Characterization of the apoptotic response of human leukemia cells to organosulfur compounds.
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.
Wong
W Wei-Lynn
WW
Division of Cancer Genomics and Proteomics, Ontario Cancer Institute, University Health Network, Toronto M5G2M1, Canada.
Boutros
Paul C
PC
Wasylishen
Amanda R
AR
Guckert
Kristal D
KD
O'Brien
Erin M
EM
Griffiths
Rebecca
R
Martirosyan
Anna R
AR
Bros
Christina
C
Jurisica
Igor
I
Langler
Richard F
RF
Penn
Linda Z
LZ
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001665:Binding Sites; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004220:Disulfides / Q000138:chemical synthesis / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000473:pathology*; D015394:Molecular Structure; D023461:Myeloid Progenitor Cells / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis / Q000494:pharmacology*
D000970:Antineoplastic Agents; D004220:Disulfides; D012333:RNA, Messenger; D013450:Sulfones