Abstract
Aromatase is a particularly attractive target in the treatment of estrogen receptor positive breast cancer. Aromatase levels in breast cancer cells are enhanced by prostaglandins and reduced by COX inhibitors. The synthesis and biological evaluation of a novel series of sulfonanilide analogues derived from the COX-2 selective inhibitor NS-398 are described. The compounds suppress aromatase enzyme activity in SK-BR-3 breast cancer cells in a dose- and time-dependent manner. The effect of these compounds on COX-2 inhibition is investigated in breast cancer cells as well. Structure-activity analysis does not find a correlation between aromatase suppression and COX-2 inhibition. Microsomal aromatase inhibition studies rule out the possibility of direct enzyme inhibition. Real-time PCR analysis demonstrates that the sulfonanilide analogues decrease aromatase gene transcription in SK-BR-3 cells. These studies suggest that the novel sulfonanilide compounds suppress aromatase activity and transcription in SK-BR-3 breast cancer cells independent of COX-2 inhibition.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Aniline Compounds / chemical synthesis*
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Aniline Compounds / chemistry
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Aniline Compounds / pharmacology
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Aromatase / biosynthesis
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Aromatase / genetics
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Aromatase / metabolism*
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Aromatase Inhibitors / chemical synthesis*
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Aromatase Inhibitors / chemistry
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Aromatase Inhibitors / pharmacology
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Breast Neoplasms
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Cell Line, Tumor
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Cyclooxygenase 2 / metabolism*
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Cyclooxygenase Inhibitors / chemical synthesis*
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Cyclooxygenase Inhibitors / chemistry
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Cyclooxygenase Inhibitors / pharmacology
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Dinoprostone / biosynthesis
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Drug Screening Assays, Antitumor
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Female
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Humans
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Microsomes / drug effects
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Microsomes / enzymology
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Neoplasms, Hormone-Dependent
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Nitrobenzenes / chemical synthesis*
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Nitrobenzenes / chemistry
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Nitrobenzenes / pharmacology
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Placenta / enzymology
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Placenta / ultrastructure
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Polymerase Chain Reaction
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RNA, Messenger / biosynthesis
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Sulfonamides / chemical synthesis*
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Sulfonamides / chemistry
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Sulfonamides / pharmacology
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Transcription, Genetic
Substances
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Aniline Compounds
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Aromatase Inhibitors
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Cyclooxygenase Inhibitors
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Nitrobenzenes
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RNA, Messenger
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Sulfonamides
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N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
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Aromatase
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Cyclooxygenase 2
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Dinoprostone