INHIBITION OF ATP-SENSITIVE POTASSIUM CHANNELS CAUSES REVERSIBLE CELL-CYCLE ARREST OF HUMAN BREAST-CANCER CELLS IN TISSUE-CULTURE

The purpose of this study was to determine if potassium channel activi ty is required for the proliferation of MCF-7 human mammary carcinoma cells. We examined the sensitivities of proliferation and progress thr ough the cell cycle to each of nine potassium channel antagonists. Fiv e of the potassium channel antagonists produced a concentration-depend ent inhibition of cell proliferation with no evidence of cytotoxicity following a 3-day or 5-day exposure to drug. The IC,, values for these five drugs, quinidine (25 mu M), glibenclamide (50 mu M), linogliride (770 mu M), 4-aminopyridine (1.6 mM), and tetraethylammonium (5.8 mM) were estimated from their respective concentration-response curves. F our other potassium channel blockers were tested at supra-maximal chan nel blocking concentrations, including charybdotoxin (200 nM), iberiot oxin (100 nM), margatoxin (10 nM), and apamin (500 nM), and they had n o effect on MCF-7 cell proliferation, viability, or cell cycle distrib ution. Of the five drugs that inhibited proliferation, only quinidine, glibenclamide, and linogliride also affected the cell cycle distribut ion. Cell populations exposed to each of these drugs for 3 days showed a statistically significant accumulation in G0/G1 phase and a signifi cant proportional reduction in S phase and G2/M phase cells. The inhib ition of cell proliferation correlated significantly with the extent o f cell accumulation in G0/G1 phase, and the threshold concentrations f or inhibition of growth and G0/G1 arrest were similar. The G0/G1 arres t produced by quinidine and glibenclamide was reversed by removing the drug, and cells released from arrest entered S phase synchronously wi th a lag period of similar to 24 hours. Based on the differential sens itivity of cell proliferation and cell cycle progression to the nine p otassium channel antagonists, we conclude that inhibition of ATP-sensi tive potassium channels in these human mammary carcinoma cells reversi bly arrests the cells in the G0/G1 phase of the cell cycle, resulting in an inhibition of cell proliferation. (C) 1995 Wiley-Liss, Inc.