CAT3, a novel agent for medulloblastoma and glioblastoma treatment, inhibits tumor growth by disrupting the Hedgehog signaling pathway
CAT3, a novel agent for medulloblastoma and glioblastoma treatment, inhibits tumor growth by disrupting the Hedgehog signaling pathway
复制标题
CAT3 是一种治疗髓母细胞瘤和胶质母细胞瘤的新型药物，通过破坏 Hedgehog 信号通路来抑制肿瘤生长
DOI：
10.1016/j.canlet.2016.07.030
复制
发表时间：
2016-10-28
期刊：
影响因子：
9.7
通讯作者：
Chen, Xiaoguang
中科院分区：
文献类型：
--
作者：
Chen, Ju;Lv, Haining;Chen, Xiaoguang
髓母细胞瘤(MB)和胶质母细胞瘤(GBM)是最常见的恶性脑肿瘤。寻找新的治疗策略是MB和GBM患者的当务之急。在此，我们发现13a-(S)-3-Hydroxyl-6，7-dimethoxyphenanthro[9，10-b]-indolizidine(PF403)对Hedgehog(HH)途径过度激活的MB和GBM细胞具有很强的抑制活性，其半数抑制浓度(IC_(50))为0.01 nM。设计并合成了作为PF403前体药物的Cat3，并在体内显示了对MB和GBM的显著抑制作用。机制研究表明，Cat3主要通过阻断HH信号通路来抑制MB和GBM。在分子水平上，PF403通过直接结合或增强Smo与抑制子ptch1的相互作用来抑制细胞表面Smoothened(Smo)受体的聚集。此外，PF403通过促进Sufu-Gli1和PKA-Gli1的相互作用，显著抑制Gli1的核积累和转录。总而言之，我们的研究支持这样的假设，即Cat3是治疗HH驱动的MB和GBM的一种有前途的治疗剂。(C)2016爱思唯尔爱尔兰有限公司。保留所有权利。
Medulloblastoma (MB) and glioblastoma (GBM) are the most prevalent malignant brain tumors. The identification of novel therapeutic strategies is urgent for MB and GBM patients. Herein, we discovered 13a-(S)-3-Hydroxyl-6,7-dimethoxyphenanthro[9,10-b]-indolizidine (PF403) strongly exhibited inhibitory activity against Hedgehog (Hh) pathway-hyperactivated MB and GBM cells with a 50% inhibitory concentration (IC50) of 0.01 nM. CAT3 was designed and synthesized as the prodrug of PF403 and displayed significant in vivo efficacy against MB and GBM. Mechanistic study revealed that CAT3 inhibited MB and GBM primarily by interrupting the Hh signaling pathway. At the molecular level, PF403 inhibited the cell surface accumulation of the Smoothened (Smo) receptor by directly binding or enhancing the interaction of Smo with the repressor Ptch1. Furthermore, PF403 significantly repressed Gli1 nuclear accumulation and transcription by promoting Sufu-Gli1 and PKA-Gli1 interactions. Collectively, our studies support the hypothesis that CAT3 is a promising therapeutic agent for the treatment of Hh-driven MB and GBM. (C) 2016 Elsevier Ireland Ltd. All rights reserved.