Source:http://linkedlifedata.com/resource/pubmed/id/11356934
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
3
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| pubmed:dateCreated |
2001-5-17
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| pubmed:abstractText |
Compounds that inhibit aromatase activity are used for the treatment of breast cancer. A group of sesquiterpene lactones inhibit aromatase activity and also exert cytotoxicity through their reactive alpha-methylene-gamma-lactone group. To synthesize sesquiterpene lactones with greater specificity for aromatase inhibition and lower cytotoxicity, we chemically reduced the alpha-methylene-gamma-lactone group in the active aromatase inhibitor 10-epi-8-deoxycumambrin B (compound 1), to obtain the new compound 11betaH,13-dihydro-10-epi-8-deoxycumambrin B (compound 2). Reduction of the alpha-methylene-gamma-lactone group abrogated the cytotoxic activity of compound 1 against the JEG-3, HeLa, and COS-7 cell lines. Compound 2 had higher aromatase inhibitory activity than compound 1 (IC(50) = 2 +/- 0.5 microM versus 7 +/- 0.5 microM, K(i) = 1.5 microM versus 4.0 microM) and was a more potent type II ligand to the heme iron present in the cytochrome P450(arom) active site. Compound 2 inhibited aromatase activity in JEG-3 cells in a comparable manner to the inhibitor aminoglutethimide (AG) used clinically for the treatment of breast cancer. Additionally, compound 2 inhibited androstenedione-induced uterine hypertrophy in sexually immature mice (41% of uterine weight suppression for compound 2 versus 51% for AG). We conclude that the anti-aromatase activity of sesquiterpene lactones does not depend on the presence of the highly reactive alpha-methylene-gamma-lactone group, whereas their cytotoxicity does. These findings may facilitate the development of safer agents for breast cancer therapy.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Aminoglutethimide,
http://linkedlifedata.com/resource/pubmed/chemical/Androstenedione,
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Aromatase,
http://linkedlifedata.com/resource/pubmed/chemical/Aromatase Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Lactones,
http://linkedlifedata.com/resource/pubmed/chemical/Sesquiterpenes
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| pubmed:status |
MEDLINE
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| pubmed:month |
Jun
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| pubmed:issn |
0022-3565
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| pubmed:author | |
| pubmed:issnType |
Print
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| pubmed:volume |
297
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
1099-105
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| pubmed:dateRevised |
2006-11-15
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| pubmed:meshHeading |
pubmed-meshheading:11356934-Aminoglutethimide,
pubmed-meshheading:11356934-Androstenedione,
pubmed-meshheading:11356934-Animals,
pubmed-meshheading:11356934-Antineoplastic Agents,
pubmed-meshheading:11356934-Aromatase,
pubmed-meshheading:11356934-Aromatase Inhibitors,
pubmed-meshheading:11356934-Cell Line,
pubmed-meshheading:11356934-Cell Survival,
pubmed-meshheading:11356934-Choriocarcinoma,
pubmed-meshheading:11356934-Dose-Response Relationship, Drug,
pubmed-meshheading:11356934-Female,
pubmed-meshheading:11356934-Humans,
pubmed-meshheading:11356934-Hypertrophy,
pubmed-meshheading:11356934-Lactones,
pubmed-meshheading:11356934-Mice,
pubmed-meshheading:11356934-Microsomes,
pubmed-meshheading:11356934-Mitochondria,
pubmed-meshheading:11356934-Organ Size,
pubmed-meshheading:11356934-Placenta,
pubmed-meshheading:11356934-Sesquiterpenes,
pubmed-meshheading:11356934-Spectrum Analysis,
pubmed-meshheading:11356934-Structure-Activity Relationship,
pubmed-meshheading:11356934-Uterine Diseases,
pubmed-meshheading:11356934-Uterine Neoplasms
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| pubmed:year |
2001
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| pubmed:articleTitle |
Aromatase inhibition by an 11,13-dihydroderivative of a sesquiterpene lactone.
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| pubmed:affiliation |
Department of Clinical Biochemistry, Consejo Nacional de Investigaciones Científicas y Técnicas, Faculty of Chemical Sciences, National University of Córdoba, Córdoba, Argentina. javier.blanco@stjude.org
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| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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