Dual inhibition of sodium-mediated proton and calcium efflux triggers non-apoptotic cell death in malignant gliomas.
Dual inhibition of sodium-mediated proton and calcium efflux triggers non-apoptotic cell death in malignant gliomas.
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DOI：
10.1016/j.brainres.2010.09.059
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发表时间：
2010-12-02
期刊：
影响因子：
2.9
通讯作者：
Gorin FA
中科院分区：
文献类型：
--
作者：
Harley W;Floyd C;Dunn T;Zhang XD;Chen TY;Hegde M;Palandoken H;Nantz MH;Leon L;Carraway KL 3rd;Lyeth B;Gorin FA
恶性胶质瘤细胞通过持续激活钠-质子转运在缺氧缺血性肿瘤微环境中维持升高的细胞内pH（pHi）。阿米洛利已被报道选择性地杀死人类恶性胶质瘤细胞系，但不初级星形胶质细胞。虽然阿米洛利通过抑制钠-质子交换（NHE1）亚型1降低恶性胶质瘤的pHi，但直接酸化显示出细胞抑制作用而非细胞毒性。在细胞毒性浓度下，阿米洛利具有多个药物靶点，包括抑制NHE 1和钠钙交换。阿米洛利的神经胶质瘤细胞毒性可以解释，至少部分地，通过双重抑制NHE 1和钠钙交换器（NCX1.1）的亚型1.1的Na+依赖性钙流出，增加[Ca 2 +] i和启动神经胶质瘤细胞死亡。作为持续NHE 1活性的结果，与正常星形胶质细胞相比，U87和C6胶质瘤细胞中的胞质游离钠（[Na +] i）水平升高3倍。基础细胞溶质游离钙水平（[Ca2 +] i）也增加了5倍。2 ′，4 ′-二氯苯扎明（DCB）对钠依赖性钙转运蛋白（NCX1.1）的抑制作用强于NHE1。DCB在胶质瘤细胞中以浓度依赖性方式使用，在≤ 1 uM时选择性抑制NCX1.1的正向模式，而在≥ 20 uM时双重抑制NHE 1和NCX1.1。DCB（1 μ M）对胶质瘤细胞无细胞毒性，而DCB（20 μ M）进一步增加了胶质瘤细胞中[Ca2 +] i的基础升高水平，随后细胞死亡。Cariporide和SEA 0400分别是比阿米洛利或DCB更特异的NHE 1和NCX1.1抑制剂。单独地，Cariporide和SEA 0400不是细胞毒性的，但是组合诱导胶质瘤细胞死亡。与阿米洛利一样，Cariporide和SEA 0400的组合在没有明显的半胱天冬酶激活的情况下产生神经胶质瘤细胞死亡。
Malignant glioma cells maintain an elevated intracellular pH (pHi) within hypoxic-ischemic tumor microenvironments through persistent activation of sodium-proton transport. Amiloride has been reported to selectively kill human malignant glioma cell lines but not primary astrocytes. 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 ≤1uM, while dually inhibiting both NHE1 and NCX1.1 at ≥20uM. DCB (1uM) was not cytotoxic to glioma cells, while DCB (20μM) further increased basal elevated levels of [Ca2+]i in glioma cells that was followed by cell demise. Cariporide and SEA0400 are more specific 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.
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影响因子：
4.7
作者：
Deitmer, JW;Bröer, A;Bröer, S
通讯作者：
Bröer, S
影响因子：
4.8
作者：
Chalmers, S;Nicholls, DG
通讯作者：
Nicholls, DG
影响因子：
4.7
作者：
AMRUTHESH, SC;BOERSCHEL, MF;ELLIS, EF
通讯作者：
ELLIS, EF
影响因子：
3.3
作者：
Korkolopoulou, Penelope;Perdiki, Marina;Patsouris, Efstratios
通讯作者：
Patsouris, Efstratios
DOI：
10.1124/jpet.103.065029
发表时间：
2004-07-01
影响因子：
3.5
作者：
Hegde, M;Roscoe, J;Gorin, F
通讯作者：
Gorin, F