title: Very low intensity alternating current decreases cell proliferation.
abstract: Electric fields impact cellular functions by activation of ion channels or by interfering with cell membrane integrity. Ion channels can regulate cell cycle and play a role in tumorigenesis. While the cell cycle may be directly altered by ion fluxes, exposure to direct electric current of sufficient intensity may decrease tumor burden by generating chemical products, including cytotoxic molecules or heat. We report that in the absence of thermal influences, low-frequency, low-intensity, alternating current (AC) directly affects cell proliferation without a significant deleterious contribution to cell survival. These effects were observed in normal human cells and in brain and prostate neoplasms, but not in lung cancer. The effects of AC stimulation required a permissive role for GIRK2 (or K(IR)3.2) potassium channels and were mimicked by raising extracellular potassium concentrations. Cell death could be achieved at higher AC frequencies (>75 Hz) or intensities (>8.5 microA); at lower frequencies/intensities, AC stimulation did not cause apoptotic cellular changes. Our findings implicate a role for transmembrane potassium fluxes via inward rectifier channels in the regulation of cell cycle. Brain stimulators currently used for the treatment of neurological disorders may thus also be used for the treatment of brain (or other) tumors.
authors.affiliation: Division of Cerebrovascular Research, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio 44195, USA.
authors.forename: Luca
authors.initials: L
authors.lastname: Cucullo
authors.forename: Gabriele
authors.initials: G
authors.lastname: Dini
authors.forename: Kerri L
authors.initials: KL
authors.lastname: Hallene
authors.forename: Vincent
authors.initials: V
authors.lastname: Fazio
authors.forename: Erin V
authors.initials: EV
authors.lastname: Ilkanich
authors.forename: Chiazor
authors.initials: C
authors.lastname: Igboechi
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Kight
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Agarwal
authors.forename: Mary
authors.initials: M
authors.lastname: Garrity-Moses
authors.forename: Damir
authors.initials: D
authors.lastname: Janigro
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D001253:Astrocytes / Q000502:physiology; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology; D049109:Cell Proliferation; D004558:Electric Stimulation; D004827:Epilepsy / Q000473:pathology; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D006358:Hot Temperature; D006801:Humans; D007150:Immunohistochemistry; D009369:Neoplasms / Q000473:pathology* / Q000628:therapy; D011188:Potassium / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C497069:Kcnj6 protein, mouse; D024661:Potassium Channels, Inwardly Rectifying; D000263:Adenylate Kinase; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D001973:Bromodeoxyuridine; D011188:Potassium