EFFECT OF β-ADRENERGIC STIMULANTS ON CYTOTOXICITY OF MITOMYCIN C IN HeLa CELLS

Abstract

Effects of several autonomic agents on the cytotoxicity of mitomycin C in HeLa cells were studied. When β-adrenergic stimulants such as isoproterenol, epinephrine, terbutaline and turobuterol were added at concentrations over 10¹⁴ M 15 to 60 min before mitomycin C, the colony-forming ability of HeLa cells was significantly inhibited more than by mitomycin C alone. The action of isoproterenol and epinephrine on the colony-forming ability of the cells was abolished by propranolol. The intracellular cyclic AMP level of HeLa cells reached the peak of about twofold the basal level at 30 min after the addition of 10^-8 M isoproterenol. In combination with mitomycin C, the high level of intracellular cyclic AMP induced by isoproterenol was maintained for a significantly longer period in comparison with that by isoproterenol alone, while mitomycin C alone caused essentially no change in the cyclic AMP level. The pretreatment with dibutyryl cyclic AMP also enhanced the effect of mitomycin C. From these findings, it is strongly suggested that the synergistic effect of β-adrenergic stimulants on the cytotoxicity of mitomycin C is mediated via stimulation of the β-adrenoceptors of HeLa cells which elevates the intracellular cyclic AMP for a long time in combination with mitomycin C.