Stimulation of MCF-7 breast cancer cell proliferation by estrone sulfate and dehydroepiandrosterone sulfate: inhibition by novel non-steroidal steroid sulfatase inhibitors
Stimulation of MCF-7 breast cancer cell proliferation by estrone sulfate and dehydroepiandrosterone sulfate: inhibition by novel non-steroidal steroid sulfatase inhibitors
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DOI：
10.1016/s0960-0760(00)00077-7
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发表时间：
2000-07-01
影响因子：
4.1
通讯作者：
Lehr, P
中科院分区：
文献类型：
--
作者：
Billich, A;Nussbaumer, P;Lehr, P
类固醇硫酸酯酶（STS）调节系统前体如硫酸雌酮和硫酸脱氢表雄酮（DHEAS）形成活性类固醇。在乳腺组织中，这一途径是局部产生雌激素的来源，雌激素支持内分泌依赖性肿瘤的生长。因此，STS抑制剂可能具有治疗潜力。在这项研究中，我们报道了取代氨基磺酸铬酮作为一类新的非甾体不可逆STS抑制剂。当对纯化STS进行测试时，这些化合物比以前描述的非甾体抑制剂类型有效得多（6- 80倍）。在MCF-7乳腺癌细胞中，它们抑制STS活性的IC50低于100 pM。重要的是，这些化合物还能有效地阻断硫酸雌酮刺激的MCF-7细胞的生长，IC50也低于100 pM。对于一种化合物，我们还观察到在高浓度（1mum）下缺乏任何雌激素效应。我们也首次证明了STS抑制剂可以阻断dheas刺激的MCF-7细胞的生长。有趣的是，这不能通过芳香酶的特异性抑制剂来实现，这表明DHEAS对MCF-7细胞生长的刺激遵循芳香酶独立的途径。这进一步证明类固醇硫酸酯酶抑制剂是治疗乳腺癌的潜在药物。(C) 2000 Elsevier Science Ltd.版权所有。
Steroid sulfatase (STS) regulates the formation of active steroids from systemic precursors, such as estrone sulfate and dehydroepiandrosterone sulfate (DHEAS). In breast tissues, this pathway is a source for local production of estrogens, which support the growth of endocrine-dependent tumours. Therefore, inhibitors of STS could have therapeutic potential. In this study, we report on substituted chromenone sulfamates as a novel class of non-steroidal irreversible inhibitors of STS. The compounds are substantially more potent (6- to 80-fold) than previously described types of non-steroidal inhibitors when tested against purified STS. In MCF-7 breast cancer cells, they inhibit STS activity with IC50 below 100 pM. Importantly, the compounds also potently block estrone sulfate-stimulated growth of MCF-7 cells, again with IC50 below 100 pM. For one compound, we also observed a lack of any estrogenic effect at high concentrations (1 muM). We also demonstrate for the first time that STS inhibitors can block the DHEAS-stimulated growth of MCF-7 cells. Interestingly, this cannot be achieved with specific inhibitors of the aromatase, suggesting that stimulation of MCF-7 cell growth by DHEAS follows an aromatase-independent pathway. This gives further justification to consider steroid sulfatase inhibitors as potential drugs in the therapy of breast cancer. (C) 2000 Elsevier Science Ltd. All rights reserved.