Survivin inhibitor YM155 suppresses gastric cancer xenograft growth in mice without affecting normal tissues.
Survivin inhibitor YM155 suppresses gastric cancer xenograft growth in mice without affecting normal tissues.
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生存素抑制剂 YM155 可抑制小鼠胃癌异种移植物的生长，而不影响正常组织。
DOI：
10.18632/oncotarget.6898
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发表时间：
2016-02-09
期刊：
影响因子：
--
通讯作者：
Tu SP
中科院分区：
文献类型：
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作者：
Cheng XJ;Lin JC;Ding YF;Zhu L;Ye J;Tu SP
Survivin过表达与人胃癌预后不良有关，是胃癌治疗的靶点。YM155最初被鉴定为Survivin的特异性抑制剂。在本研究中，我们研究了YM155对人胃癌的抑制作用。结果表明，YM155以剂量依赖的方式抑制细胞增殖，减少集落形成，诱导胃癌细胞凋亡。相应地，YM155在不影响XIAP表达的情况下显著降低Survivin的表达，增加凋亡相关蛋白Caspase3、7、8、9的裂解。YM155显著抑制胃癌细胞球体的形成，抑制形成的球体(肿瘤干细胞样细胞)的扩张和生长，并下调胃癌细胞中β-Catenin、c-Myc、Cyclin D1和CD44的蛋白水平。YM155 5 mg/kg/d连续7d给药对裸鼠移植瘤生长有明显的抑制作用。免疫组织化学染色和Western Blot结果显示，YM155治疗可抑制裸鼠移植瘤组织中Survivin和CD44的表达，诱导肿瘤细胞凋亡，减少CD44+CSCs的表达。YM155组小鼠的心、肝、肺、肾等脏器未见明显的病理改变。我们的结果表明，YM155抑制细胞增殖，诱导细胞凋亡，减少肿瘤干细胞的扩张，并抑制胃癌细胞的异种移植瘤生长。我们的结果阐明了YM155通过抑制CSCs抑制胃癌生长的新机制。YM155可能是一种很有前途的胃癌治疗药物。
Survivin overexpression is associated with poor prognosis of human gastric cancer, and is a target for gastric cancer therapy. YM155 is originally identified as a specific inhibitor of survivin. In this study, we investigated the antitumor effect of YM155 on human gastric cancer. Our results showed that YM155 treatment significantly inhibited cell proliferation, reduced colony formation and induced apoptosis of gastric cancer cells in a dose-dependent manner. Accordingly, YM155 treatment significantly decreased survivin expression without affecting XIAP expression and increased the cleavage of apoptosis-associated proteins caspase 3, 7, 8, 9. YM155 significantly inhibited sphere formation of gastric cancer cells, suppressed expansion and growth of the formed spheres (cancer stem cell-like cells, CSCs) and downregulated the protein levels of β-catenin, c-Myc, Cyclin D1 and CD44 in gastric cancer cells. YM155 infusion at 5 mg/kg/day for 7 days markedly inhibited growth of gastric cancer xenograft in a nude mouse model. Immunohistochemistry staining and Western Blot showed that YM155 treatment inhibited expression of survivin and CD44, induced apoptosis and reduced CD44+ CSCs in xenograft tumor tissues in vivo. No obvious pathological changes were observed in organs (e.g. heart, liver, lung and kidney) in YM155-treated mice. Our results demonstrated that YM155 inhibits cell proliferation, induces cell apoptosis, reduces cancer stem cell expansion, and inhibits xenograft tumor growth in gastric cancer cells. Our results elucidate a new mechanism by which YM155 inhibits gastric cancer growth by inhibition of CSCs. YM155 may be a promising agent for gastric cancer treatment.