Sodium ion channel mutations in glioblastoma patients correlate with shorter survival

Molecular Cancer

Research

Avadhut D Joshi¹  Gregory J Riggins²  Victor E Velculescu³  D Williams Parsons⁴ 

[1] Department of Neurosurgery, Johns Hopkins University Medical School, 21231, Baltimore, MD, USA;Department of Neurosurgery, Johns Hopkins University Medical School, 21231, Baltimore, MD, USA;Ludwig Center for Cancer Genetics and Therapeutics, The Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, 21231, Baltimore, MD, USA;Ludwig Center for Cancer Genetics and Therapeutics, The Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, 21231, Baltimore, MD, USA;Ludwig Center for Cancer Genetics and Therapeutics, The Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, 21231, Baltimore, MD, USA;Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, 77030, Houston, TX, USA;

关键词: Digoxin;    Sodium Channel;    Ouabain;    IDH1 Mutation;    Cardiac Glycoside;   

DOI  :  10.1186/1476-4598-10-17

 received in 2010-06-21, accepted in 2011-02-11,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundGlioblastoma 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.ResultsNearly 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).ConclusionsThese 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.

【 授权许可】

Unknown   
© Joshi et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.