CAT3，一种新型的神经母细胞瘤和胶质母细胞瘤治疗药物，通过阻断 Hedgehog 信号通路抑制肿瘤生长。

CAT3, a novel agent for medulloblastoma and glioblastoma treatment, inhibits tumor growth by disrupting the Hedgehog signaling pathway.

机构信息

State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.

Shenyang Pharmaceutical University, Shenyang 110015, China.

出版信息

Cancer Lett. 2016 Oct 28;381(2):391-403. doi: 10.1016/j.canlet.2016.07.030. Epub 2016 Aug 2.

DOI:10.1016/j.canlet.2016.07.030

PMID:27495899

Abstract

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.

摘要

髓母细胞瘤（MB）和胶质母细胞瘤（GBM）是最常见的恶性脑肿瘤。对于 MB 和 GBM 患者来说，迫切需要寻找新的治疗策略。在此，我们发现 13a-(S)-3-羟基-6,7-二甲氧基菲并[9,10-b]-吲唑啶（PF403）强烈抑制 Hedgehog（Hh）通路过度激活的 MB 和 GBM 细胞，其 50%抑制浓度（IC50）为 0.01 nM。CAT3 被设计并合成作为 PF403 的前药，对 MB 和 GBM 具有显著的体内疗效。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 与抑制蛋白 Ptch1 的相互作用来抑制 Smo 受体在细胞表面的积累。此外，PF403 通过促进 Sufu-Gli1 和 PKA-Gli1 相互作用，显著抑制 Gli1 的核积累和转录。综上所述，我们的研究支持 CAT3 是一种有前途的治疗 Hh 驱动的 MB 和 GBM 的治疗剂的假说。