Evidence for Inhibitory Actions of Temozolomide an Alkylator of the Imidazotetrazine Family on Intermediate-Conductance Ca2+-Activated K+ Channels in U373-MG Glioblastoma Cells

摘要

Temozolomide (TMZ) an oral alkylator of the imidazotetrazine family is currently the most effective antineoplastic drug in the treatment of glioma cells According to pharmacological report TMZ causes alkylation of O6 position of guanine and lead to mispairing with thymine and apoptosis of the affected cells However whether this drug has any effects on membrane ion channels in glioma cells remain largely unclear This study was conducted to investigate the possible effects of this drug on ionic currents present in U373-MG glioma cells In whole-cell recordings addition of TMZ decreased the amplitude of voltage-dependent K+ currents (IK) in U373-MG cells TMZ-induced inhibition of IK was reversed by further addition of ionomycin or 1-ethyl-2-benzimidazolinone (1-EBIO) In cell-attached current recordings cell exposure to TMZ decreased the activity of intermediate-conductance Ca2+-activated K+ (IKCa) channels in a concentration-dependent manner with an IC50 value of 9 2 ?M Chlorzoxazone or 1-EBIO counteracted TMZ-induced inhibition of IKCa channels Despite the inability of TMZ to modify single-channel conductance the inhibition by this drug of IKCa channels was weakly voltage-dependent and accompanied by a significant prolongation in the slow component of mean closed time However neither large-conductance Ca2+-activated (BKCa) nor inwardly rectifying K+ (Kir) channels in these cells became altered in the presence of TMZ Paxilline and BaCl2 was effective at suppressing BKCa and Kir channels respectively Under current-clamp recordings TMZ depolarized cell membrane and 1-EBIO reversed TMZ-induced depolarization The mRNA expression of KCNN4 (KCa3 1) detected in U373-MG glioma cells was unaltered during exposure to TMZ Therefore besides its DNA damage this inhibitory effect on IKCa channels accompanied by membrane depolarization could be an additional but important mechanism underlying TMZ-induced anti-neoplastic actions provided these actions occur in vivo The IKCa channel could be an alternative target for therapy of glioblastomas

獎項日期	2015 8月 12
原文	English
監督員	Sheng-Nan Wu (Supervisor)