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 quinidine, a potassium channel blocker, was investigated in a tissue culture cell line, MCF-7, derived from a human breast carcinoma. The earliest 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 accumulation 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 site of arrest in early G1 preceding the lovastatin G1 arrest site by 5-6 hr. There was a close correspondence among the concentration-dependent arrest by quinidine in G1, depolarization of the membrane potential, and the inhibition of ATP-sensitive potassium currents, supporting a model in which hyperpolarization of the membrane potential and progression through G1 are functionally linked. Furthermore, the G1 arrest by quinidine was overcome by valinomycin, a potassium ionophore that hyperpolarized the membrane potential in the presence of quinidine. With sustained exposure of MCF-7 cells to quinidine, expression of the Ki67 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.
Program in Genetics and Developmental Biology, West Virginia University, Morgantown, USA.
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S
Wang
Z
Z
Melkoumian
K A
KA
Woodfork
C
C
Cather
A G
AG
Davidson
W F
WF
Wonderlin
J S
JS
Strobl
D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D016193:G1 Phase / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007476:Ionophores / Q000494:pharmacology; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008148:Lovastatin / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D015221:Potassium Channels / Q000502:physiology*; D011802:Quinidine / Q000494:pharmacology; D016192:Resting Phase, Cell Cycle / Q000187:drug effects / Q000502:physiology; D016196:S Phase / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D014634:Valinomycin / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D000970:Antineoplastic Agents; D007476:Ionophores; D019394:Ki-67 Antigen; D015221:Potassium Channels; D014634:Valinomycin; D008148:Lovastatin; D011802:Quinidine