title: Cholesterol biosynthesis inhibitors as potent novel anti-cancer agents: suppression of hormone-dependent breast cancer by the oxidosqualene cyclase inhibitor RO 48-8071.
abstract: In most human breast cancers, tumor cell proliferation is estrogen dependent. Although hormone-responsive tumors initially respond to anti-estrogen therapies, most of them eventually develop resistance. Our goal was to identify alternative targets that might be regulated to control breast cancer progression. Sulforhodamine B assay was used to measure the viability of cultured human breast cancer cell lines exposed to various inhibitors. Protein expression in whole-cell extracts was determined by Western blotting. BT-474 tumor xenografts in nude mice were used for in vivo studies of tumor progression. RO 48-8071 ([4'-[6-(Allylmethylamino)hexyloxy]-4-bromo-2'-fluorobenzophenone fumarate]; RO), a small-molecule inhibitor of oxidosqualene cyclase (OSC, a key enzyme in cholesterol biosynthesis), potently reduced breast cancer cell viability. In vitro exposure of estrogen receptor (ER)-positive human breast cancer cells to pharmacological levels of RO or a dose close to the IC50 for OSC (nM) reduced cell viability. Administration of RO to mice with BT-474 tumor xenografts prevented tumor growth, with no apparent toxicity. RO degraded ERα while concomitantly inducing the anti-proliferative protein ERβ. Two other cholesterol-lowering drugs, Fluvastatin and Simvastatin, were less effective in reducing breast cancer cell viability and were found not to induce ERβ. ERβ inhibition or knockdown prevented RO-dependent loss of cell viability. Importantly, RO had no effect on the viability of normal human mammary cells. RO is a potent inhibitor of hormone-dependent human breast cancer cell proliferation. The anti-tumor properties of RO appear to be in part due to an off-target effect that increases the ratio of ERβ/ERα in breast cancer cells.
authors.affiliation: Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, 65211, USA.
authors.forename: Yayun
authors.initials: Y
authors.lastname: Liang
authors.forename: Cynthia
authors.initials: C
authors.lastname: Besch-Williford
authors.forename: Johannes D
authors.initials: JD
authors.lastname: Aebi
authors.forename: Benford
authors.initials: B
authors.lastname: Mafuvadze
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Cook
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Zou
authors.forename: Salman M
authors.initials: SM
authors.lastname: Hyder
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001577:Benzophenones / Q000008:administration & dosage / Q000494:pharmacology*; D053898:Biosynthetic Pathways / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D047628:Estrogen Receptor alpha / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors*; D051379:Mice
chemical_list: D000970:Antineoplastic Agents; D001577:Benzophenones; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; C105726:Ro 48-8071; D002784:Cholesterol; D019751:Intramolecular Transferases; C021924:lanosterol synthase