title: Cytotoxic effects of 2-arylbenzofuran phytoestrogens on human cancer cells: modulation by adrenal and gonadal steroids.
abstract: Although 2-arylbenzofuran phytoalexins are known for decades, their anticancer activity has not been studied systematically. We have previously reported on the isolation and the estrogen receptor (ER) modulation properties of three new 2-arylbenzofurans from Onobrychis ebenoides, ebenfuran I [2-(2,4-dihydroxyphenyl)-5-hydroxy-6-methoxy-benzofuran], ebenfuran II [2-(2,4-dihydroxyphenyl)-3-formyl-4-hydroxy-6-methoxy-benzofuran] and ebenfuran III [2-(2,4-dihydroxyphenyl)-3-formyl-4-hydroxy-6-methoxy-5-(3-methyl-buten-2-yl)-benzofuran]. We now show that, while I and II could stimulate the proliferation of MCF-7 cells, III was inhibitory in a proliferation-dependent manner. III inhibited the growth of all human cancer cells examined, regardless of ER or multidrug resistance status. Estradiol rendered MCF-7 cells more sensitive to III, and this coincided with the ability of the hormone at concentrations > or = 0.1 nM to bind to the ER of the cells and stimulate their proliferation in the presence of III. Cell proliferation stimulating concentrations of I and II also enhanced the effect of III on MCF-7 cells. However, dehydroepiandrosterone and dihydrotestosterone were ineffective in this respect. III-treated MCF-7 cells exhibited G1 phase arrest followed by detachment-induced cell death and/or apoptosis in the adherent fraction, pronounced induction of Bax and suppression of estradiol induction of Bcl-2. Our data indicate that the largely unexplored pool of benzofuran phytoalexins includes entities potentially suitable for chemoprevention and treatment of human cancer.
authors: Molecular Endocrinology Program, Institute of Biological Research and Biotechnology, National Hellenic Research Foundation, 48 Vas. Constantinou Avenue, 11635 Athens, Greece.
authors: Efrosini S
authors: ES
authors: Katsanou
authors: Maria
authors: M
authors: Halabalaki
authors: Nektarios
authors: N
authors: Aligiannis
authors: Sofia
authors: S
authors: Mitakou
authors: Alexios-Leandros
authors: AL
authors: Skaltsounis
authors: Xanthippi
authors: X
authors: Alexi
authors: Harris
authors: H
authors: Pratsinis
authors: Michael N
authors: MN
authors: Alexis
mesh_terms: D000311:Adrenal Glands / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001572:Benzofurans / Q000494:pharmacology; D001943:Breast Neoplasms / Q000473:pathology*; D002396:Catechols / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003603:Cytotoxins / Q000494:pharmacology; D004347:Drug Interactions; D005663:Furans / Q000494:pharmacology*; D012739:Gonadal Steroid Hormones / Q000494:pharmacology*; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D008954:Models, Biological; D048789:Phytoestrogens / Q000494:pharmacology*; D012717:Sesquiterpenes; D013256:Steroids / Q000378:metabolism / Q000494:pharmacology*; D013729:Terpenes / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D000094162:Phytoalexins
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001572:Benzofurans; D002396:Catechols; D003603:Cytotoxins; D005663:Furans; D012739:Gonadal Steroid Hormones; D036341:Intercellular Signaling Peptides and Proteins; D048789:Phytoestrogens; D012717:Sesquiterpenes; D013256:Steroids; D013729:Terpenes; D000094162:Phytoalexins