NOVEL GROWTH-INHIBITORY EFFECT OF 8-CL-CAMP IS DEPENDENT ON SERUM FACTORS THAT MODULATE PROTEIN-KINASE-A EXPRESSION BUT NOT THE HYDROLYSIS OF 8-CL-CAMP

8-Chloro-cyclic AMP (8-Cl-cAMP) exhibits growth inhibition in vitro an d in vivo in a broad spectrum of cancer cell lines. We examined whethe r the hydrolyzed metabolite is involved in the effect of 8-Cl-cAMP. 8- Cl-cAMP (5 mu M, 3 days) exerted varying degrees (0-51%) of growth inh ibition on the same cell line cultured in the medium containing differ ent heat-inactivated serum. HPLC analysis neither detected 8-Cl-adenos ine in the medium nor demonstrated any correlation between the decreas e in 8-Cl-cAMP concentration in the medium and the degree of growth in hibition. The low K-m phosphodiesterase activity in the sera did not c orrelate with the varying degrees of growth inhibition. The cAMP-depen dent protein kinase RI(alpha) subunit expression in the same cell line varied widely with the different serum supplements. 8-Cl-CAMP-, but n ot 8-Cl-adenosine-induced, growth inhibition correlated with the basal levels of RI(alpha) and specific downregulation of RI(alpha). 8-Cl-cA MP, but not 8-Cl-phenyl-thio-cAMP or N-6-benzyl-cAMP, inhibited cell g rowth in serum-free medium. These results show that 8-Cl-cAMP induces growth inhibition through down-regulation of protein kinase A type I i n the absence of its hydrolysis.