In Vitro Antitumor Mechanism of (E)-N-(2-methoxy-5-(((2,4,6-trimethoxystyryl)sulfonyl)methyl)pyridin-3-yl)methanesulfonamide
In Vitro Antitumor Mechanism of (E)-N-(2-methoxy-5-(((2,4,6-trimethoxystyryl)sulfonyl)methyl)pyridin-3-yl)methanesulfonamide
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DOI：
10.1124/mol.114.093245
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发表时间：
2015-01-01
影响因子：
3.6
通讯作者：
Bradshaw, Tracey D.
中科院分区：
文献类型：
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作者：
Lu, Tiangong;Laughton, Charles A.;Bradshaw, Tracey D.
ON01910。Na [（E）-2-（2-甲氧基-5-（（2，4，6-三甲氧基苯乙烯磺酰基）甲基）苯基氨基）乙酸钠; Rigosertib，Estybon]，一种苯乙烯基苄基砜，是一种III期抗癌药物。这种非ATP竞争性激酶抑制剂具有多靶点活性，促进有丝分裂阻滞和凋亡。ON 01910的广泛I/II期研究。Na，在实体瘤和血液系统癌症患者中进行，表现出优异的疗效。然而，问题仍然影响其发展。这些包括对抗肿瘤机制的不完全理解，口服生物利用度低和不可预测的药代动力学。我们已经鉴定了一种新的（E）-苯乙烯基磺酰基甲基吡啶[（E）-N-（2-甲氧基-5-（（2，4，6-三甲氧基苯乙烯基磺酰基）甲基）吡啶-3-基）甲磺酰胺（TL-77）]，其与ON 01910相比显示出改善的口服生物利用度。Na.在这里，我们提出了详细的细胞机制TL-77相比，ON 01910。Na. TL-77在体外显示出有效的生长抑制活性（对HCT-116细胞的GI（50）< 1 μ M），与正常细胞相比，对肿瘤细胞系的效力高3至10倍。细胞周期分析显示，TL-77导致癌细胞明显的G2/M停滞，随后开始细胞凋亡。在无细胞条件下，TL-77有效抑制微管蛋白聚合。有丝分裂停滞的细胞显示多极纺锤体和染色体错位，表明TL-77干扰癌细胞中的有丝分裂纺锤体组装。这些作用伴随着DNA损伤的诱导、Cdc 25 C磷酸化的抑制[指示Plk 1抑制]和细胞周期蛋白B1的下游抑制。然而，激酶测定未能证实Plk 1的抑制。TL-77处理后，观察到对磷酸肌醇3-激酶/Akt信号转导的无显著影响。细胞凋亡信号通路的分析表明，TL-77下调B细胞淋巴瘤2家族蛋白（Bid，Bcl-xl和Mcl-1）的表达，并刺激caspase激活。综上所述，TL-77代表了一种值得进一步评价的有前途的抗癌剂。
ON01910. Na [sodium(E)-2-(2-methoxy-5-((2,4,6-trimethoxystyrylsulfonyl)methyl)phenylamino)acetate; Rigosertib, Estybon], a styryl benzylsulfone, is a phase III stage anticancer agent. This non-ATP competitive kinase inhibitor has multitargeted activity, promoting mitotic arrest and apoptosis. Extensive phase I/II studies with ON01910. Na, conducted in patients with solid tumors and hematologic cancers, demonstrate excellent efficacy. However, issues remain affecting its development. These include incomplete understanding of antitumor mechanisms, low oral bioavailability, and unpredictable pharmacokinetics. We have identified a novel (E)-styrylsulfonyl methylpyridine [(E)-N-(2-methoxy-5-((2,4,6-trimethoxystyrylsulfonyl)methyl)pyridin-3-yl)methanesulfonamide(TL-77)] which has shown improved oral bioavailability compared with ON01910. Na. Here, we present detailed cellular mechanisms of TL-77 in comparison with ON01910. Na. TL-77 displays potent growth inhibitory activity in vitro (GI(50) < 1 mu M against HCT-116 cells), demonstrating 3-to 10-fold greater potency against tumor cell lines when compared with normal cells. Cell-cycle analyses reveal that TL-77 causes significant G2/M arrest in cancer cells, followed by the onset of apoptosis. In cell-free conditions, TL-77 potently inhibits tubulin polymerization. Mitotically arrested cells display multipolar spindles and misalignment of chromosomes, indicating that TL-77 interferes with mitotic spindle assembly in cancer cells. These effects are accompanied by induction of DNA damage, inhibition of Cdc25C phosphorylation [indicative of Plk1 inhibition], and downstream inhibition of cyclin B1. However, kinase assays failed to confirm inhibition of Plk1. Nonsignificant effects on phosphoinositide 3-kinase/Akt signal transduction were observed after TL-77 treatment. Analysis of apoptotic signaling pathways reveals that TL-77 downregulates expression of B-cell lymphoma 2 family proteins (Bid, Bcl-xl, and Mcl-1) and stimulates caspase activation. Taken together, TL-77 represents a promising anticancer agent worthy of further evaluation.