Background/Objectives:Endocrine therapies that comprise anti-estrogens and aromatase inhibitors (AIs) are the standard treatment for estrogen receptor-positive (ER+) (Luminal A) breast cancer—the most prevalent subtype. However, the emergence of resistance restricts their success by causing tumor relapse and re-growth, which demands a switch towards other therapeutic approaches in order to minimize or overcome resistance. Indeed, this clinical limitation highlights the search for new molecules to improve cancer treatment. Recently, strategies that address multiple targets have been emerging, and multi-target drugs have the potential to become the future anti-cancer molecules. Our group has been searching for new multi-target compounds, and as part of this, our study aims to understand the anti-cancer and multi-target potential of three new steroidal aromatase inhibitors (AIs): 7α-methylandrost-4-en-17-one (6), 7α-methylandrost-4-ene-3,17-dione (10a) and androsta-4,9(11)-diene-3,17-dione (13).Methods:Their in vitro actions and molecular mechanisms were elucidated in a sensitive ER+ aromatase-overexpressing breast cancer cell line, MCF-7aro cells, as well as in an AI-resistant ER+ breast cancer cell line, LTEDaro cells.Results:All the new AIs (10 µM) prevented the proliferation of MCF-7aro cells by arresting cell cycle progression. Interestingly, all AIs (10 µM) act as androgen receptor (AR) agonists and modulate ER levels, synthesis and signaling to induce the apoptosis of ER+ breast cancer cells. Additionally, these new AIs (10 µM) also re-sensitize resistant cells by promoting apoptosis, offering a therapeutic benefit.Conclusions:Overall, new steroidal polypharmacological compounds have been discovered that, by acting as AIs, ER modulators and AR agonists, impair ER+ breast cancer cell growth. Overall, this study is a breakthrough on drug discovery as it presents new molecules with appealing anti-cancer properties and multi-target action for the treatment of ER+ breast cancer.
背景/目的：内分泌疗法，包括抗雌激素药物和芳香化酶抑制剂（AIs），是雌激素受体阳性（ER+）（Luminal A型）乳腺癌——这一最常见亚型的标准治疗方法。然而，耐药性的出现限制了其疗效，导致肿瘤复发和再生长，这要求转向其他治疗方法以最小化或克服耐药性。实际上，这一临床局限性凸显了寻找新分子以改善癌症治疗的必要性。近年来，针对多靶点的策略不断涌现，多靶点药物有望成为未来的抗癌分子。我们团队一直在寻找新的多靶点化合物，作为其中的一部分，本研究旨在了解三种新型甾体类芳香化酶抑制剂（AIs）的抗癌及多靶点潜力：7α-甲基雄甾-4-烯-17-酮（6）、7α-甲基雄甾-4-烯-3,17-二酮（10a）和雄甾-4,9(11)-二烯-3,17-二酮（13）。 方法：在敏感的ER+芳香化酶过表达乳腺癌细胞系MCF-7aro细胞以及AI耐药的ER+乳腺癌细胞系LTEDaro细胞中，阐明了这些化合物的体外作用及其分子机制。 结果：所有新型AIs（10 µM）均通过阻滞细胞周期进程抑制了MCF-7aro细胞的增殖。有趣的是，所有AIs（10 µM）均作为雄激素受体（AR）激动剂发挥作用，并通过调节ER水平、合成及信号传导诱导ER+乳腺癌细胞凋亡。此外，这些新型AIs（10 µM）还能通过促进凋亡使耐药细胞重新敏感化，提供了治疗益处。 结论：总体而言，本研究发现了新型甾体多药理化合物，它们通过作为AIs、ER调节剂和AR激动剂，损害ER+乳腺癌细胞的生长。总之，这项研究在药物发现领域取得了突破，因为它提出了具有吸引力的抗癌特性和多靶点作用的新型分子，可用于治疗ER+乳腺癌。
肿瘤(癌症)患者之家