title: Marketed Drugs Can Inhibit Cytochrome P450 27A1, a Potential New Target for Breast Cancer Adjuvant Therapy.
abstract: Cytochrome P450 CYP27A1 is the only enzyme in humans converting cholesterol to 27-hydroxycholesterol, an oxysterol of multiple functions, including tissue-specific modulation of estrogen and liver X receptors. Both receptors seem to mediate adverse effects of 27-hydroxycholesterol in breast cancer when the levels of this oxysterol are elevated. The present work assessed druggability of CYP27A1 as a potential antibreast cancer target. We selected 26 anticancer and noncancer medications, most approved by the Food and Drug Administration, and evaluated them first in vitro for inhibition of purified recombinant CYP27A1 and binding to the enzyme active site. Six strong CYP27A1 inhibitors/binders were identified. These were the two antibreast cancer pharmaceuticals anastrozole and fadrozole, antiprostate cancer drug bicalutamide, sedative dexmedetomidine, and two antifungals ravuconazole and posaconazole. Anastrozole was then tested in vivo on mice, which received subcutaneous drug injections for 1 week. Mouse plasma and hepatic 27-hydroxycholesterol levels were decreased 2.6- and 1.6-fold, respectively, whereas plasma and hepatic cholesterol content remained unchanged. Thus, pharmacologic CYP27A1 inhibition is possible in the whole body and individual organs, but does not negatively affect cholesterol elimination. Our results enhance the potential of CYP27A1 as an antibreast cancer target, could be of importance for the interpretation of Femara versus Anastrozole Clinical Evaluation Trial, and bring attention to posaconazole as a potential complementary anti-breast cancer medication. More medications on the US market may have unanticipated off-target inhibition of CYP27A1, and we propose strategies for their identification.
authors.affiliation: Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Natalia
authors.initials: N
authors.lastname: Mast
authors.affiliation: Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Lin
authors.affiliation: Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio iap8@case.edu.
authors.forename: Irina A
authors.initials: IA
authors.lastname: Pikuleva
mesh_terms: D000277:Adjuvants, Pharmaceutic / Q000737:chemistry / Q000494:pharmacology*; D000077384:Anastrozole; D000813:Anilides / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy; D053493:Cholestanetriol 26-Monooxygenase / Q000037:antagonists & inhibitors*; D020927:Dexmedetomidine / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017316:Fadrozole / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006993:Hypnotics and Sedatives / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology; D014105:Tosyl Compounds / Q000737:chemistry / Q000494:pharmacology; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000277:Adjuvants, Pharmaceutic; D000813:Anilides; D000935:Antifungal Agents; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006993:Hypnotics and Sedatives; D009570:Nitriles; D013844:Thiazoles; D014105:Tosyl Compounds; D014230:Triazoles; D000077384:Anastrozole; D020927:Dexmedetomidine; C101425:posaconazole; C104066:ER 30346; C053541:bicalutamide; D053493:Cholestanetriol 26-Monooxygenase; C506832:Cyp27a1 protein, mouse; D017316:Fadrozole