Identification of selective inhibitors for diffuse-type gastric cancer cells by screening of annotated compounds in preclinical models.
Identification of selective inhibitors for diffuse-type gastric cancer cells by screening of annotated compounds in preclinical models.
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DOI：
10.1038/s41416-018-0008-y
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发表时间：
2018-04
影响因子：
8.8
通讯作者：
Tanaka S
中科院分区：
文献类型：
--
作者：
Shimada S;Akiyama Y;Mogushi K;Ishigami-Yuasa M;Kagechika H;Nagasaki H;Fukamachi H;Yuasa Y;Tanaka S
弥漫型胃癌（DGC）表现出快速的疾病进展和不良的患者预后。我们以前建立了一个E-cadherin/p53双条件性敲除（DCKO）小鼠系作为第一个基因工程，其形态和分子重演人类DGC。在这项研究中，我们探索了选择性消除小鼠和人类DGC细胞的低分子量药物。我们从DCKO小鼠的DGC中获得小鼠胃癌（GC）细胞系，证明免疫缺陷小鼠的致瘤活性增强，并获得对细胞毒性抗癌剂的耐受性。我们对1535种注释的化合物进行了合成致死筛选，并确定了27种选择性杀死GC细胞系的候选化合物。最有效的药物美雌醇，一种雌激素衍生物，和其他雌激素受体调节剂，通过诱导DNA损伤前的细胞凋亡，特异性地减弱GC细胞系的细胞活力。此外，mestranol可以显着抑制肿瘤生长的GC细胞皮下移植到裸鼠，与更长的生存时间在雌性DCKO小鼠比雄性一致。在体外和体内实验中，E-cadherin突变和E-cadherin低表达的胃癌细胞对雌激素药物的敏感性明显高于E-cadherin完整的胃癌细胞。这些发现可能导致针对DGC的新治疗策略的发展。
Diffuse-type gastric cancer (DGC) exhibits rapid disease progression and poor patient prognosis. We have previously established an E-cadherin/p53 double conditional knockout (DCKO) mouse line as the first genetically engineered one, which morphologically and molecularly recapitulates human DGC. In this study, we explored low-molecular-weight drugs selectively eliminating mouse and human DGC cells. We derived mouse gastric cancer (GC) cell lines from DGC of the DCKO mice demonstrating enhanced tumourigenic activity in immunodeficient mice and acquired tolerance to cytotoxic anti-cancer agents. We performed a synthetic lethal screening of 1535 annotated chemical compounds, and identified 27 candidates selectively killing the GC cell lines. The most potent drug mestranol, an oestrogen derivative, and other oestrogen receptor modulators specifically attenuated cell viability of the GC cell lines by inducing apoptosis preceded by DNA damage. Moreover, mestranol could significantly suppress tumour growth of the GC cells subcutaneously transplanted into nude mice, consistent with longer survival time in the female DCKO mice than in the male. Expectedly, human E-cadherin-mutant and -low gastric cancer cells showed higher susceptibility to oestrogen drugs in contrast to E-cadherin-intact ones in vitro and in vivo. These findings may lead to the development of novel therapeutic strategies targeting DGC.
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影响因子：
29.4
作者：
Huh WJ;Khurana SS;Geahlen JH;Kohli K;Waller RA;Mills JC
通讯作者：
Mills JC
DOI：
10.1158/1940-6207.capr-11-0185
发表时间：
2011-05
期刊：
Cancer prevention research (Philadelphia, Pa.)
影响因子：
--
作者：
Jordan VC;Ford LG
通讯作者：
Ford LG
影响因子：
2.1
作者：
Yang, Dongyun;Hendifar, Andrew;Lenz, Heinz-Josef
通讯作者：
Lenz, Heinz-Josef
影响因子：
64.8
作者：
Garnett, Mathew J.;Edelman, Elena J.;Heidorn, Sonja J.;Greenman, Chris D.;Dastur, Anahita;Lau, King Wai;Greninger, Patricia;Thompson, I. Richard;Luo, Xi;Soares, Jorge;Liu, Qingsong;Iorio, Francesco;Surdez, Didier;Chen, Li;Milano, Randy J.;Bignell, Graham R.;Tam, Ah T.;Davies, Helen;Stevenson, Jesse A.;Barthorpe, Syd;Lutz, Stephen R.;Kogera, Fiona;Lawrence, Karl;McLaren-Douglas, Anne;Mitropoulos, Xeni;Mironenko, Tatiana;Thi, Helen;Richardson, Laura;Zhou, Wenjun;Jewitt, Frances;Zhang, Tinghu;O'Brien, Patrick;Boisvert, Jessica L.;Price, Stacey;Hur, Wooyoung;Yang, Wanjuan;Deng, Xianming;Butler, Adam;Choi, Hwan Geun;Chang, JaeWon;Baselga, Jose;Stamenkovic, Ivan;Engelman, Jeffrey A.;Sharma, Sreenath V.;Delattre, Olivier;Saez-Rodriguez, Julio;Gray, Nathanael S.;Settleman, Jeffrey;Futreal, P. Andrew;Haber, Daniel A.;Stratton, Michael R.;Ramaswamy, Sridhar;McDermott, Ultan;Benes, Cyril H.
通讯作者：
Benes, Cyril H.
影响因子：
64.5
作者：
Gupta PB;Onder TT;Jiang G;Tao K;Kuperwasser C;Weinberg RA;Lander ES
通讯作者：
Lander ES