YM155 and chrysin cooperatively suppress survivin expression in SMARCB1/INI1-deficient tumor cells
YM155 and chrysin cooperatively suppress survivin expression in SMARCB1/INI1-deficient tumor cells
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DOI：
10.1007/s12032-022-01843-4
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发表时间：
2022-09-29
期刊：
影响因子：
3.4
通讯作者：
Yanagimachi, Masakatsu
中科院分区：
文献类型：
--
作者：
Yoshino, Yuki;Goto, Hiroaki;Yanagimachi, Masakatsu
SMARCB 1/INI 1缺陷见于几种恶性肿瘤，包括恶性横纹肌样瘤（MRT），一种高度侵袭性的儿科恶性肿瘤。SMARCB 1/INI 1功能的丧失改变了多种致癌细胞信号，使得难以发现有效的靶向治疗。通过利用体外药物筛选系统，有效的治疗药物对SMARCB 1/INI 1缺陷的肿瘤在这项研究中探索。在体外药物敏感性试验中，在一组5个SMARCB 1/INI 1缺陷肿瘤细胞系中筛选了80种具有各种作用的药物的细胞毒性。基于布利斯独立模型筛选组合效应。在常规二维培养和胶原包埋三维培养系统中测定生长抑制作用。通过蛋白质印迹分析测定试剂暴露后Survivin的表达。发现所有五种细胞系对选择性存活素抑制剂YM 155敏感。在药物组合筛选中，YM 155显示出与包括白杨素在内的各种药剂的相加至协同效应。在SMARCB 1/INI 1缺陷肿瘤细胞暴露于两种药物6小时后，Escherin增强了YM 155诱导的凋亡，但不增强线粒体去极化。YM 155和白杨素协同抑制生存素的表达，特别是在TTN 45细胞中，这种抑制早在暴露于两种药剂后6小时就观察到。Survivin被认为是MRT和其他SMARCB 1/INI 1缺陷肿瘤的治疗靶点。在植物中广泛分布的黄酮类化合物-黄嘌呤协同抑制survivin的表达，增强YM 155的细胞毒性。
SMARCB1/INI1 deficiency is seen in several malignant tumors including malignant rhabdoid tumor (MRT), a highly aggressive pediatric malignancy. Loss of SMARCB1/INI1 function alters diverse oncogenic cellular signals, making it difficult to discover effective targeting therapy. By utilizing an in vitro drug screening system, effective therapeutic agents against SMARCB1/INI1-deficient tumors were explored in this study. In the in vitro drug sensitivity test, 80 agents with various actions were screened for their cytotoxicity in a panel of five SMARCB1/INI1-deficient tumor cell lines. The combination effect was screened based on the Bliss independent model. The growth-inhibitory effect was determined in both the conventional two-dimensional culture and the collagen-embedded three-dimensional culture system. Survivin expression after agent exposure was determined by Western blot analysis. All five cell lines were found to be sensitive to YM155, a selective survivin inhibitor. In the drug combination screening, YM155 showed additive to synergistic effects with various agents including chrysin. Chrysin enhanced YM155-induced apoptosis, but not mitochondrial depolarization upon exposure of SMARCB1/INI1-deficient tumor cells to the two agents for 6 h. YM155 and chrysin synergistically suppressed survivin expression, especially in TTN45 cells in which such suppression was observed as early as 6 h after exposure to the two agents. Survivin is suggested to be a therapeutic target in MRT and other SMARCB1/INI1-deficient tumors. Chrysin, a flavone that is widely distributed in plants, cooperatively suppressed survivin expression and enhanced the cytotoxicity of YM155.