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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.
AuthorsYayun Liang, Cynthia Besch-Williford, Johannes D Aebi, Benford Mafuvadze, Matthew T Cook, Xiaoqin Zou, Salman M Hyder
JournalBreast cancer research and treatment (Breast Cancer Res Treat) Vol. 146 Issue 1 Pg. 51-62 (Jul 2014) ISSN: 1573-7217 [Electronic] Netherlands
PMID24878988 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Antineoplastic Agents
  • Benzophenones
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Ro 48-8071
  • Cholesterol
  • Intramolecular Transferases
  • lanosterol synthase
Topics
  • Animals
  • Antineoplastic Agents (administration & dosage, pharmacology)
  • Apoptosis (drug effects)
  • Benzophenones (administration & dosage, pharmacology)
  • Biosynthetic Pathways (drug effects)
  • Breast Neoplasms (drug therapy, metabolism)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Cell Survival (drug effects)
  • Cholesterol (biosynthesis)
  • Dose-Response Relationship, Drug
  • Estrogen Receptor alpha (metabolism)
  • Estrogen Receptor beta (metabolism)
  • Female
  • Humans
  • Inhibitory Concentration 50
  • Intramolecular Transferases (antagonists & inhibitors)
  • Mice

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