Stimulation of electroporation‐induced inward currents in glioblastoma cell lines by the heat shock protein inhibitor AUY 922

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.