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Stimulation of electroporation‐induced inward currents in glioblastoma cell lines by the heat shock protein inhibitor AUY 922
Author(s) -
Chiang NaiJung,
Wu ShengNan,
Kao ChingAn,
Huang YanMing,
Chen LiTzong
Publication year - 2014
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/1440-1681.12273
Subject(s) - chemistry , depolarization , hyperpolarization (physics) , stimulation , biophysics , electroporation , pharmacology , medicine , biochemistry , biology , stereochemistry , nuclear magnetic resonance spectroscopy , gene
Summary Membrane electroporation (MEP) increases the electrical conductivity of the plasma membrane by addition of an external electrical field. Combining MEP‐induced current ( I MEP ) with antineoplastic agents has been increasingly considered as a new therapeutic manoeuvre, especially in the treatment of malignant gliomas. Thus, the aim of the present study was to evaluate the effect of AUY922 (AUY), a potent inhibitor of heat‐shock protein 90 (HSP90), on I MEP in glioblastoma cells. The I MEP in glioblastoma cells (U373) was generated by repetitive hyperpolarization from −80 to −200 mV . The amplitude of I MEP was increased by AUY in a concentration‐dependent manner, with an EC 50 of 0.32 μ mol/L. In addition AUY shortened the latency to I MEP generation. Before depolarization to +50 mV , hyperpolarization to −200 mV for 50 msec produced Ca 2+ influx and subsequently increased the amplitude of the Ca 2+ ‐activated K + current ( I K(Ca) ). The amplitude of I K(Ca) and Ca 2+ influx was further increased by AUY through its ability to activate I MEP . Other HSP90 inhibitors, namely 17‐(allylamino)‐17‐demethoxygeldanamycin (17‐AAG; 1 μ mol/L) and 6‐chloro‐9‐[(4‐methoxy‐3,5‐dimethylpyridin‐2‐yl)methyl]‐9 H ‐purin‐2‐amine (BIIB021; 1 μ mol/L), only slightly (albeit significantly) increased the amplitude of I MEP in glioblastoma cells. A 50 msec depolarizing step elevated Ca 2+ influx and subsequently increased the amplitude of I K(Ca) in the presence of these three inhibitors. These data indicate that the AUY‐mediated stimulation of I MEP and I K(Ca) in glioblastoma cells is independent of HSP90 inhibition. Moreover, these results indicate that AUY‐stimulated I MEP and the subsequent activation of I K(Ca) may create important signalling events in glioblastoma cells. Thus, AUY is a drug that could potentially be used to augment the effectiveness of electrochemotherapy.