Novel carbazole sulfonamide microtubule destabilizing agents exert potent antitumor activity against esophageal squamous cell carcinoma
Novel carbazole sulfonamide microtubule destabilizing agents exert potent antitumor activity against esophageal squamous cell carcinoma
复制标题
新型咔唑磺酰胺微管不稳定剂对食管鳞状细胞癌发挥有效的抗肿瘤活性。
DOI：
10.1016/j.canlet.2018.01.066
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Zhao X
中科院分区：
文献类型：
--
作者：
Niu F;Liu Y;Jing Z;Han G;Sun L;Yan L;Zhou L;Wu Y;Xu Y;Hu L;Zhao X
食管鳞状细胞癌（ESCC）是世界上最常见的癌症之一，由于其耐药性和预后差。目前，缺乏有效的小分子药物用于治疗ESCC。微管是癌症治疗的一个有吸引力的靶点，因为它们在各种基本细胞功能中发挥核心作用。我们首次在体外体内研究了两种咔唑磺酰胺衍生物小分子微管蛋白配体SL-3-19和SL-1-73的抗ESCC活性及其机制。这些药物之前从具有超过450种化合物的小分子文库中筛选，并针对高水溶性进行了优化[1，2]。在这里，我们揭示了这些化合物对食管癌的有前途的活动。SL-3-19和SL-1-73均通过诱导细胞凋亡和使细胞周期阻滞于G2/M期来抑制ESCC细胞生长，且呈剂量依赖性。这些药物能有效抑制微管的组装，通过下调乙酰化的α-tubulin而显著破坏微管的成熟，并通过阻断毛细血管样管的形成而显著破坏血管结构。SL-3-19和SL-1-73在体内对食管鳞癌移植瘤生长和微血管密度的抑制作用与其体外活性一致。综上所述，SL-3-19和SL-1-73是一种新型的微管去稳定剂，在体外和体内均具有潜在的抗食管鳞癌作用，其中SL-3-19的活性高于SL-1-73，但其IC 50值较低，体内抗肿瘤活性明显，提示SL-3-19可能是一种新的治疗食管鳞癌的候选药物。
Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide due to its chemoresistance and poor prognosis. Currently, there is a lack of effective small molecule drugs for the treatment of ESCC. Microtubules are an attractive target for cancer therapy since they play a central role in various fundamental cell functions. We investigated the anti-ESCC activity and mechanisms of the small molecule tubulin ligands, SL-3-19 and SL-1-73, which are two carbazole sulfonamide derivatives,in vitroandin vivofor the first time. These drugs were previously screened from a small molecule library with over 450 compounds and optimized for high aqueous solubility [1,2]. Here, we reveal the promising activities of these compounds against esophageal cancer. Mechanistically, both SL-3-19 and SL-1-73 inhibited ESCC cell growth by inducing cell apoptosis and arresting the cell cycle at G2/M phase in a dose-dependent manner. These drugs effectively inhibited microtubule assembly, greatly disrupted microtubule maturation by down-regulating acetylated α-tubulin, and significantly disrupted the vascular structure by obstructing the formation of capillary-like tubesin vitro. Consistent with theirin vitroactivities, SL-3-19 and SL-1-73 inhibited the growth of ESCC xenografts and inhibited the microvessel densityin vivo. In summary, SL-3-19 and SL-1-73 are novel microtubule-destabilizing agents that have a potential antitumor effect on ESCC bothin vitroandin vivo, and SL-3-19 had a higher activity than SL-1-73, with a low IC50value and an observable antitumor activityin vivo.These results indicate that SL-3-19 may be a new therapeutic candidate for ESCC treatment.