title: Stimulation of electroporation-induced inward currents in glioblastoma cell lines by the heat shock protein inhibitor AUY922.
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 Ca(2+) influx and subsequently increased the amplitude of the Ca(2+) -activated K(+) current (IK(Ca) ). The amplitude of IK(Ca) and Ca(2+) 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 Ca(2+) 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.
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan City, Taiwan; Division of Hematology/Oncology, Department of Internal Medicine, Tainan City, Taiwan.
authors.forename: Nai-Jung
authors.initials: NJ
authors.lastname: Chiang
authors.forename: Sheng-Nan
authors.initials: SN
authors.lastname: Wu
authors.forename: Ching-An
authors.initials: CA
authors.lastname: Kao
authors.forename: Yan-Ming
authors.initials: YM
authors.lastname: Huang
authors.forename: Li-Tzong
authors.initials: LT
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D018274:Electroporation / Q000379:methods; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects* / Q000502:physiology; D011188:Potassium / Q000378:metabolism; D012118:Resorcinols / Q000494:pharmacology*
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D012118:Resorcinols; D011188:Potassium; D002118:Calcium
keywords: AUY922; electroporation; glioblastoma cells; heat shock protein inhibitor; ion current