DNA damage-associated cell cycle and cell death control is differentially modulated by caffeine in clones with p53 mutations.
Caffeine is known to potentiate the cytotoxic effects of DNA damaging agents and increases the sensitivity of p53-deficient cells to X-irradiation (X-IR). We have analyzed the cell cycle and cell death control after X-IR in the absence or presence of caffeine in hematological cell lines with various configurations of the p53 gene; EBV-immortalized lymphoblastoid cells with heterozygous p53 mutation (wt/mt), human leukemia cell lines HL60 and KOPM28 with no and mutant p53 expression, respectively. These cell lines display an impaired G0/G1 checkpoint and G2 delay following X-IR, and resistance to apoptosis, which are in accordance with findings previously reported. When irradiated in combination with caffeine, all these cell lines overrode the G2 delay and accumulated at G0/G1. The cell cycle modifications in these cell lines correlated with the increase in radiation-induced p34Cdc2 kinase activity by caffeine. These cell cycle control modifications by caffeine, however, were not associated with enhancement of radiation-induced apoptosis or reduction of clonogenic growth activity in these cell lines. These results suggest that the cytocidal effect of caffeine may need to be verified independently of its cell cycle regulatory activities at least in some cases with p53 mutation.
Department of Virology, The National Children's Medical Research Center, Juntendo University School of Medicine, Tokyo, Japan.
M
M
Takagi
T
T
Shigeta
M
M
Asada
S
S
Iwata
S
S
Nakazawa
Y
Y
Kanke
K
K
Ishimoto
S
S
Mizutani
D019943:Amino Acid Substitution; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002110:Caffeine / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002461:Cell Line, Transformed; D002999:Clone Cells; D004249:DNA Damage; D004789:Enzyme Activation; D016158:Genes, p53; D018095:Germ-Line Mutation; D018922:HL-60 Cells; D004854:Herpesvirus 4, Human / Q000235:genetics*; D006801:Humans; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D011003:Ploidies; D017354:Point Mutation; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics; D014965:X-Rays
D016159:Tumor Suppressor Protein p53; D002110:Caffeine; D016203:CDC2 Protein Kinase