Membrane electroporation (MEP) increases the electrical conductivity of the plasma membrane by addition of an external electrical field. Combining MEP-induced current (IMEP ) with anti-neoplastic agents has been increasingly considered as a new therapeutic manoeuvre, especially in treating 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 was generated by repetitive hyperpolarization from -80 to -200 mV. AUY increased the amplitude of IMEP in a concentration-dependent fashion with an EC50 of 0.32 muM and also shortened the latency to IMEP generation. Before depolarization to +50 mV, hyperpolarization to -200 mV for 50 ms produced Ca2+ influx, and subsequently increased the amplitude of the Ca2+ -activated K+ current (IK(Ca) ). AUY further increased the amplitude of IK(Ca) and Ca2+ influx through its ability to activate IMEP . 17-AAG or BIIB021, other HSP90 inhibitors, only slightly increased the amplitude of IMEP in glioblastoma cells. A 50-ms depolarizing step elevated the Ca2+ influx and subsequently increased the amplitude of IK(Ca) in the presence of these 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. AUY is a potential drug that could be used to augment the effectiveness of electro-chemotherapy.
Date:
2014-10
Relation:
Clinical and Experimental Pharmacology and Physiology. 2014 Oct;41(10):830-837.
