title: High effectiveness of triptolide, an active diterpenoid triepoxide, in suppressing Kir-channel currents from human glioma cells.
abstract: Triptolide (Trip), a diterpene triepoxide isolated from medicinal vine Trypterygium wilfordii Hook. F. possessed multiple biological activities including antineoplastic actions. However, no report concerning its effects on ion currents has been published. In this study, we attempted to determine whether this compound has any effects on ion currents in malignant glioma cells. The mRNA expression of KCNJ10 (Kir4.1) was detected in U373 glioma cells. The inwardly rectifying K(+) currents (IK(IR)) in U373 cells were almost fully blocked by BaCl2 (1mM). Trip (30 nM-10 μM) effectively decreased the amplitude of IK(IR) in a concentration-dependent manner with an IC50 value of 0.72 μM. In chlorotoxin-treated U373 cells, Trip-mediated block of IK(IR) remained effective. Addition of Trip (3 μM) slightly inhibited the amplitude of Ca(2+)-activated K(+) current and sustained K(+) outward current in U373 cells. In cell-attached configuration, when Trip was added to the bath, the activity of inwardly rectifying K(+) (Kir) channels diminished with no change in single-channel conductance. Its suppression of Kir channels was accompanied by a reduction in the slow component of mean open time. Under current-clamp conditions, addition of Trip depolarized the membrane along with changes in frequency histogram of resting potential. Block by this component of Kir4.1 channels may be an important mechanism underlying its actions on the functional activity of glioma cells. Targeting at Kir4.1 channels may be clinically useful as an adjunctive regimen to anti-cancer drugs.
authors.affiliation: Department of Anesthesia & Medical Research, China Medical University-An Nan Hospital, Tainan City, Taiwan; Department of Anesthesia, China Medical University, Taichung City, Taiwan; Department of Anesthesia, Nan Shan branch of Gilu Hospital, Shandong University, Shandong Province, P.R. China. Electronic address: edmundsotw@gmail.com.
authors.forename: Edmund Cheung
authors.initials: EC
authors.lastname: So
authors.affiliation: Department of Pharmacology, Kaohsiung Medical University, Kaohsiung City, Taiwan. Electronic address: yichlo@kmu.edu.tw.
authors.forename: Yi-Ching
authors.initials: YC
authors.lastname: Lo
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan City, Taiwan. Electronic address: k153chen@gmail.com.
authors.forename: Li-Tzong
authors.initials: LT
authors.lastname: Chen
authors.affiliation: Department of Physiology, National Cheng Kung University Medical College, No. 1, University Road, Tainan City 70101, Taiwan. Electronic address: eric33132000@hotmail.com.
authors.forename: Chin-An
authors.initials: CA
authors.lastname: Kao
authors.affiliation: Department of Physiology, National Cheng Kung University Medical College, No. 1, University Road, Tainan City 70101, Taiwan; Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan City, Taiwan. Electronic address: snwu@mail.ncku.edu.tw.
authors.forename: Sheng-Nan
authors.initials: SN
authors.lastname: Wu
mesh_terms: D045744:Cell Line, Tumor; D004224:Diterpenes / Q000494:pharmacology*; D055724:Electrophysiological Phenomena / Q000187:drug effects*; D004852:Epoxy Compounds / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D005910:Glioma / Q000473:pathology*; D006801:Humans; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D010616:Phenanthrenes / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012604:Scorpion Venoms / Q000494:pharmacology; D000098854:Kcnj10 Channel
chemical_list: D004224:Diterpenes; D004852:Epoxy Compounds; D000098854:Kcnj10 Channel; D010616:Phenanthrenes; D024661:Potassium Channels, Inwardly Rectifying; D012333:RNA, Messenger; D012604:Scorpion Venoms; C091539:Chlorotoxin; C001899:triptolide; D011188:Potassium
keywords: Glioma cell; Inwardly rectifying K(+) channel; K(+) current; Membrane potential; Triptolide (PubChem CID 107985)