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.
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Authors | Nai-Jung Chiang, Sheng-Nan Wu, Ching-An Kao, Yan-Ming Huang, Li-Tzong Chen |
Journal | Clinical and experimental pharmacology & physiology
(Clin Exp Pharmacol Physiol)
Vol. 41
Issue 10
Pg. 830-7
(Oct 2014)
ISSN: 1440-1681 [Electronic] Australia |
PMID | 24909268
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2014 Wiley Publishing Asia Pty Ltd. |
Chemical References |
- 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide
- Antineoplastic Agents
- HSP90 Heat-Shock Proteins
- Isoxazoles
- Resorcinols
- Potassium
- Calcium
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Topics |
- Antineoplastic Agents
(pharmacology)
- Calcium
(metabolism)
- Cell Line, Tumor
- Cell Membrane
(drug effects, metabolism)
- Electroporation
(methods)
- Glioblastoma
(drug therapy, metabolism, physiopathology)
- HSP90 Heat-Shock Proteins
(antagonists & inhibitors, metabolism)
- Humans
- Isoxazoles
(pharmacology)
- Membrane Potentials
(drug effects, physiology)
- Potassium
(metabolism)
- Resorcinols
(pharmacology)
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