Activation of the cellular stress response by small molecules

Written on Wednesday 26 February 2014

Small therapeutics molecules of different functions seem to give similar results over a wide range of genetic illnesses suggesting they could induce the same cellular mechanisms. These drugs are 4-phenylbutyrate, trichostatin A, hydroxyurea and sulforaphane.

In a previous study, Dr. Smith’s laboratory showed normalization of elevated very long chain fatty acids, the hallmark of adrenoleukodystrophy (ALD), after treatment of skin cells from ALD patients and sick mice with 4-phenylbutyrate and trichostatin A.
In this new study, 4-phenylbutyrate, trichostatin A, hydroxyurea and sulforaphane, tested in healthy skin cells or in those of patients suffering from ALD, induce:

  1. the generation of new mitochondria, the specialized components within the cell allowing the retrieval and storage of energy,
  2. the proliferation of peroxysomes, the cell elements involved  in the breakdown of very long chain fatty acids,
  3. a cellular stress response, known to protect from damages, improve cell survival and restore cell balance.

The cellular stress response to non-toxic doses of these molecules, followed by a return to cell equilibrium, could have a beneficial effect on disease-related metabolic stress by correcting the cell abnormalities without directly targeting the gene causing the disease.

Therapies regulating the cellular stress response could be useful for diseases with mitochondrial or peroxisomal impairments like adrenoleukodystrophy, but also for aging diseases or complex illnesses where the genetic cause remains unknown.

Disease: Adrenoleukodystrophy
Experimental model: Skin cells from patients
Type of study: Therapeutic approach
Laboratory: Dr.  Kirby  D.  Smith, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA

Source: R.D. Brose, G. Shin, M.C. McGuinness, T. Schneidereith, S. Purvis, G.X. Dong, J. Keefer, F. Spencer, K.D Smith. Activation of the stress proteome as a mechanism for small molecule therapeutics. Hum Mol Genet. 2012, 21(19):4237-52.

Scientific information provided in collaboration with the INIST-CNRS Institute, Institute for Scientific and Technical Information