Radiomimetic cell cycle delay induced by tetranodecanoyl phorbol acetate is enhanced by caffeine and by the protein kinase inhibitor 2-aminopurine.

Abstract

The tumour promoter and protein kinase C agonist, 12-O-tetranodecanoyl-phorbol-13-acetate (TPA), has been reported to show a radiomimetic action because it transiently delays the passage of HeLa cells through the G2 phase, as do ionizing radiation and other DNA damaging agents. Caffeine is known to override the G2 delay imposed by DNA damage; it is shown here that caffeine does not override the radiomimetic delay imposed by TPA in HeLa, but instead enhances it, without affecting G2 progression in control cells. Most of the other agents which more specifically affect some of the diverse range of caffeine targets either do not affect G2 progression after TPA, or delay G2 progression in control cells and exert a further delay in the presence of TPA. The exception is 2-aminopurine, a protein kinase inhibitor which has been shown to have an action similar to that of caffeine is allowing progression of the cell cycle to mitosis after the inhibition of DNA synthesis, without affecting normal cycle progression through G2. This agent, like caffeine, also has the contrary action of retarding cycle progression after TPA. It is concluded that the G2 delays induced by ionizing radiation and by TPA operate by different mechanisms, which are modulated in opposite senses by mechanisms involving protein kinase inhibition.