Apigenin inhibits endothelial-cell proliferation in G(2)/M phase whereas it stimulates smooth-muscle cells by inhibiting P21 and P27 expression.
Apigenin is a plant flavonoid that is thought to play a role in the prevention of carcinogenesis. However, its mechanism of action has not yet been elucidated. Because of the importance of angiogenesis in tumor growth, we investigated the effect of apigenin on endothelial and smooth-muscle cells in an in vitro model. Apigenin markedly inhibited the proliferation, and, to a lesser degree, the migration of endothelial cells, and capillary formation in vitro, independently of its inhibition of hyaluronidase activity. In contrast, it strongly stimulated vascular smooth-muscle-cell proliferation. The molecular mechanisms of apigenin activity were analyzed in these 2 types of cells. Our results show that apigenin inhibits endothelial-cell proliferation by blocking the cells in the G(2)/M phase as a result of the accumulation of the hyperphosphorylated form of the retinoblastoma protein. Apigenin stimulation of smooth-muscle cells was attributed to the reduced expression of 2 cyclin-dependent kinase inhibitors, p21 and p27, which negatively regulate the G(1)-phase cyclin-dependent kinase.
Trochon
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INSERM U353, Institut d'Hématologie, Hôpital Saint-Louis, Université Paris 7, Paris, France.
Blot
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Cymbalista
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Engelmann
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Tang
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Thomaïdis
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Vasse
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Soria
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Lu
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Soria
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D000818:Animals; D047310:Apigenin; D002196:Capillaries / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D002417:Cattle; D002448:Cell Adhesion / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D016213:Cyclins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D005340:Fibrinogen; D005419:Flavonoids / Q000494:pharmacology*; D016195:G2 Phase; D006801:Humans; D008840:Microfilament Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D008938:Mitosis; D009124:Muscle Proteins; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D014162:Transfection
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D005419:Flavonoids; D008840:Microfilament Proteins; D009124:Muscle Proteins; C058992:Tagln protein, mouse; D047310:Apigenin; D005340:Fibrinogen; D018844:Cyclin-Dependent Kinases