Caffeine and the G2/M block override: a concept resulting from a misleading cell kinetic delay, independent of functional p53.
In the literature the sensitization of DNA to radiation-induced damage by caffeine has been attributed to an override of the G2/M block. This process was supposed to involve the tumor suppressor gene p53 as it was described that p53 negative cells were more sensitive to checkpoint inhibition by caffeine than the wildtype phenotype. We have recently shown that caffeine does not cause an override of the G2/M block induced by radiation in normal human fibroblasts. We demonstrate here that this also applies to a human transformed cell line, the thyroid carcinoma K1, when submitted to gamma- rays irradiation. Within 9 hr after irradiation over 70% of the cells accumulated in the G2/M phase. This block persisted at 16 hr. In caffeine containing cultures the percentage of cells attaining the G2/M phase was reduced by over 30% at 16 hr. This was reflected in an accumulation of the cells in G1 phase and an inhibition of the S phase traverse. Cell cycle analyses from further time points combined with cell proliferation measurements confirmed these data. These results were independent of p53 status as experiments performed with variant K1 cell lines having defective p53 functions, led to similar conclusions. In addition, caffeine restored a G1 delay after irradiation in the cell lines with abrogated p53 functions. The effects of caffeine undeniably cumulate with damages induced by irradiation but probably by inhibiting DNA repair mechanisms or by intervening with purine and pyrimidine metabolisms and not by causing a G2/M block override.
Deplanque
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Laboratoire de Cancérologie Expérimentale et de Radiobiologie, Institut de Recherche contre les Cancers de l'Appareil Digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Céraline
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J
Mah-Becherel
M C
MC
Cazenave
J P
JP
Bergerat
J P
JP
Klein-Soyer
C
C
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002110:Caffeine / Q000494:pharmacology*; D002453:Cell Cycle; D002455:Cell Division; D002461:Cell Line, Transformed; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D003703:Demecolcine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000378:metabolism; D016195:G2 Phase / Q000187:drug effects* / Q000528:radiation effects; D005720:Gamma Rays; D005799:Genes, Dominant; D006801:Humans; D007700:Kinetics; D008938:Mitosis / Q000187:drug effects* / Q000528:radiation effects; D009154:Mutation; D010641:Phenotype; D011687:Purines / Q000378:metabolism; D011743:Pyrimidines / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D000972:Antineoplastic Agents, Phytogenic; D000697:Central Nervous System Stimulants; D011687:Purines; D011743:Pyrimidines; D016159:Tumor Suppressor Protein p53; D002110:Caffeine; D004247:DNA; C030986:pyrimidine; C030985:purine; D003703:Demecolcine