Marketed Drugs Can Inhibit Cytochrome P450 27A1, a Potential New Target for Breast Cancer Adjuvant Therapy
Marketed Drugs Can Inhibit Cytochrome P450 27A1, a Potential New Target for Breast Cancer Adjuvant Therapy
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DOI：
10.1124/mol.115.099598
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发表时间：
2015-09-01
影响因子：
3.6
通讯作者：
Pikuleva, Irina A.
中科院分区：
文献类型：
--
作者：
Mast, Natalia;Lin, Joseph B.;Pikuleva, Irina A.
细胞色素P450 CYP27A1是人体内唯一一种将胆固醇转化为27-羟基胆固醇的酶，27-羟基胆固醇是一种具有多种功能的氧合固醇，包括对雌激素和肝脏X受体的组织特异性调节。当27-羟基胆固醇的氧固醇水平升高时，这两种受体似乎都介导了27-羟基胆固醇对乳腺癌的不利影响。目前的工作评估了CYP27A1作为潜在的抗乳腺癌靶点的可药性。我们选择了美国食品和药物管理局批准最多的26种抗癌和非癌症药物，并首先在体外评估了它们对纯化的重组CYP27A1的抑制作用和与酶活性部位的结合。鉴定出6种强的CYP27A1抑制剂/结合剂。这是两种抗乳腺癌药物阿那曲唑和法洛唑，抗前列腺癌药物比卡鲁胺，镇静剂右美托咪唑，以及两种抗真菌药物拉武康唑和泊沙康唑。阿那曲唑随后在接受皮下药物注射1周的小鼠身上进行了体内测试。小鼠血浆和肝脏的27-羟基胆固醇水平分别降低了2.6倍和1.6倍，而血浆和肝脏的胆固醇含量保持不变。因此，药物抑制CYP27A1在全身和个别器官中是可能的，但不会对胆固醇的消除产生负面影响。我们的结果增强了CYP27A1作为抗乳腺癌靶点的潜力，可能对解释Femara与阿那曲唑的临床评估试验有重要意义，并引起人们对泊沙康唑作为潜在的辅助抗乳腺癌药物的关注。美国市场上更多的药物可能具有意想不到的对CYP27A1的非靶点抑制，我们提出了识别它们的策略。
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.