%0 Journal Article
%T Characterization of the apoptotic response of human leukemia cells to organosulfur compounds
%A W Wei-Lynn Wong
%A Paul C Boutros
%A Amanda R Wasylishen
%A Kristal D Guckert
%A Erin M O'Brien
%A Rebecca Griffiths
%A Anna R Martirosyan
%A Christina Bros
%A Igor Jurisica
%A Richard F Langler
%A Linda Z Penn
%J BMC Cancer
%D 2010
%I BioMed Central
%R 10.1186/1471-2407-10-351
%X 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.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).Taken together, these data establish OSCs derivatized from dysoxysulfone as a novel group of compounds for development as anti-cancer agents.The ultimate goal of drug development is to create therapeutic agents that kill tumor cells but spare normal cells. Novel therapies that selectively induce tumor cell death are urgently needed in the clinical management of cancers. Advances in cancer biology have revealed that tumor cells retain their intrinsic ability to commit suicide, known as apoptosis [1,2]. Because of this, compounds are being developed to trigger apoptosis in a tumor-specific manner. Triggering non-inflammatory elimination of tumor cells by inducing them to undergo apoptosis is highly desirable [3].To this end, there has been interest in exploiting the anti-proliferative effects of several natural organosulfur compounds (OSCs), such as those found in garlic, onions and mahogany trees [4,5]. Compounds from garlic, such as diallyl disulfide (DADS), have been shown to have limited toxicity and reduce tumor load in vivo [6]. The anti-proliferative mechanism is thought to involve
%U http://www.biomedcentral.com/1471-2407/10/351