EVIDENCE FOR AN EARLY G1 IONIC EVENT NECESSARY FOR CELL-CYCLE PROGRESSION AND SURVIVAL IN THE MCF-7 HUMAN BREAST-CARCINOMA CELL-LINE

The mechanism of the G0/G1 arrest and inhibition of proliferation by q uinidine, a potassium channel blocker, was investigated in a tissue cu lture cell line, MCF-7, derived from a human breast carcinoma. The ear liest measurable effect of quinidine on the cell cycle was a decrease in the fraction of cells in S phase at 12 hr, followed by the accumula tion of cells in G1/G0 phases at 30 hr. Arrest and release of the cell cycle established quinidine as a cell synchronization agent, with a s ite of arrest in early G1 preceding the lovastatin G1 arrest site by 5 -6 hr. There was a close correspondence among the concentration-depend ent arrest by quinidine in G1, depolarization of the membrane potentia l, and the inhibition of ATP-sensitive potassium currents, supporting a model in which hyperpolarization oi the membrane potential and progr ession through G1 are functionally linked. Furthermore, the G1 arrest by quinidine was overcome by valinomycin, a potassium ionophore that h yperpolarized the membrane potential in the presence of quinidine. Wit h sustained exposure of MCF-7 cells to quinidine, expression of the Ki 67 antigen, a marker for cells in cycle, decreased, and apoptotic and necrotic cell death ensued. We conclude that MCF-7 cells that fail to progress through the quinidine-arrest site in G1 die. J. Cell. Physiol . 176:456-464, 1998. (C) 1998 Wiley-Liss, Inc.