title: Impact of Apparent Antagonism of Estrogen Receptor β by Fulvestrant on Anticancer Activity of 2-Methoxyestradiol.
abstract: Osteosarcoma is one of the most malignant bone tumors of childhood and adolescence. Interestingly, the presence of estrogen receptors α and β has been reported in human bone cells, including osteosarcoma. Thus, inhibitors of estrogens such as fulvestrant, are considered candidates for novel endocrine therapy in treatment of osteosarcoma. Another anticancer agent that seems to be very effective in treatment of osteosarcoma is a derivative of 17β-estradiol, 2-methoxyestradiol. The aim of this study was to determine the anticancer activities of pure anti-estrogen, fulvestrant and combined treatment of fulvestrant and 2-methoxyestradiol towards highly metastatic osteosarcoma 143B cells. 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay was used in order to determine the antiproliferative potential of the compounds, and western blotting for estrogen receptors α and β. Flow cytometry was used in order to determine induction of cell death, cell-cycle arrest, mitochondrial depolarization, and DNA damage. Herein, we showed that fulvestrant has anticancer activity only at high concentrations. We were able to find and expression of estrogen receptor β, while we did not detect estrogen receptor α in osteosarcoma 143B cells. Moreover, fulvestrant down-regulated the expression of estrogen receptor β, and this effect was reversed by 2-methoxyestradiol. Thus, the obtained data suggest that 2-methoxyestradiol may exert part of its anticancer activity through modulation of expression of estrogen receptor β.
authors.affiliation: Department of Medical Chemistry, Medical University of Gdansk, Gdansk, Poland m.gorska@gumed.edu.pl.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Gorska
authors.affiliation: Department of Medical Chemistry, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Roksana Maja
authors.initials: RM
authors.lastname: Wyszkowska
authors.affiliation: Department of Medical Chemistry, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Alicja
authors.initials: A
authors.lastname: Kuban-Jankowska
authors.affiliation: Department of Medical Chemistry, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Michal
authors.initials: M
authors.lastname: Wozniak
mesh_terms: D000077584:2-Methoxyestradiol; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000473:pathology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000096:biosynthesis / Q000235:genetics; D047629:Estrogen Receptor beta / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D012516:Osteosarcoma / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects
chemical_list: D018931:Antineoplastic Agents, Hormonal; C506487:ESR1 protein, human; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; C468783:H2AX protein, human; D006657:Histones; D009363:Neoplasm Proteins; D000077267:Fulvestrant; D004958:Estradiol; D000077584:2-Methoxyestradiol
keywords: 2-methoxyestradiol; Fulvestrant; cancer cell death; estrogen receptors; osteosarcoma