Sodium ion channel mutations in glioblastoma patients correlate with shorter survival.
Sodium ion channel mutations in glioblastoma patients correlate with shorter survival.
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DOI：
10.1186/1476-4598-10-17
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发表时间：
2011-02-11
期刊：
影响因子：
37.3
通讯作者：
Riggins GJ
中科院分区：
文献类型：
--
作者：
Joshi AD;Parsons DW;Velculescu VE;Riggins GJ
多形性胶质母细胞瘤（GBM）是最常见的侵袭性星形细胞肿瘤，预后差。GBM患者的治疗已经取得了进展，但中位生存期仍然只有15个月。在最近的一项研究中，对来自21名GBM患者的20，000个基因进行了测序，确定了离子通道基因的频繁突变。本研究的目的是确定离子通道突变是否在疾病进展中起作用，以及离子通道的分子靶向是否是GBM患者有希望的治疗策略。因此，我们根据钙、钾和钠离子转运基因突变的存在与否来比较GBM患者的生存率。然后测试强心苷（已知的钠通道抑制剂）抑制GBM细胞增殖的能力。近90%的患者在离子转运基因中显示出至少一个突变。与无钠通道突变的患者相比，钠通道突变的GBM患者的生存期显著缩短，而基于钙或钾离子通道突变状态的类似比较显示无生存差异。实验上，与非肿瘤星形胶质细胞（NTA）相比，用强心苷如地高辛和哇巴因靶向GBM细胞显示出对U-87和D54 GBM细胞的优先细胞毒性。这些对钠通道突变的GBM患者的初步研究表明，钠通道突变与更具侵袭性的疾病和显著较短的生存期有关。此外，离子通道抑制剂如强心苷对GBM细胞的抑制表明了用相对安全的药物靶向GBM离子通道突变的治疗策略。关键词：多形性胶质母细胞瘤，离子通道，突变，小分子抑制剂，强心苷。
Glioblastoma Multiforme (GBM) is the most common and invasive astrocytic tumor associated with dismal prognosis. Treatment for GBM patients has advanced, but the median survival remains a meager 15 months. In a recent study, 20,000 genes from 21 GBM patients were sequenced that identified frequent mutations in ion channel genes. The goal of this study was to determine whether ion channel mutations have a role in disease progression and whether molecular targeting of ion channels is a promising therapeutic strategy for GBM patients. Therefore, we compared GBM patient survival on the basis of presence or absence of mutations in calcium, potassium and sodium ion transport genes. Cardiac glycosides, known sodium channel inhibitors, were then tested for their ability to inhibit GBM cell proliferation. Nearly 90% of patients showed at least one mutation in ion transport genes. GBM patients with mutations in sodium channels showed a significantly shorter survival compared to patients with no sodium channel mutations, whereas a similar comparison based on mutational status of calcium or potassium ion channel mutations showed no survival differences. Experimentally, targeting GBM cells with cardiac glycosides such as digoxin and ouabain demonstrated preferential cytotoxicity against U-87 and D54 GBM cells compared to non-tumor astrocytes (NTAs). These pilot studies of GBM patients with sodium channel mutations indicate an association with a more aggressive disease and significantly shorter survival. Moreover, inhibition of GBM cells by ion channel inhibitors such as cardiac glycosides suggest a therapeutic strategy with relatively safe drugs for targeting GBM ion channel mutations. Key Words: glioblastoma multiforme, ion channels, mutations, small molecule inhibitors, cardiac glycosides.
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DOI：
10.1073/pnas.0600930103
发表时间：
2006-07-05
影响因子：
11.1
作者：
Wang, James K. T.;Portbury, Stuart;Lo, Donald C.
通讯作者：
Lo, Donald C.
DOI：
10.1126/science.1164382
发表时间：
2008-09-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Parsons DW;Jones S;Zhang X;Lin JC;Leary RJ;Angenendt P;Mankoo P;Carter H;Siu IM;Gallia GL;Olivi A;McLendon R;Rasheed BA;Keir S;Nikolskaya T;Nikolsky Y;Busam DA;Tekleab H;Diaz LA Jr;Hartigan J;Smith DR;Strausberg RL;Marie SK;Shinjo SM;Yan H;Riggins GJ;Bigner DD;Karchin R;Papadopoulos N;Parmigiani G;Vogelstein B;Velculescu VE;Kinzler KW
通讯作者：
Kinzler KW
影响因子：
2.4
作者：
Schönherr, R
通讯作者：
Schönherr, R
影响因子：
4.8
作者：
Diss, JKJ;Stewart, D;Djamgoz, MBA
通讯作者：
Djamgoz, MBA
影响因子：
7.3
作者：
Mijatovic, T.;Roland, I.;Kiss, R.
通讯作者：
Kiss, R.