| dc.contributor |
Wichita State University. Department of Chemistry |
en_US |
| dc.contributor.author |
Samms, Warren C. |
en_US |
| dc.contributor.author |
Perera, Rohan P. |
en_US |
| dc.contributor.author |
Wimalasena, D. Shyamali |
en_US |
| dc.contributor.author |
Wimalasena, Kandatege |
en_US |
| dc.date.accessioned |
2012-02-06T17:16:53Z |
|
| dc.date.available |
2012-02-06T17:16:53Z |
|
| dc.date.issued |
2007-09-01 |
en_US |
| dc.identifier |
17576792 |
en_US |
| dc.identifier |
0035623 |
en_US |
| dc.identifier |
mol.107.035873 |
en_US |
| dc.identifier |
NS39423 |
en_US |
| dc.identifier.citation |
Molecular pharmacology. 2007 Sep; 72(3): 744-52. |
en_US |
| dc.identifier.issn |
0026-895X |
en_US |
| dc.identifier.uri |
http://dx.doi.org/10.1124/mol.107.035873 |
en_US |
| dc.identifier.uri |
http://hdl.handle.net/10057/4360 |
|
| dc.description |
Click on the DOI link below to access the article. |
en_US |
| dc.description.abstract |
We have recently characterized a series of 3-amino-2-phenyl-propene (APP) derivatives as reversible inhibitors for the bovine adrenal chromaffin granule vesicular monoamine transporter (VMAT) that have been previously characterized as potent irreversible dopamine-beta-monooxygenase (DbetaM) and monoamine oxidase (MAO) inhibitors. Halogen substitution on the 4'-position of the aromatic ring gradually increases VMAT inhibition potency from 4'-F to 4'-I, parallel to the hydrophobicity of the halogen. We show that these derivatives are taken up into both neuronal and non-neuronal cells, and into resealed chromaffin granule ghosts efficiently through passive diffusion. Uptake rates increased according to the hydrophobicity of the 4'-substituent. More importantly, these derivatives are highly toxic to human neuroblastoma SH-SY5Y but not toxic to M-1, Hep G2, or human embryonic kidney 293 non-neuronal cells at similar concentrations. They drastically perturb dopamine (DA) uptake and metabolism in SH-SY5Y cells under sublethal conditions and are able to deplete both vesicular and cytosolic catecholamines in a manner similar to that of amphetamines. In addition, 4'-IAPP treatment significantly increases intracellular reactive oxygen species (ROS) and decreases glutathione (GSH) levels in SH-SY5Y cells, and cell death is significantly attenuated by the common antioxidants alpha-tocopherol, N-acetyl-l-cysteine and GSH, but not by the nonspecific caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone. DNA fragmentation analysis further supports that cell death is probably due to a caspase-independent ROS-mediated apoptotic pathway. Based on these and other findings, we propose that drastic perturbation of DA metabolism in SH-SY5Y cells by 4'-halo APP derivatives causes increased oxidative stress, leading to apoptotic cell death. |
en_US |
| dc.description.sponsorship |
NINDS NIH HHS |
en_US |
| dc.format.extent |
744-52 |
en_US |
| dc.language.iso |
eng |
en_US |
| dc.publisher |
American Society for Pharmacology and Experimental Therapeutics |
en_US |
| dc.relation.ispartofseries |
Molecular pharmacology |
en_US |
| dc.relation.ispartofseries |
Mol. Pharmacol. |
en_US |
| dc.source |
NLM |
en_US |
| dc.subject |
Research Support, N.I.H., Extramural |
en_US |
| dc.subject |
Research Support, U.S. Gov't, Non-P.H.S. |
en_US |
| dc.subject.mesh |
Allyl Compounds/pharmacology |
en_US |
| dc.subject.mesh |
Animals |
en_US |
| dc.subject.mesh |
Apoptosis/drug effects |
en_US |
| dc.subject.mesh |
Benzene Derivatives/pharmacology |
en_US |
| dc.subject.mesh |
Cell Death/drug effects |
en_US |
| dc.subject.mesh |
Cell Line, Tumor |
en_US |
| dc.subject.mesh |
Cell Survival/drug effects |
en_US |
| dc.subject.mesh |
Dopamine/metabolism |
en_US |
| dc.subject.mesh |
Dose-Response Relationship, Drug |
en_US |
| dc.subject.mesh |
Hydrocarbons, Halogenated/chemistry |
en_US |
| dc.subject.mesh |
Mice |
en_US |
| dc.subject.mesh |
Neuroblastoma/pathology |
en_US |
| dc.subject.mesh |
Oxidative Stress/drug effects |
en_US |
| dc.subject.mesh |
Propane/analogs & derivatives |
en_US |
| dc.subject.mesh |
Time Factors |
en_US |
| dc.subject.mesh |
Allyl Compounds/toxicity |
en_US |
| dc.subject.mesh |
Benzene Derivatives/toxicity |
en_US |
| dc.subject.mesh |
Hydrocarbons, Halogenated/pharmacology |
en_US |
| dc.subject.mesh |
Propane/chemistry |
en_US |
| dc.subject.mesh |
Propane/pharmacology |
en_US |
| dc.title |
Perturbation of dopamine metabolism by 3-amino-2-(4'-halophenyl)propenes leads to increased oxidative stress and apoptotic SH-SY5Y cell death |
en_US |
| dc.type |
Article |
en_US |
| dc.coverage.spacial |
United States |
en_US |
| dc.description.version |
peer reviewed |
en_US |
| dc.rights.holder |
Copyright © 2007 The American Society for Pharmacology and Experimental Therapeutics |
en_US |