Marketed Drugs Can Inhibit Cytochrome P450 27A1 (CYP27A1), a Potential New Target for Breast Cancer Adjuvant Therapy.
Mol Pharmacol. 2015 Jun 16;
Authors: Mast N, Lin JB, Pikuleva IA
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 were found 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 anti-breast cancer target. We selected 26 anti-cancer and non-cancer medications, most approved by the FDA, 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 anti-breast cancer pharmaceuticals anastrozole and fadrozole, anti-prostate cancer drug bicalutamide, sedative dexmedetomidine, and two anti-fungals ravuconazole and posaconazole. Anastrozole was then tested in vivo on mice, which received subcutaneous drug injections for one 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 anti-breast 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.
PMID: 26082378 [PubMed - as supplied by publisher]