Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
Cancer. 2013 Feb 15;119(4):774-81. doi: 10.1002/cncr.27742. Epub 2012 Sep 18.
Anaplastic thyroid cancer (ATC) is a very aggressive thyroid gland malignancy with very poor prognosis. It is suspected that the Notch signaling pathway, which is not active in ATC, may have a tumor suppressor function in this neoplasm. However, it remains unknown whether activation of Notch can yield therapeutic efficacies in ATC.
The purpose of this study was to evaluate the effect of chrysin, a potential Notch inducer identified via high-throughput screening, on ATC both in vitro and in vivo.
Chrysin treatment of ATC cells led to a dose-dependent inhibition of cellular growth. Protein and messenger RNA levels of Notch1 and Hes1 (hairy/enhancer of split 1), a downstream Notch1 effector, were both up-regulated with treatment. Luciferase reporter assays incorporating the C promoter-binding factor 1 (CBF1) binding site also confirmed the functional activity of chrysin-induced Notch1. Oral administration of chrysin suppressed the growth of ATC xenografts by an average of 59% compared with the vehicle control group (P = .002). In addition, calculated median time to tumor progression was 11 days for control mice and 21 days for the chrysin treatment group (P = .008). Analysis of chrysin-treated ATC tumors revealed an increase in the active intracellular domain of Notch1 protein. Activation of Notch1 in vivo was associated with the induction of cleaved Poly ADP ribose polymerase (PARP) protein, indicating that the growth inhibition was due to apoptosis.
The novel Notch1 activator chrysin inhibits tumor growth in ATC both in vitro and in vivo. Chrysin could be a promising therapeutic candidate for ATC, and this justifies further clinical studies.
间变性甲状腺癌（ATC）是一种侵袭性很强的甲状腺恶性肿瘤，预后极差。据推测，在 ATC 中不活跃的 Notch 信号通路可能在这种肿瘤中具有肿瘤抑制功能。然而，目前尚不清楚 Notch 的激活是否能在 ATC 中产生治疗效果。
本研究旨在评估金雀异黄素（一种通过高通量筛选发现的潜在 Notch 诱导剂）对 ATC 的体内外作用。
金雀异黄素处理 ATC 细胞导致细胞生长呈剂量依赖性抑制。Notch1 和 Hes1（头发/分裂增强子 1）的蛋白和信使 RNA 水平均随治疗而上调，Hes1 是 Notch1 的下游效应物。包含 C 结合因子 1（CBF1）结合位点的荧光素酶报告基因分析也证实了金雀异黄素诱导的 Notch1 的功能活性。与对照组相比，金雀异黄素的口服给药抑制 ATC 异种移植物的生长平均为 59%（P =.002）。此外，计算出对照组小鼠的肿瘤进展中位时间为 11 天，金雀异黄素治疗组为 21 天（P =.008）。对金雀异黄素处理的 ATC 肿瘤的分析显示 Notch1 蛋白的活性细胞内结构域增加。体内 Notch1 的激活与切割的多聚 ADP 核糖聚合酶（PARP）蛋白的诱导有关，表明生长抑制是由于细胞凋亡。
新型 Notch1 激活剂金雀异黄素在体外和体内均能抑制 ATC 的肿瘤生长。金雀异黄素可能是 ATC 有前途的治疗候选药物，这证明了进一步的临床研究是合理的。
