Laboratory of Biochemistry, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, no 228, 4050-313 Porto, Portugal.
J Steroid Biochem Mol Biol. 2013 May;135:51-9. doi: 10.1016/j.jsbmb.2012.12.017. Epub 2013 Jan 11.
Several therapeutic approaches are used in estrogen receptor positive (ER(+)) breast cancers, being one of them the use of aromatase inhibitors (AIs). Although AIs demonstrate higher efficacy than tamoxifen, they can also exhibit de novo or acquired resistance after prolonged treatment. Recently, we have described the synthesis and biochemical evaluation of four steroidal AIs, 3β-hydroxyandrost-4-en-17-one (1), androst-4-en-17-one (12), 4α,5α-epoxyandrostan-17-one (13a) and 5α-androst-2-en-17-one (16), obtained from modifications in the A-ring of the aromatase substrate, androstenedione. In this study, it was investigated the biological effects of these AIs in different breast cancer cell lines, an ER(+) aromatase-overexpressing human breast cancer cell line (MCF-7aro cells), an estrogen-receptor negative (ER(-)) human breast cancer cell line (SK-BR-3 cells), and a late stage of acquired resistance cell line (LTEDaro cells). The effects of an autophagic inhibitor (3-methyladenine) plus AIs 1, 12, 13a or exemestane in LTEDaro cells were also studied to understand the involvement of autophagy in AI acquired resistance. Our results showed that these steroids inhibit aromatase of MCF-7aro cells and decrease cell viability in a dose- and time-dependent manner. The new AI 1 is the most potent inhibitor, although the AI 12 demonstrates to be the most effective in decreasing cell viability. Besides, and in advantage over exemestane, AIs 12 and 13a also reduced LTEDaro cells viability. The use of the autophagic inhibitor allowed AIs to diminish viability of LTEDaro cells, presenting a similar behavior to the sensitive cells. Thus, inhibition of autophagy may sensitize hormone-resistant cancer cells to anti-estrogen therapies.
几种治疗方法用于雌激素受体阳性（ER(+））乳腺癌，其中之一是使用芳香酶抑制剂（AIs）。虽然 AIs 比他莫昔芬显示出更高的疗效，但它们在长期治疗后也可能表现出新的或获得性耐药。最近，我们描述了四种甾体 AIs 的合成和生化评价，3β-羟基雄甾-4-烯-17-酮（1）、雄甾-4-烯-17-酮（12）、4α,5α-环氧雄烷-17-酮（13a）和 5α-雄甾-2-烯-17-酮（16），它们是从芳香酶底物雄烯二酮的 A 环修饰中获得的。在这项研究中，研究了这些 AIs 在不同乳腺癌细胞系中的生物学效应，一种 ER(+)芳香酶过表达的人乳腺癌细胞系（MCF-7aro 细胞）、一种雌激素受体阴性（ER(-））人乳腺癌细胞系（SK-BR-3 细胞）和一种晚期获得性耐药细胞系（LTEDaro 细胞）。还研究了自噬抑制剂（3-甲基腺嘌呤）加 AIs 1、12、13a 或依西美坦在 LTEDaro 细胞中的作用，以了解自噬在 AI 获得性耐药中的作用。我们的结果表明，这些甾体抑制 MCF-7aro 细胞的芳香酶，并以剂量和时间依赖的方式降低细胞活力。新的 AI 1 是最有效的抑制剂，尽管 AI 12 在降低细胞活力方面最为有效。此外，与依西美坦相比，AIs 12 和 13a 还降低了 LTEDaro 细胞的活力。自噬抑制剂的使用使 AIs 能够降低 LTEDaro 细胞的活力，表现出与敏感细胞相似的行为。因此，抑制自噬可能使激素抵抗的癌细胞对抗雌激素治疗敏感。
