亲爱的研友该休息了!由于当前在线用户较少,发布求助请尽量完整的填写文献信息,科研通机器人24小时在线,伴您度过漫漫科研夜!身体可是革命的本钱,早点休息,好梦!

Augmented antitumor activity by olaparib plus AZD1775 in gastric cancer through disrupting DNA damage repair pathways and DNA damage checkpoint

奥拉帕尼 PARP抑制剂 DNA损伤 第1周 癌症研究 DNA修复 聚ADP核糖聚合酶 生物 支票1 癌症 合成致死 细胞周期检查点 PARP1 分子生物学 细胞周期 细胞周期蛋白依赖激酶1 聚合酶 DNA 遗传学
作者
Xun Lin,Dongshao Chen,Cheng Zhang,Xiaotian Zhang,Zhongwu Li,Bin Dong,Jing Gao,Lin Shen
出处
期刊:Journal of Experimental & Clinical Cancer Research [Springer Nature]
卷期号:37 (1) 被引量:39
标识
DOI:10.1186/s13046-018-0790-7
摘要

Targeting poly ADP-ribose polymerase (PARP) has been recently identified as a promising option against gastric cancer (GC). However, PARP inhibitors alone achieve limited efficacy. Combination strategies, especially with homologous recombination (HR) impairment, are of great hope to optimize PARP inhibitor's efficacy and expand target populations but remains largely unknown. Herein, we investigated whether a WEE1/ Polo-like kinase 1 (PLK1) dual inhibitor AZD1775 reported to impair HR augmented anticancer activity of a PARP inhibitor olaparib and its underlying mechanisms.GC cell lines and in vivo xenografts were employed to determine antitumor activity of PARP inhibitor combined with WEE1/PLK1 dual inhibitor AZD1775. Western blot, genetic knockdown by siRNA, flow cytometry, Immunohistochemistry were performed to explore the underlying mechanisms.AZD1775 dually targeting WEE1/PLK1 enhanced effects of olaparib on growth inhibition and apoptotic induction in GC cells. Mechanistic investigations elucidate that WEE1/PLK1 blockade downregulated several HR-related proteins and caused an accumulation in γH2AX. As confirmed in both GC cell lines and mice bearing GC xenografts, these effects were enhanced by AZD1775-olaparib combination compared to olaparib alone, suggesting that disrupting HR-mediated DNA damage repairs (DDR) by WEE1/PLK1 blockade might be responsible for improved GC cells' response to PARP inhibitors. Given the DNA damage checkpoint as a primary target of WEE1 inhibition, our data also demonstrate that AZD1775 abrogated olaparib-activated DNA damage checkpoint through CDC2 de-phosphorylation, followed by mitotic progression with unrepaired DNA damage (marked by increased pHH3-stained and γH2AX-stained cells, respectively).PARP inhibitor olaparib combined with WEE1/PLK1 dual inhibitor AZD1775 elicited potentiated anticancer activity through disrupting DDR signaling and the DNA damage checkpoint. It sheds light on the combination strategy of WEE1/PLK1 dual inhibitors with PARP inhibitors in the treatment of GC, even in HR-proficient patients.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
刘小花完成签到 ,获得积分10
1秒前
1437594843完成签到 ,获得积分10
36秒前
明理丹烟应助科研通管家采纳,获得20
37秒前
科研通AI2S应助科研通管家采纳,获得10
37秒前
明理丹烟应助科研通管家采纳,获得20
37秒前
哭泣的丝完成签到 ,获得积分10
1分钟前
隐形问萍完成签到,获得积分10
1分钟前
隐形问萍发布了新的文献求助10
1分钟前
信勇完成签到 ,获得积分10
1分钟前
科研通AI2S应助科研通管家采纳,获得10
2分钟前
明理丹烟应助科研通管家采纳,获得10
2分钟前
2分钟前
Jing发布了新的文献求助10
2分钟前
3分钟前
Raunio完成签到,获得积分10
3分钟前
李健的小迷弟应助小白菜采纳,获得30
4分钟前
4分钟前
4分钟前
小白菜完成签到,获得积分10
4分钟前
小白菜发布了新的文献求助30
4分钟前
赎罪完成签到 ,获得积分10
4分钟前
Puan发布了新的文献求助10
4分钟前
科研通AI2S应助科研通管家采纳,获得10
4分钟前
4分钟前
ma发布了新的文献求助10
5分钟前
科研通AI2S应助科研通管家采纳,获得10
6分钟前
汉堡包应助科研通管家采纳,获得10
6分钟前
Alicia完成签到 ,获得积分10
6分钟前
郑夏岚完成签到,获得积分20
7分钟前
314gjj完成签到,获得积分10
7分钟前
daishuheng完成签到 ,获得积分10
7分钟前
uss完成签到,获得积分10
7分钟前
徐芳菲完成签到 ,获得积分10
8分钟前
华仔应助科研通管家采纳,获得10
8分钟前
逝水完成签到 ,获得积分10
9分钟前
MET1应助ma采纳,获得10
10分钟前
spark810完成签到 ,获得积分0
10分钟前
明理丹烟应助科研通管家采纳,获得10
10分钟前
千早爱音完成签到,获得积分10
11分钟前
asdf完成签到,获得积分10
11分钟前
高分求助中
中国国际图书贸易总公司40周年纪念文集 大事记1949-1987 2000
TM 5-855-1(Fundamentals of protective design for conventional weapons) 1000
草地生态学 880
Threaded Harmony: A Sustainable Approach to Fashion 799
Basic Modern Theory of Linear Complex Analytic 𝑞-Difference Equations 510
中国有机(类)肥料 500
Queer Politics in Times of New Authoritarianisms: Popular Culture in South Asia 500
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3059522
求助须知:如何正确求助?哪些是违规求助? 2715495
关于积分的说明 7445289
捐赠科研通 2361022
什么是DOI,文献DOI怎么找? 1251174
科研通“疑难数据库(出版商)”最低求助积分说明 607698
版权声明 596448