Subject: Antitumor Medicine Improves HD in Mice
Date: 1/12/2005Chemotherapy for the brain: the antitumor antibiotic mithramycin prolongs survival in a mouse model of Huntington’s disease
RJ Ferrante, H Ryu, JK Kubilus, S D’Mello, KL Sugars, J Lee, P Lu, K Smith, A Brown, MF Beal, BS Kristal, IG Stavroskya, S Hewett, DC Rubinsztein, B Langley, RR Ratan
J Neuroscience 2004;24:10335-10342
An FDA-approved cancer treatment increases longevity by 29% in Huntington’s disease mice, longer than any other experimental treatment to date, according to this study.
R6/2 mice containing an expanded CAG repeat were treated with daily intraperitoneal injections of mithramycin, an approved treatment for hypercalcemia and testicular tumors. Mithramycin is also known as mithracin and plicamycin. Results showed:
--At 150 micrograms per kilogram per day, survival was extended by 29.1%, “greater than any other single neuroprotective agent reported to date,” according to the authors. At twice that dose, animals experiences morbidity, and at four times that dose, mortality.
--Rotarod improvement was 43% compared to controls. Treatment also almost normalized gross brain atrophy, brain weight, ventricular hypertrophy, and neuronal size.
To determine the likely mechanism of action, several experiments were performed. Results from these showed that mithramycin:
--does not alter mutant htt gene expression
--does not alter glutamate receptor expression or activity
--does not affect the mitochondrial permeability transition pore
--does not affect acetylation of histones or transcription factors.
The authors note that while mithramycin is known to displace the transcription factor Sp1, this is unlikely to be involved in the protective mechanism of the drug, since mutant htt itself has been shown to prevent Sp1-DNA binding ( http://www.mdvu.org/emove/article.asp?ID=475 ) .
Instead, the authors present evidence that mithramycin normalizes the methylation of histone H3, which is aberrantly elevated by mutant htt.
The authors conclude, “That mithramycin prevented htt-induced hypermethylation is compatible with a model in which mithramycin could displace the GC-rich DNA binding of a histone methyltransferase (HMT),” reversing the aberrant gene silencing caused by the HMT. “Although no HMT-interacting GC-rich DNA binding proteins have been reported to date, the idea that mithramycin could displace such a factor is an appealing one. The ensuing enhanced gene expression may counteract the toxicity of the HD mutation.”
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