title: Inhibition of Ca2+-activated and voltage-dependent K+ currents by 2-mercaptophenyl-1,4-naphthoquinone in pituitary GH3 cells: contribution to its antiproliferative effect.
abstract: Quinones have been shown to possess antineoplastic activity; however, their effects on ionic currents remain unclear. The effects of 2-mercaptophenyl-1,4-naphthoquinone (2-MPNQ), menadione (MD) and 1,4-naphthoquinone (1,4 NQ) on cell proliferation and ionic currents in pituitary GH3 lactotrophs were investigated in this study. 2-MPNQ was more potent than menadione or 1,4-naphthoquinone in inhibiting the growth of GH3 cells. 2-MPNQ decreased cell proliferation in a concentration-dependent manner with an IC50 value of 3 microM. In whole-cell recording experiments, 2-MPNQ reversibly caused an inhibition of Ca2+-activated K+ current (I(K(Ca)) in a concentration-dependent manner. The IC50 value for 2-MPNQ-induced inhibition of I(K(Ca)) was 7 microM. In the inside-out configuration of single channel recording, 2-MPNQ (30 microM) applied intracellularly suppressed the activity of large-conductance Ca2+-activated K+ (BK(Ca)) channels but did not modify single channel conductance. Menadione (30 microM) had no effect on the channel activity, whereas 1,4-naphthoquinone (30 microM) suppressed it by about 26%. Both 2-MPNQ and thimerosal suppressed the dithiothreitol-stimulated channel activity. 2-MPNQ also blocked voltage-dependent K+ currents, but it produced a slight reduction of L-type Ca2+ inward current. However, unlike E-4031, 2-MPNQ (30 microM) did not suppress inwardly rectifying K+ current present in GH3 cells. Under the current clamp configuration, the presence of 2-MPNQ (30 microM) depolarized the cells, and increased the frequency and duration of spontaneous action potentials. The 2-MPNQ-mediated inhibition of K+ currents would affect hormone secretion and cell excitability. The blockade of these ionic channels by 2-MPNQ may partly explain its inhibitory effect on the proliferation of GH3 cells.
authors.affiliation: Department of Pharmaceutical Science, Foo Yin Institute of Technology, Ta-Liao, Kaohsiung County, Taiwan, ROC.
authors.forename: Mei-Han
authors.initials: MH
authors.lastname: Huang
authors.forename: Sheng-Nan
authors.initials: SN
authors.lastname: Wu
authors.forename: Chi-Pien
authors.initials: CP
authors.lastname: Chen
authors.forename: Ai-Yu
authors.initials: AY
authors.lastname: Shen
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D009285:Naphthoquinones / Q000494:pharmacology*; D010911:Pituitary Neoplasms / Q000473:pathology; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D013849:Thimerosal / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D024483:Vitamin K 3 / Q000494:pharmacology
chemical_list: C120142:2-mercaptophenyl-1,4-naphthoquinone; D020746:Calcium Channels, L-Type; D009285:Naphthoquinones; D015221:Potassium Channels; D013849:Thimerosal; D024483:Vitamin K 3; C035342:1,4-naphthoquinone; D002118:Calcium