Protein kinase C inhibitors arrest the C6 glioma cell cycle at a mid-G1 phase restriction point: Implications for the antiproliferative action of valproate

Toxicology in Vitro : an International Journal Published in Association with BIBRA
E O'Brien, C M Regan

Abstract

The teratogenic mechanism(s) of valproate (VPA) have been suggested to arise through inhibition of proliferation coupled with differentiation at a mid-G1 phase restriction point in the cell cycle. As protein kinase C (PKC) plays a pivotal role in cell proliferation and differentiation, the effect of inhibitors specific for the catalytic and regulatory domains on transit through the G1 phase of the cell cycle was determined. Calphostin C and bisindolylmaleimide GF 109203X produced a dose-dependent decrease in proliferation of C6 glioma with approximate 50% inhibitory concentration values of 10nm and 1mum, respectively. Flow cytometric analysis indicated proliferative arrest to be in the G1 phase with the expected concomitant decrease of cells in the G2/M and S phases. Following release from drug-induced proliferative arrest, cells exhibited a synchronous entry into S phase as evidenced by an increase in [(3)H]thymidine incorporation after approximately 6-8hr, indicating the restriction point to be in the mid-G1 phase. Using mitotically synchronized cells continuously exposed to valproate (2mm), PKC activity was found to be significantly reduced in the mid-G1 phase (5.5hr) but not at an earlier (2.5hr) time point, implying VPA to...Continue Reading

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Citations

Mar 6, 2004·Neurotoxicology and Teratology·Helen C GallagherCiaran M Regan
Mar 10, 2000·International Journal of Developmental Neuroscience : the Official Journal of the International Society for Developmental Neuroscience·G O'LearyC M Regan
Dec 2, 2005·Archives of Microbiology·Allison M L van de MeeneRobert W Roberson
Oct 22, 2010·Nature·Nick Lane, William Martin

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