Characterization of the apoptotic response of human leukemia cells to organosulfur compounds
- Equal contributors
1 Division of Cancer Genomics and Proteomics, Ontario Cancer Institute, University Health Network, Toronto, M5G 2M1, Canada
2 Department of Medical Biophysics, University of Toronto, Toronto, M5G 2M1, Canada
3 Division of Signaling Biology, Ontario Cancer Institute, University Health Network, Toronto, M5G 2M1, Canada
4 Department of Computer Science, University of Toronto, Toronto, M5S 1A8, Canada
5 Department of Chemistry, Mount Allison University, Sackville, E4L 1G8, Canada
6 Department of Biochemistry, LaTrobe University, Australia
7 Ontario Institute of Cancer Research, Toronto, M5G 0A3, Canada
BMC Cancer 2010, 10:351 doi:10.1186/1471-2407-10-351Published: 2 July 2010
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.
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.