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 IC50 values for these five drugs, quinidine (25 microM), glibenclamide (50 microM), linogliride (770 microM), 4-aminopyridine (1.6 mM), and tetraethylammonium (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 G0/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 G0/G1 phase and the threshold concentrations for inhibition of growth and G0/G1 arrest were similar. The G0/G1 arrest produced by quinidine and glibenclamide were reversed by removing the drug, and cells released from arrest entered S phase synchronously with a lag period of approximately 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 G0/G1 phase of the cell cycle, resulting in an inhibition of cell proliferation.

Re-expression of Detachment-inducible Chloride Channel mCLCA5 Suppresses Growth of Metastatic Breast Cancer Cells

“…proliferation of multiple cell types, including normal lymphocytes, melanoma, breast and prostate cancer cell lines, and glial cells (43)(44)(45)(46)(47). Concordantly, some K ϩ channels are upregulated during tumorigenesis and are pro-oncogenic.…”

Tumor Suppression by a Proapoptotic Calcium-activated Chloride Channel in Mammary Epithelium

“…Indeed, a number of recent studies link plasma membrane ion channels to cell proliferation and cycle progression. For example, induction of potassium channels was found to stimulate proliferation of hepatocytes, while channel blockade reduced proliferation of these cells (47), T lymphocytes (48), melanoma (49), breast cancer cells (50), keratinocytes (51), and glial cells (52). The last study linked these effects to changes in pH i .…”

Rapid Induction of Histone Hyperacetylation and Cellular Differentiation in Human Breast Tumor Cell Lines following Degradation of Histone Deacetylase-1

“…Hypophosphorylated pRb protein is prominent in quinidine-treated MCF-7 cells, and this could act to sustain the G 1 state by preventing the transition into S phase. The G 1 arrest induced by quinidine in MCF-7 cells was correlated with the blockade of ATP-sensitive potassium channels in MCF-7 cells (12,54,55). Direct evidence for the involvement of potassium ions in the G 1 arrest was provided using valinomycin, a potassium-selective ionophore to stimulate a G 1 -S phase transition in the presence of quinidine (12).…”