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

Robert J. Ferrante, Hoon Ryu, James K. Kubilus, Santosh D'Mello, Katharine L. Sugars, Junghee Lee, Peiyuan Lu, Karen Smith, Susan Browne, M. Flint Beal, Bruce S. Kristal, Irina G. Stavrovskaya, Sandra Hewett, David C. Rubinsztein, Brett Langley, Rajiv R. Ratan

Research output: Contribution to journalArticlepeer-review

171 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)10335-10342
Number of pages8
JournalJournal of Neuroscience
Issue number46
StatePublished - Nov 17 2004
Externally publishedYes


  • HD
  • Histone methylation
  • Htt
  • Huntingtin
  • Huntington's disease
  • Mithramycin
  • Neuroprotection
  • Transcription

ASJC Scopus subject areas

  • General Neuroscience


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