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Inhibition of the Chemotactic Peptide-induced Elevation of Intracellular Calcium in Differentiated Human Leukemic (HL-60) Cells by the Phorbol Ester Phorbol 12-Myristate 13-Acetate¹

Cancer Research Campaign Experimental Chemotherapy Group, Pharmaceutical Sciences Institute, Aston University, Aston Triangle, Birmingham B4 7ET, United Kingdom

The chemotactic peptide formylmethionylleucylphenylalanine rapidly elevated the intracellular calcium concentration, in a concentration-dependent manner, of human leukemic (HL-60) cell which had been differentiated to polymorphonuclear leukocyte-like cells by pretreatment with dimethyl sulfoxide (1.3%). Preincubation of the cells with phorbol 12-myristate 13-acetate, a protein kinase C-activating phorbol ester, inhibited the formylmethionylleucylphenylalanine-induced rise in intracellular calcium in a time- and concentration-dependent manner. 4-Phorbol 12,13-didecanoate, which does not activate protein kinase C, was inactive in this capacity. The use of calcium-free medium suggested that the elevation of intracellular calcium by formylmethionylleucylphenylalanine consisted of rapid intracellular release followed by calcium influx. Phorbol 12-myristate 13-acetate (10^-7 M) inhibited both components of the elevation of intracellular calcium, whereas 10^-8 M phorbol 12-myristate 13-acetate inhibited only the calcium influx. The influx of calcium was not prevented by verapamil, which blocks the voltage-dependent calcium channels. These data suggest that, in differentiated HL-60 cells, 12-O-tetradecanoylphorbol-13-acetate rapidly inhibits both the intracellular release of calcium and calcium influx through nonvoltage-dependent calcium channels in response to formylmethionylleucylphenylalanine.

¹ Supported by Grant SP 1518 from the Cancer Research Campaign.

² To whom requests for reprints should be addressed.

Received 4/21/87. Revised 9/28/87. Revised 1/22/88. Accepted 2/ 1/88.