Inhibition of ATP‐sensitive potassium channels causes reversible cell‐cycle arrest of human breast cancer cells in tissue culture

Abstract

The purpose of this study was to determine if potassium channel activity is required for the proliferation of MCF‐7 human mammary carcinoma cells. We examined the sensitivities of proliferation and progress through the cell cycle to each of nine potassium channel antagonists. Five of the potassium channel antagonists produced a concentration‐dependent inhibition of cell proliferation with no evidence of cytotoxicity following a 3‐day or 5‐day exposure to drug. The IC 50 values for these five drugs, quinidine (25 μM), glibenclamide (50 μM), linogliride (770 μM), 4‐aminopyridine (1.6 mM), and tetraethylammmonium (5.8 mM) were estimated from their respective concentration‐response curves. Four other potassium channel blockers were tested at supra‐maximal channel blocking concentrations, including charybdotoxin (200 nM), iberiotoxin (100 nM), margatoxin (10 nM), and apamin (500 nM), and they had no effect on MCF‐7 cell proliferation, viability, or cell cycle distribution. Of the five drugs that inhibited proliferation, only quinidine, glibenclamide, and linogliride also affected the cell cycle distribution. Cell populations exposed to each of these drugs for 3 days showed a statistically significant accumulation in GO/G1 phase and a significant proportional reduction in S phase and G2/M phase cells. The inhibition of cell proliferation correlated significantly with the extent of cell accumulation in GO/G1 phase, and the threshold concentrations for inhibition of growth and GO/G1 arrest were similar. The GO/G1 arrest produced by quinidine and glibenclamide was reversed by removing the drug, and cells released from arrest entered S phase synchronously with a lag period of ∼24 hours. Based on the differential sensitivity of cell proliferation and cell cycle progression to the nine potassium channel antagonists, we conclude that inhibition of ATP‐sensitive potassium channels in these human mammary carcinoma cells reversibly arrests the cells in the GO/G1 phase of the cell cycle, resulting in an inhibition of cell proliferation. © 1995 Wiley‐Liss, Inc.