Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226031, U.P., India.
Steroids. 2013 Nov;78(11):1071-86. doi: 10.1016/j.steroids.2013.07.004. Epub 2013 Jul 26.
In an endeavor to develop novel and improved selective estrogen receptor modulators as anti-breast cancer agents, the benzopyran compounds have been synthesized and identified which act as potent anti-estrogen at uterine level. The present study evaluates the anti-tumor activity of 2-[piperidinoethoxyphenyl]-3-phenyl-2H-benzo(b)pyran (CDRI-85/287) and explores the mechanism of action with a view to describe its potential to inhibit proliferation in ER-positive breast cancer cells MCF-7 and T47D. The compound decreased the expression of ERα while increased the expression of ERβ thereby altering ERα/ERβ ratio in both cell lines. Although the compound showed low binding affinity to ERs, it acted as ERα antagonist and ERβ agonist in decreasing ERE- or AP-1-mediated transcriptional activation in these cells. Transactivation studies in ERα/β-transfected MDA-MB231 cells suggested that at cyclin D1 promoter, compound antagonized the action of ERα-mediated E2 response while acted as estrogen agonist via ERβ. Further, the compound led to decreased expression of ERα-dependent proliferation markers and ERβ-dependent cell cycle progression markers. The expression of cell cycle inhibitory protein p21 was increased leading to G2/M phase arrest. In parallel, compound also interfered with EGFR activation, caused inhibition of PI-3-K/Akt pathway and subsequent induction of apoptosis via intrinsic pathway. A significant reduction in tumor mass and volume was observed in 85/287-treated mice bearing MCF-7 xenograft. We conclude that compound 85/287 exhibits significant anti-tumor activity via modulation of genomic as well as non-genomic mechanisms involved in cellular growth and arrested the cells in G2 phase in both MCF-7 and T47D breast cancer cells. Study suggests that CDRI-85/287 may have therapeutic potential in ER-positive breast cancer.
为了开发新型和改良的选择性雌激素受体调节剂作为抗乳腺癌药物，已经合成并鉴定了苯并吡喃化合物，它们在子宫水平上表现出很强的抗雌激素作用。本研究评估了 2-[哌啶乙氧基]苯基-3-苯基-2H-苯并（b）吡喃（CDRI-85/287）的抗肿瘤活性，并探讨了其作用机制，以期描述其抑制 ER 阳性乳腺癌细胞 MCF-7 和 T47D 增殖的潜力。该化合物降低了 ERα 的表达，同时增加了 ERβ 的表达，从而改变了这两种细胞系中 ERα/ERβ 的比例。尽管该化合物对 ERs 的结合亲和力较低，但它在降低这些细胞中 ERE 或 AP-1 介导的转录激活方面表现为 ERα 拮抗剂和 ERβ 激动剂。在 ERα/β 转染的 MDA-MB231 细胞中转录激活研究表明，在 cyclin D1 启动子上，化合物拮抗 ERα 介导的 E2 反应，而通过 ERβ 发挥雌激素激动剂的作用。此外，该化合物导致 ERα 依赖性增殖标志物和 ERβ 依赖性细胞周期进展标志物的表达减少。细胞周期抑制蛋白 p21 的表达增加，导致 G2/M 期停滞。同时，该化合物还干扰了 EGFR 的激活，抑制了 PI-3-K/Akt 途径，随后通过内在途径诱导细胞凋亡。在 MCF-7 异种移植瘤荷瘤小鼠中，85/287 治疗组肿瘤质量和体积显著减少。我们得出结论，化合物 85/287 通过调节参与细胞生长的基因组和非基因组机制显示出显著的抗肿瘤活性，并使 MCF-7 和 T47D 乳腺癌细胞停滞在 G2 期。研究表明，CDRI-85/287 可能在 ER 阳性乳腺癌中有治疗潜力。
