Inhibition of cell-cycle progression by acute treatment with various degrees of hypoxia: Modifications induced by low concentrations of misonidazole present during hypoxia

Abstract

The effect on cell-cycle progression in various phases of the cell cycle caused by an acute exposure to hypoxia in absence and presence of misonidazole (MISO) was investigated. Exponentially growing and synchronized cells of the human line NHIK 3025 were exposed to different degrees of hypoxia for a short period (1.5 or 3 h). The cell-cycle progression was studied both during and after hypoxia by flow-cytometric recording of DNA-histograms from treated and untreated cells. The rate of cell-cycle progression was reduced during hypoxia only if the O2-concentration was below 1000 ppm. The inhibition was phase specific with a strong effect in S (reduced DNA-synthesis), and a specific cell-cycle inhibition in late G1, probably at the G1/S-border. For cells inhibited (or arrested for extreme hypoxia) at the G1/S-border, the cell-cycle progression changed back to normal shortly after aerobic conditions were re-established. For cells rendered hypoxic and inhibited during S, hypoxia exerted a lasting effect expressed by a low cell-cycle progression rate even after aerobic conditions were re-established. This effect was strongly dependent on both the degree and the duration of the hypoxic treatment. The presence of a low concentration of MISO (0.05 mM) during hypoxia did not affect the cell-cycle progression during hypoxia at any O2-concentration. For cells rendered hypoxic during S, however, MISO (0.05 mM) counteracted the lasting effect of hypoxia for all concentrations of O2 where this lasting effect was observed.