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首页> 外文期刊>Steroids: An International Journal >Benzopyran derivative CDRI-85/287 induces G2-M arrest in estrogen receptor-positive breast cancer cells via modulation of estrogen receptors α- And β-mediated signaling, in parallel to EGFR signaling and suppresses the growth of tumor xenograft
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Benzopyran derivative CDRI-85/287 induces G2-M arrest in estrogen receptor-positive breast cancer cells via modulation of estrogen receptors α- And β-mediated signaling, in parallel to EGFR signaling and suppresses the growth of tumor xenograft

机译：苯并吡喃衍生物CDRI-85 / 287通过调节雌激素受体α-和β介导的信号传导（与EGFR信号传导平行）诱导雌激素受体阳性乳腺癌细胞中的G2-M阻滞并抑制异种移植物的生长

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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.
机译：为了开发新颖和改进的选择性雌激素受体调节剂作为抗乳腺癌剂，已经合成并鉴定了苯并吡喃化合物在子宫水平上起有效的抗雌激素作用。本研究评估了2- [哌啶子基乙氧基苯基] -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描述其抑制增殖的潜力。在ER阳性乳腺癌细胞MCF-7和T47D中。该化合物降低了ERα的表达，同时增加了ERβ的表达，从而改变了两种细胞系中的ERα/ERβ比。尽管该化合物对ER的结合亲和力很低，但它在减少这些细胞中ERE-或AP-1介导的转录激活中起ERα拮抗剂和ERβ激动剂的作用。在ERα/β转染的MDA-MB231细胞中的反式激活研究表明，在细胞周期蛋白D1启动子处，化合物可拮抗ERα介导的E2反应，而通过ERβ充当雌激素激动剂。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降低。细胞周期抑制蛋白p21的表达增加，导致G2 / M期阻滞。同时，化合物还干扰EGFR的活化，引起PI-3-K / Akt途径的抑制，并随后通过内在途径诱导凋亡。在接受MCF-7异种移植的85/287处理小鼠中观察到肿瘤质量和体积的显着减少。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以及非基因组机制表现出显着的抗肿瘤活性，并将细胞停滞在MCF-7和T47D乳腺癌细胞的G2期。研究表明CDRI-85 / 287在ER阳性乳腺癌中可能具有治疗潜力。

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