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Characterization of the apoptotic response of human leukemia cells to organosulfur compounds


Wong, W W; Boutros, P C; Wasylishen, A R; Guckert, K D; O'Brien, E M; Griffiths, R; Martirosyan, A R; Bros, C; Jurisica, I; Langler, R F; Penn, L Z (2010). Characterization of the apoptotic response of human leukemia cells to organosulfur compounds. BMC Cancer, 10:351.

Abstract

Background: Novel therapeutic agents that selectively induce tumor cell death are urgently needed in the clinical
management of cancers. Such agents would constitute effective adjuvant approaches to traditional chemotherapy
regimens. Organosulfur compounds (OSCs), such as diallyl disulfide, have demonstrated anti-proliferative effects on
cancer cells. We have previously shown that synthesized relatives of dysoxysulfone, a natural OSC derived from the
Fijian medicinal plant, Dysoxylum richi, possess tumor-specific antiproliferative effects and are thus promising lead
candidates.
Methods: Because our structure-activity analyses showed that regions flanking the disulfide bond mediated
specificity, we synthesized 18 novel OSCs by structural modification of the most promising dysoxysulfone derivatives.
These compounds were tested for anti-proliferative and apoptotic activity in both normal and leukemic cells.
Results: Six OSCs exhibited tumor-specific killing, having no effect on normal bone marrow, and are thus candidates
for future toxicity studies. We then employed mRNA expression profiling to characterize the mechanisms by which
different OSCs induce apoptosis. Using Gene Ontology analysis we show that each OSC altered a unique set of
pathways, and that these differences could be partially rationalized from a transcription factor binding site analysis. For
example, five compounds altered genes with a large enrichment of p53 binding sites in their promoter regions (p <
0.0001).
Conclusions: Taken together, these data establish OSCs derivatized from dysoxysulfone as a novel group of
compounds for development as anti-cancer agents.

Background: Novel therapeutic agents that selectively induce tumor cell death are urgently needed in the clinical
management of cancers. Such agents would constitute effective adjuvant approaches to traditional chemotherapy
regimens. Organosulfur compounds (OSCs), such as diallyl disulfide, have demonstrated anti-proliferative effects on
cancer cells. We have previously shown that synthesized relatives of dysoxysulfone, a natural OSC derived from the
Fijian medicinal plant, Dysoxylum richi, possess tumor-specific antiproliferative effects and are thus promising lead
candidates.
Methods: Because our structure-activity analyses showed that regions flanking the disulfide bond mediated
specificity, we synthesized 18 novel OSCs by structural modification of the most promising dysoxysulfone derivatives.
These compounds were tested for anti-proliferative and apoptotic activity in both normal and leukemic cells.
Results: Six OSCs exhibited tumor-specific killing, having no effect on normal bone marrow, and are thus candidates
for future toxicity studies. We then employed mRNA expression profiling to characterize the mechanisms by which
different OSCs induce apoptosis. Using Gene Ontology analysis we show that each OSC altered a unique set of
pathways, and that these differences could be partially rationalized from a transcription factor binding site analysis. For
example, five compounds altered genes with a large enrichment of p53 binding sites in their promoter regions (p <
0.0001).
Conclusions: Taken together, these data establish OSCs derivatized from dysoxysulfone as a novel group of
compounds for development as anti-cancer agents.

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5 citations in Web of Science®
5 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Experimental Immunology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2010
Deposited On:11 Mar 2012 15:11
Last Modified:05 Apr 2016 15:33
Publisher:BioMed Central
ISSN:1471-2407
Publisher DOI:10.1186/1471-2407-10-351
PubMed ID:20598143
Permanent URL: http://doi.org/10.5167/uzh-58094

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