration than the nonlipophilic iron chelator deferoxamine. Treatment of growth-synchronized VSMC with the desferri-exochelin results in down-regulation of cyclin E/ Cdk2 and cyclin A/Cdk2 activity but does not affect the cyclin D/Cdk4/retinoblastoma phosphorylation pathway. Both DNA replication and RNA transcription are inhibited in exochelin-treated cells, but protein synthesis is not. The ability of desferri-exochelin 772SM to reversibly block the growth of VSMC in vitro with no apparent cytotoxicity suggests that the exochelin may be useful as a therapeutic agent to limit restenosis in injured vessels.
Pahl
P M
PM
Division of Cardiology, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
Yan
X D
XD
Hodges
Y K
YK
Rosenthal
E A
EA
Horwitz
M A
MA
Horwitz
L D
LD
D001011:Aorta; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D003676:Deferoxamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005290:Ferric Compounds / Q000494:pharmacology*; D006801:Humans; D007083:Iliac Artery; D007502:Iron Chelating Agents / Q000494:pharmacology*; D007700:Kinetics; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects; D009169:Mycobacterium tuberculosis; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D012501:Saphenous Vein
D019927:Cyclin E; D005290:Ferric Compounds; D007502:Iron Chelating Agents; D010456:Peptides, Cyclic; D016160:Retinoblastoma Protein; C410730:desferriexochelin 772SM; C016451:ferriexochelin; D004815:Epidermal Growth Factor; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D003676:Deferoxamine