Next Article in Journal
In Silico Veritas: The Pitfalls and Challenges of Predicting GPCR-Ligand Interactions
Next Article in Special Issue
Improved Histone Deacetylase Inhibitors as Therapeutics for the Neurodegenerative Disease Friedreich’s Ataxia: A New Synthetic Route
Previous Article in Journal
Molecular Determinants of the Response of Tumor Cells to Boswellic Acids
Previous Article in Special Issue
Clinical Toxicities of Histone Deacetylase Inhibitors
Article Menu

Export Article

Open AccessArticle
Pharmaceuticals 2011, 4(8), 1183-1195; doi:10.3390/ph4081183

Histone Deacetylase Inhibitors and Mithramycin A Impact a Similar Neuroprotective Pathway at a Crossroad between Cancer and Neurodegeneration

Burke-Cornell Medical Research Institute, 785 Mamaroneck Ave, White Plains, New York, NY 10605, USA
Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 525 E. 68th St., New York, NY 10065, USA
Department of Pharmaceutical Sciences, University of Kentucky, 789 S. Limestone St., Lexington, KY 40536, USA
Authors to whom correspondence should be addressed.
Received: 25 July 2011 / Revised: 11 August 2011 / Accepted: 15 August 2011 / Published: 22 August 2011
(This article belongs to the Special Issue HDAC Inhibitors)
View Full-Text   |   Download PDF [571 KB, uploaded 22 August 2011]   |  


Mithramycin A (MTM) and histone deacetylase inhibitors (HDACi) are effective therapeutic agents for cancer and neurodegenerative diseases. MTM is a FDA approved aureolic acid-type antibiotic that binds to GC-rich DNA sequences and interferes with Sp1 transcription factor binding to its target sites (GC box). HDACi, on the other hand, modulate the activity of class I and II histone deacetylases. They mediate their protective function, in part, by regulating the acetylation status of histones or transcription factors, including Sp1, and in turn chromatin accessibility to the transcriptional machinery. Because these two classes of structurally and functionally diverse compounds mediate similar therapeutic functions, we investigated whether they act on redundant or synergistic pathways to protect neurons from oxidative death. Non-protective doses of each of the drugs do not synergize to create resistance to oxidative death suggesting that these distinct agents act via a similar pathway. Accordingly, we found that protection by MTM and HDACi is associated with diminished expression of the oncogene, Myc and enhanced expression of a tumor suppressor, p21waf1/cip1. We also find that neuroprotection by MTM or Myc knockdown is associated with downregulation of class I HDAC levels. Our results support a model in which the established antitumor drug MTM or canonical HDACi act via distinct mechanisms to converge on the downregulation of HDAC levels or activity respectively. These findings support the conclusion that an imbalance in histone acetylase and HDAC activity in favor of HDACs is key not only for oncogenic transformation, but also neurodegeneration.
Keywords: mithramycin A; HDAC inhibition; Myc; neurons; oxidative stress mithramycin A; HDAC inhibition; Myc; neurons; oxidative stress
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

Scifeed alert for new publications

Never miss any articles matching your research from any publisher
  • Get alerts for new papers matching your research
  • Find out the new papers from selected authors
  • Updated daily for 49'000+ journals and 6000+ publishers
  • Define your Scifeed now

SciFeed Share & Cite This Article

MDPI and ACS Style

Sleiman, S.F.; Berlin, J.; Basso, M.; S.Karuppagounder, S.; Rohr, J.; Ratan, R.R. Histone Deacetylase Inhibitors and Mithramycin A Impact a Similar Neuroprotective Pathway at a Crossroad between Cancer and Neurodegeneration. Pharmaceuticals 2011, 4, 1183-1195.

Show more citation formats Show less citations formats

Related Articles

Article Metrics

Article Access Statistics



[Return to top]
Pharmaceuticals EISSN 1424-8247 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top