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Chemoprevention of cancer by organoselenium compounds
K el-Bayoumy1, P Upadhyaya, Y H Chae
1American Health Foundation, Valhalla, NY 10595, USA.
Abstract:
A major research goal of our laboratories is the development of new organoselenium cancer chemopreventive agents with less toxicity compared to some of the historical selenium compounds, such as sodium selenite. Ideally, such agents would be employed to inhibit tumor development in different organs caused by a variety of chemical carcinogens, particularly those present in the human environment. A series of organoselenium compounds has been synthesized and evaluated for their chemopreventive efficacy in vivo. Parallel to these studies, short-term in vitro and in vivo assays were employed to understand the mechanism of action and to rapidly evaluate their efficacy in eventual long-term preclinical investigations. We demonstrated that one of the most effective of these organoselenium compounds, 1,4-phenylenebis(methylene)selenocyanate (p-XSC, Fig. 1), is capable of inhibiting tumors in the mammary glands, colon, and lung of laboratory animals. Dietary p-XSC inhibited mammary tumor development induced by 7,12-dimethylbenz(a)anthracene (DMBA) during both the initiation and post-initiation phases of carcinogenesis in female CD rats. p-XSC inhibited DMBA-DNA adduct formation in the mammary glands. In collaboration with other laboratories, we demonstrated that p-XSC inhibited thymidine kinase in mammary tumor cell lines derived from both humans and rats. Employing mammary carcinoma cell lines, p-XSC was also shown to inhibit cell growth and induce a dose-dependent increase in cell death by apoptosis. In these assays p-XSC appears superior to selenite and to its sulfur analog, 1,4-phenylenebis(methylene)thiocyanate. Dietary p-XSC decreased colon tumor induction by azoxymethane in F344 rats during both phases of carcinogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
New organoselenium compounds, like 1,4-phenylenebis(methylene)selenocyanate (p-XSC), show promise as less toxic cancer chemopreventive agents. p-XSC effectively inhibited tumor development in multiple organs in animal models.
Area of Science:
- Oncology
- Medicinal Chemistry
- Toxicology
Background:
- Development of novel organoselenium compounds for cancer chemoprevention is crucial.
- Existing selenium compounds like sodium selenite can exhibit significant toxicity.
- Targeting chemically induced tumors in various organs requires effective and safer agents.
Purpose of the Study:
- To synthesize and evaluate novel organoselenium compounds for cancer chemoprevention.
- To assess the efficacy of 1,4-phenylenebis(methylene)selenocyanate (p-XSC) in inhibiting tumor development.
- To elucidate the mechanism of action and compare p-XSC with other selenium compounds.
Main Methods:
- In vivo chemopreventive efficacy studies in animal models.
- In vitro and in vivo mechanistic assays.
- Evaluation of carcinogen-DNA adduct formation and enzyme inhibition.
- Assessment of cell growth inhibition and apoptosis induction.
Main Results:
- 1,4-phenylenebis(methylene)selenocyanate (p-XSC) demonstrated significant chemopreventive efficacy against mammary, colon, and lung tumors.
- p-XSC inhibited 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumors during initiation and post-initiation.
- p-XSC inhibited DMBA-DNA adducts, thymidine kinase, cell growth, and induced apoptosis in mammary tumor cells.
- p-XSC showed superior efficacy to selenite and its sulfur analog in tested assays.
- Dietary p-XSC decreased azoxymethane-induced colon tumors in rats.
Conclusions:
- 1,4-phenylenebis(methylene)selenocyanate (p-XSC) is a potent organoselenium chemopreventive agent with broad efficacy.
- p-XSC demonstrates a favorable profile compared to traditional selenium compounds, with potential for reduced toxicity.
- Further preclinical investigations into p-XSC are warranted for cancer prevention strategies.