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Permanent link (DOI): https://doi.org/10.7939/R39S1KW71

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An investigation of aminoglutethimide cytotoxicity and its role in activation of cell death signaling pathways Open Access

Descriptions

Other title
Subject/Keyword
Drug-induced agranulocytosis
Idiosyncratic drug reactions
HL-60 cells
Free radicals
Proteomics
Apoptosis
Aminoglutethimide
SILAC
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Baghdasarian, Argishti
Supervisor and department
Siraki, Arno (Pharmacy and Pharmaceutical Sciences)
Examining committee member and department
Fahlman, Richard (Medicine and Dentistry)
Seubert, John (Pharmacy and Pharmaceutical Sciences)
Department
Specialization
Pharmaceutical Sciences
Date accepted
2013-08-30T10:18:21Z
Graduation date
2013-11
Degree
Master of Science
Degree level
Master's
Abstract
Aminoglutethimide (AG), a drug used for the treatment of breast and ovarian cancers, is known to cause toxicities such as agranulocytosis. To investigate its toxicity mechanisms, we have used quantitative proteomic analysis to gain insight into the proteome of Human Leukemia 60 (HL-60) treated with AG. We identified 43 proteins that were changed significantly upon AG treatment among which 18 (42%) and 25 (58%) were up and down-regulated, respectively. The quantitative proteomics data showed that AG treatment led to the down-regulation of critical anti-apoptotic proteins responsible for inhibiting the release of pro-apoptotic factors from the mitochondria as well as cytoskeletal proteins such as nuclear lamina. This overall pro-apoptotic response was confirmed with flow cytometry which demonstrated apoptosis to be the main factor of cell death. This response correlated with the intensity of AG-induced protein radical formation in HL-60 cells, which may have an important role in cell death signaling mechanisms.
Language
English
DOI
doi:10.7939/R39S1KW71
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
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File title: Rabbit anti-DMPO and anti-SSB antibodies were purchased from Abcam Inc. (Toronto, ON) (Cat No. ab23702 and ab124932, respectively). Rabbit anti-COMT antibody was purchased from Sigma-Aldrich Canada Co. (Cat No. C6870).
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