Bromodeoxyuridine Induces p53-Dependent and -Independent Cell Cycle Arrests in Human Gastric Carcinoma Cell Lines

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Abstract
Objectives: This study was designed to clarify the effects of bromodeoxyuridine (BrdU) on cell cycle progression and induction of apoptosis, and to demonstrate the role of P53 in these processes. Methods: We continuously exposed four human gastric carcinoma cell lines with different P53 status (P53 wild-type AGS and MKN-45, P53-mutated MKN-28 and P53-deleted KATO-III) to BrdU in asynchronous and synchronous culture conditions, and analyzed DNA histograms of apoptotic and nonapoptotic cells determined by static DNA cytofluorometry. Results: Continuous exposure to 20 µM BrdU after synchronization with hydroxyurea resulted in S phase delay and G1 arrest in MKN-45 and an increase of apoptosis in the first S/G2 phase in AGS and MKN-45. In the second S phase, a delay of 3–6 h was observed in all the four cell lines. In asynchronous cultures, continuous exposures to 20 and 200 µM BrdU for 72 h or more caused growth suppression with G1 and G2 arrests, respectively, in all the cell lines. Conclusions: These data suggested that the BrdU-induced growth suppression of the cell lines examined was mainly caused by cell cycle arrest rather than cell death, and that the cell cycle arrests in the first S and G1 phases (elicited by BrdU in the single DNA strand) and those in the second S, G2 and G1 phases (elicited by BrdU in the double DNA strands) were mediated by p53-dependent and -independent pathways, respectively.