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

ABSTRACT: 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.

SUBMITTER: Wong WW

PROVIDER: S-EPMC2928001 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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

Wong W Wei-Lynn WW 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

BMC cancer 20100702

<h4>Background</h4>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 rich ...[more]

PMID: 20598143

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Project description:Traditional Chinese medicine wogonin plays an important role in the treatment of leukemia. Recently, the application of drug-coated magnetic nanoparticles (MNPs) to increase water solubility of the drug and to enhance its chemotherapeutic efficiency has attracted much attention. Drugs coated with MNPs are becoming a promising way for better leukemia treatment. This study aimed to assess the possible molecular mechanisms of wogonin-coated MNP-Fe3O4 (Wog-MNPs-Fe3O4) as an antileukemia agent.After incubated for 48 h, the antiproliferative effects of MNPs, wogonin, or Wog-MNPs-Fe3O4on K562/A02 cells were determined by methyl thiazolyl tetrazolium (MTT) assay. The apoptotic rates of K562/A02 cells treated with either wogonin or Wog-MNPs-Fe3O4were determined by flow cytometer (FCM) assay. The cell cycle arrest in K562/A02 cells was determined by FCM assay. The elementary molecular mechanisms of these phenomena were explored by Western blot and reverse transcriptase polymerase chain reaction (RT-PCR).With cell viabilities ranging from 98.76% to 101.43%, MNP-Fe3O4was nontoxic to the cell line. Meanwhile, the wogonin and Wog-MNPs-Fe3O4had little effects on normal human embryonic lung fibroblast cells. The cell viabilities of the Wog-MNPs-Fe3O4group (28.64-68.36%) were significantly lower than those of the wogonin group (35.53-97.28%) in a dose-dependent manner in 48 h (P < 0.001). The apoptotic rate of K562/A02 cells was significantly improved in 50 ?mol/L Wog-MNPs-Fe3O4group (34.28%) compared with that in 50 ?mol/L wogonin group (23.46%; P< 0.001). Compared with those of the 25 and 50 ?mol/L wogonin groups, the ratios of G0/G1-phase K562/A02 cells were significantly higher in the 25 and 50 ?mol/L Wog-MNPs-Fe3O4groups (all P< 0.001). The mRNA and protein expression levels of the p21 and p27 in the K562/A02 cells were also significantly higher in the Wog-MNPs-Fe3O4group compared with those of the wogonin group (all P< 0.001).This study demonstrated that MNPs were the effective drug delivery vehicles to deliver wogonin to the leukemia cells. Through increasing cells arrested at G0/G1-phase and inducing apoptosis of K562/A02 cells, MNPs could enhance the therapeutic effects of wogonin on leukemia cells. These findings indicated that MNPs loaded with wogonin could provide a promising way for better leukemia treatment.

Dataset Information

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

Publications

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

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