Discovery of a potent hedgehog pathway inhibitor capable of activating caspase8-dependent apoptosis
Discovery of a potent hedgehog pathway inhibitor capable of activating caspase8-dependent apoptosis
复制标题
发现能够激活 caspase8 依赖性细胞凋亡的强效刺猬蛋白通路抑制剂
DOI：
10.1016/j.jphs.2018.07.001
复制
发表时间：
2018-07-01
影响因子：
3.5
通讯作者：
He, Sudan
中科院分区：
文献类型：
--
作者：
Chen, Qin;Zhang, Haoran;He, Sudan
Hedgehog (Hh) 信号传导的异常激活与多种人类癌症的发生有关。 Vismodegib 是第一个被批准用于抗癌治疗的 Hh 抑制剂，其靶向为 Hh 通路的关键调节因子 Smoothened (SMO)。然而，随着时间的推移，会对 vismodegib 产生耐药性。细胞凋亡是一种常见的程序性细胞死亡形式，由半胱天冬酶执行。诱导肿瘤细胞凋亡代表了一种有吸引力的消除肿瘤细胞的治疗策略。为了探索具有细胞凋亡诱导活性的新型 Hh 拮抗剂，我们筛选了一组类似于 300 种具有新型支架结构的潜在 SMO 拮抗剂。 Hh003 被发现可诱导 caspase 依赖性细胞凋亡，而 vismodegib 不会激活人结肠癌细胞和胰腺癌细胞的细胞凋亡反应。与 vismodegib 相比，Hh003 对 Hh 通路具有相似的抑制作用。 Hh003可以诱导caspase8激活，caspase8的沉默显着抑制Hh003诱导的细胞凋亡。值得注意的是，Hh003对体外肿瘤集落的形成和体内结直肠肿瘤生长的抑制作用比vismodegib更强。这些发现表明，与 vismodegib 相比，Hh003 通过激活 caspase8 依赖性细胞凋亡来发挥增强的抗肿瘤作用。 Hh003 的 Hh 抑制和细胞凋亡诱导的综合特性为开发新型抗癌疗法提供了巨大的潜力。 (c) 2018 年作者。由 Elsevier B.V. 代表日本药理学会制作和主办。
Aberrant activation of Hedgehog (Hh) signaling is associated with the development of numerous human cancers. Vismodegib is the first Hh inhibitor approved for anti-cancer therapy by targeting Smoothened (SMO), a critical regulator of the Hh pathway. However, acquisition of drug resistance to vismodegib occurs overtime. Apoptosis is a prevalent form of programmed cell death that is executed by caspases. Induction of tumor cell apoptosis represents an attractive therapeutic strategy to eliminate tumor cells. To explore new Hh antagonists with apoptosis-inducing activity, we screened a set of similar to 300 potential SMO antagonists with novel scaffold structures. Hh003 was found to induce caspase-dependent apoptosis while vismodegib did not activate apoptotic response in human colon and pancreatic cancer cells. Compared to vismodegib, Hh003 exerted similar inhibitory effects on the Hh pathway. Hh003 could induce caspase8 activation and the silence of caspase8 significantly inhibited Hh003-induced apoptosis. Remarkably, Hh003 showed stronger inhibitory effects on the formation of tumor colonies in vitro and colorectal tumor growth in vivo than vismodegib. These findings suggest that Hh003 exerts enhanced anti-tumor effects by activating caspase8-dependent apoptosis compared to vismodegib. The combined property of Hh inhibition and apoptosis induction of Hh003 presents great potential for the development of novel anti-cancer therapy. (c) 2018 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society.