TY - JOUR
T1 - Characterization of the apoptotic response of human leukemia cells to organosulfur compounds
AU - Wong, W. Wei Lynn
AU - Boutros, Paul C.
AU - Wasylishen, Amanda R.
AU - Guckert, Kristal D.
AU - O'Brien, Erin M.
AU - Griffiths, Rebecca
AU - Martirosyan, Anna R.
AU - Bros, Christina
AU - Jurisica, Igor
AU - Langler, Richard F.
AU - Penn, Linda Z.
N1 - Funding Information:
WWW was supported by a fellowship from the Canadian Institutes of Health Research. PCB was supported by fellowships from the Institute for Robotics and Intelligent Systems, the Natural Sciences and Engineering Research Council, and the Canadian Institutes of Health Research through an EIRR21 Fellowship. ARW was supported by a Canadian Breast Cancer Foundation Ontario Region Fellowship.The authors thank MedInnova Partners for supporting this research project. This study was conducted with the support of the Ontario Institute for Cancer Research to PCB through funding provided by the Government of Ontario. Additional support was provided by the Ontario Ministry of Health and Long Term Care. The views expressed do not necessarily reflect those of the OMOHLTC.
PY - 2010/7/2
Y1 - 2010/7/2
N2 - 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.
AB - 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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U2 - 10.1186/1471-2407-10-351
DO - 10.1186/1471-2407-10-351
M3 - Article
C2 - 20598143
AN - SCOPUS:77954078542
SN - 1471-2407
VL - 10
JO - BMC cancer
JF - BMC cancer
M1 - 351
ER -