Stimulation of electroporation-induced inward currents in glioblastoma cell lines by the heat shock protein inhibitor AUY922

Nai Jung Chiang, Sheng-Nan Wu, Ching An Kao, Yan Ming Huang, Li Tzong Chen

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

Membrane electroporation (MEP) increases the electrical conductivity of the plasma membrane by addition of an external electrical field. Combining MEP-induced current (IMEP) 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 IMEP in glioblastoma cells. The IMEP in glioblastoma cells (U373) was generated by repetitive hyperpolarization from -80 to -200 mV. The amplitude of IMEP was increased by AUY in a concentration-dependent manner, with an EC50 of 0.32 μmol/L. In addition AUY shortened the latency to IMEP generation. Before depolarization to +50 mV, hyperpolarization to -200 mV for 50 msec produced Ca2+ influx and subsequently increased the amplitude of the Ca2+-activated K+ current (IK(Ca)). The amplitude of IK(Ca) and Ca2+ influx was further increased by AUY through its ability to activate IMEP. Other HSP90 inhibitors, namely 17-(allylamino)-17-demethoxygeldanamycin (17-AAG; 1 μmol/L) and 6-chloro-9-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-9H-purin-2-amine (BIIB021; 1 μmol/L), only slightly (albeit significantly) increased the amplitude of IMEP in glioblastoma cells. A 50 msec depolarizing step elevated Ca2+ influx and subsequently increased the amplitude of IK(Ca) in the presence of these three inhibitors. These data indicate that the AUY-mediated stimulation of IMEP and IK(Ca) in glioblastoma cells is independent of HSP90 inhibition. Moreover, these results indicate that AUY-stimulated IMEP and the subsequent activation of IK(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.

Original languageEnglish
Pages (from-to)830-837
Number of pages8
JournalClinical and Experimental Pharmacology and Physiology
Volume41
Issue number10
DOIs
Publication statusPublished - 2014 Oct 1

All Science Journal Classification (ASJC) codes

  • Physiology
  • Pharmacology
  • Physiology (medical)

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