Chemotherapy for the brain: The antitumor antibiotic mithramycin prolongs survival in a mouse model of Huntington's disease

被引:162
作者
Ferrante, RJ
Ryu, H
Kubilus, JK
D'Mello, SR
Sugars, KL
Lee, JH
Lu, PY
Smith, K
Browne, S
Beal, MF
Kristal, BS
Stavrovskaya, IG
Hewett, S
Rubinsztein, DC
Langley, B
Ratan, RR
机构
[1] Cornell Univ, Weill Med Coll, Burke Cornell Med Res Inst, White Plains, NY 10605 USA
[2] Boston Univ, Sch Med, Geriatr Res & Educ & Clin Ctr,Vet Adm Med Ctr Bed, Dept Neurol Pathol & Psychiat, Boston, MA 02118 USA
[3] Univ Texas, Dept Mol & Cellular Biol, Richardson, TX 75083 USA
[4] Cambridge Inst Med Res, Dept Med Genet, Cambridge CB2 2XY, England
[5] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA
[6] Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA
[7] Harvard Univ, Sch Med, Ctr Neurodegenerat & Repair, Boston, MA 02115 USA
[8] Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA
[9] Cornell Univ, Weil Med Coll, Dept Neurol & Neurosci, New York, NY 10021 USA
[10] Univ Connecticut, Sch Med, Farmington, CT 06030 USA
关键词
mithramycin; Huntington's disease; HD; Huntingtin; Htt; histone methylation; neuroprotection; transcription;
D O I
10.1523/JNEUROSCI.2599-04.2004
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Huntington's disease (HD) is a fully penetrant autosomal-dominant inherited neurological disorder caused by expanded CAG repeats in the Huntingtin gene. Transcriptional dysfunction, excitotoxicity, and oxidative stress have all been proposed to play important roles in the pathogenesis of HD. This study was designed to explore the therapeutic potential of mithramycin, a clinically approved guanosine cytosine-rich DNA binding antitumor antibiotic. Pharmacological treatment of a transgenic mouse model of HD (R6/2) with mithramycin extended survival by 29.1%, greater than any single agent reported to date. Increased survival was accompanied by improved motor performance and markedly delayed neuropathological sequelae. To identify the functional mechanism for the salubrious effects of mithramycin, we examined transcriptional dysfunction in R6/2 mice. Consistent with transcriptional repression playing a role in the pathogenesis of HD, we found increased methylation of lysine 9 in histone H3, a well established mechanism of gene silencing. Mithramycin treatment prevented the increase in H3 methylation observed in R6/2 mice, suggesting that the enhanced survival and neuroprotection might be attributable to the alleviation of repressed gene expression vital to neuronal function and survival. Because it is Food and Drug Administration-approved, mithramycin is a promising drug for the treatment of HD.
引用
收藏
页码:10335 / 10342
页数:8
相关论文
共 33 条
[11]   THE HUMAN CUT HOMEODOMAIN PROTEIN REPRESSES TRANSCRIPTION FROM THE C-MYC PROMOTER [J].
DUFORT, D ;
NEPVEU, A .
MOLECULAR AND CELLULAR BIOLOGY, 1994, 14 (06) :4251-4257
[12]   Sp1 and TAFII130 transcriptional activity disrupted in early Huntington's disease [J].
Dunah, AW ;
Jeong, H ;
Griffin, A ;
Kim, YM ;
Standaert, DG ;
Hersch, SM ;
Mouradian, MM ;
Young, AB ;
Tanese, N ;
Krainc, D .
SCIENCE, 2002, 296 (5576) :2238-2243
[13]  
ELHODIRI HM, 1995, MOL CELL BIOL, V15, P3587
[14]   Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of Huntington's disease [J].
Ferrante, RJ ;
Andreassen, OA ;
Dedeoglu, A ;
Ferrante, KL ;
Jenkins, BG ;
Hersch, SM ;
Beal, MF .
JOURNAL OF NEUROSCIENCE, 2002, 22 (05) :1592-1599
[15]  
Ferrante RJ, 2003, J NEUROSCI, V23, P9418
[16]   Perspectives: Neurodegeneration - A glutamine-rich trail leads to transcription factors [J].
Freiman, RN ;
Tjian, R .
SCIENCE, 2002, 296 (5576) :2149-2150
[17]   Linking the epigenetic 'language' of covalent histone modifications to cancer [J].
Hake, SB ;
Xiao, A ;
Allis, CD .
BRITISH JOURNAL OF CANCER, 2004, 90 (04) :761-769
[18]  
JONES DE, 1995, ONCOGENE, V10, P2323
[19]   Apoptogenic ganglioside GD3 directly induces the mitochondrial permeability transition [J].
Kristal, BS ;
Brown, AM .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (33) :23169-23175
[20]   Transcriptional repression of the cystic fibrosis transmembrane conductance regulator gene, mediated by CCAAT displacement protein cut homolog, is associated with histone deacetylation [J].
Li, S ;
Moy, L ;
Pittman, N ;
Shue, G ;
Aufiero, B ;
Neufeld, EJ ;
LeLeiko, NS ;
Walsh, MJ .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (12) :7803-7815