Dual inhibition of sodium-mediated proton and calcium efflux triggers non-apoptotic cell death in malignant gliomas

William Harley, Candace Floyd, Tamara Dunn, Xiao Dong Zhang, Tsung Yu Chen, Manu Hegde, Hasan Palandoken, Michael H Nantz, Leonardo Leon, K. L. Carraway, Bruce Lyeth, Fredric A. Gorin

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Malignant glioma cells maintain an elevated intracellular pH (pH i) within hypoxic-ischemic tumor microenvironments through persistent activation of sodium-proton transport (McLean et al., 2000). Amiloride has been reported to selectively kill human malignant glioma cell lines but not primary astrocytes (Hegde et al., 2004). While amiloride reduces pHi of malignant gliomas by inhibiting isoform 1 of sodium-proton exchange (NHE1), direct acidification was shown to be cytostatic rather than cytotoxic. At cytotoxic concentrations, amiloride has multiple drug targets including inhibition of NHE1 and sodium-calcium exchange. Amiloride's glioma cytotoxicity can be explained, at least in part, by dual inhibition of NHE1 and of Na +-dependent calcium efflux by isoform 1.1 of the sodium-calcium exchanger (NCX1.1) , which increases [Ca2+]i and initiates glioma cell demise. As a result of persistent NHE1 activity, cytosolic free levels of sodium ([Na+]i) in U87 and C6 glioma cells are elevated 3-fold, as compared with normal astrocytes. Basal cytosolic free calcium levels ([Ca2+]i) also are increased 5-fold. 2′, 4′-dichlorobenzamil (DCB) inhibits the sodium-dependent calcium transporter (NCX1.1) much more potently than NHE1. DCB was employed in a concentration-dependent fashion in glioma cells to selectively inhibit the forward mode of NCX1.1 at ≤ 1 μM, while dually inhibiting both NHE1 and NCX1.1 at ≥ 20 μM. DCB (1 μM) was not cytotoxic to glioma cells, while DCB (20 μM) further increased basal elevated levels of [Ca2+] i in glioma cells that was followed by cell demise. Cariporide and SEA0400 are more selective inhibitors of NHE1 and NCX1.1 than amiloride or DCB, respectively. Individually, Cariporide and SEA0400 are not cytotoxic, but in combination induced glioma cell death. Like amiloride, the combination of Cariporide and SEA0400 produced glioma cell death in the absence of demonstrable caspase activation.

Original languageEnglish (US)
Pages (from-to)159-169
Number of pages11
JournalBrain Research
Volume1363
DOIs
StatePublished - Dec 6 2010

Keywords

  • Hypoxic-ischemic tumor microenvironment
  • Malignant glioma
  • Non-apoptotic cell death
  • Sodium-calcium exchanger
  • Sodium-hydrogen exchanger

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology
  • Developmental Biology
  • Molecular Biology

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