PROTEIN-KINASE-C AND ADENYLATE-CYCLASE AS TARGETS FOR GROWTH-INHIBITION OF HUMAN GASTRIC-CANCER CELLS

In the human gastric adenocarcinoma cell line AGS the effects of the p rotein-kinase-C-activating phorbol ester 12-O-tetradecanoylphorbol 13- acetate (TPA), the protein kinase C inhibitor staurosporine, the adeny late-cyclase activating agent forskolin, and the permeable dibutyryl-a denosine 3',5'-monophosphate (Bt2cAMP) on the proliferation were asses sed. Cell counting followed 5 days of incubation. Prolonged activation of protein kinase C by TPA, inhibition of protein kinase C by stauros porine, activation of adenylate cyclase by forskolin or a direct incre ase of the intracellular cAMP level all result in a dose-dependent gro wth inhibition of AGS gastric tumour cells. Half-maximal inhibition wa s achieved at 100 pM for TPA, 1 nM for staurosporine, 20 muM for forsk olin, and 600 muM for Bt2cAMP. It is concluded that protein kinase C a nd adenylate cyclase play a fundamental role in the growth of AGS gast ric cancer cells. Interference with these enzymes involved in the sign al transduction of growth regulation in tumour cells may represent a t arget in the development of new antiproliferative principles.