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