Steroidal Metabolites Transformed by <Emphasis Type="Italic">Marchantia polymorpha</Emphasis> Cultures Block Breast Cancer Estrogen Biosynthesis |
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Authors: | Mohamed-Elamir F Hegazy Amira M Gamal-Eldeen Ali M El-Halawany Abou El-Hamd H Mohamed Paul W Paré |
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Institution: | 1.Chemistry of Medicinal Plants Department, and Pharmaceutical Laboratory, Center of Excellence for Advanced Sciences,National Research Center,Cairo,Egypt;2.Kyoto Pharmaceutical University,Kyoto,Japan;3.Cancer Biology Laboratory, Center of Excellence for Advanced Sciences, and Biochemistry Department,National Research Center,Cairo,Egypt;4.Department of Pharmacognosy, Faculty of Pharmacy,Cairo University,Cairo,Egypt;5.Department of Chemistry, Aswan-Faculty of Science,South Valley University,Aswan,Egypt;6.Department of Chemistry and Biochemistry,Texas Tech University,Lubbock,USA |
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Abstract: | Suspension of cultured cells of Marchantia polymorpha have the potential to hydrogenate the olefinic bonds present in androst-1,4-dien-3,17-dione (boldione, 1) to afford dihydroandrost-3,17-dione derivatives including: androst-4-ene-3,17-dione (androstenedione, 4-AD, 2), 5α-androstane-3,17-dione (androstenedione, AD, 4), and the less abundant metabolite 5α-androst-1-ene-3,17-dione (1-androstenedione, 1-AD, 3). After isolation and purification, these metabolites were characterized on the basis of spectroscopic analyses using 1D
and 2D NMR as well as mass spectrometry. Cytotoxicity of the biotransformation products against breast adenocarcinoma cells
(MCF-7) was assessed by a 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay and cell death (apoptosis
or necrosis) was assayed by acridine orange/ethidium bromide staining. Aromatase (cytochrome P450 19 enzyme, CYP19) inhibitory
activity was measured by a tritiated water release assay and by direct measurement of bio-transformed steroids using the tritium
labeled substrate 3H-androst-4-ene-3,17-dione. CYP19 mRNA expression in MCF-7 cells was analyzed by real-time PCR. Steroidal products 3 and 4 revealed a highly significant inhibition of MCF-7 cell growth that was predominantly due to apoptosis not necrosis. Steroidal
products 3 and 4 are both potent inhibitors of aromatase activity and CYP19 mRNA expression, while 2 is a known substrate for aromatase. These data establish that metabolites 3 and 4 are potent chemical agents against breast cancer via aromatase inhibitory mechanism. Results were interpreted via virtual
docking of the biotransformation products to the human placental aromatase active site. |
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