Digoxin sensitizes gemcitabine-resistant pancreatic cancer cells to gemcitabine via inhibiting Nrf2 signaling pathway
Digoxin sensitizes gemcitabine-resistant pancreatic cancer cells to gemcitabine via inhibiting Nrf2 signaling pathway
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地高辛通过抑制 Nrf2 信号通路使吉西他滨耐药胰腺癌细胞对吉西他滨敏感
DOI：
10.1016/j.redox.2019.101131
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发表时间：
2019-01
期刊：
影响因子：
11.4
通讯作者：
Hu Rong
中科院分区：
文献类型：
--
作者：
Zhou Yunjiang;Zhou Yang;Yang Mengdi;Wang Keke;Liu Yisi;Zhang Mingda;Yang Yunjia;Jin Chenyu;Wang Rui;Hu Rong
化疗耐药性是胰腺导管腺癌（PDAC）治疗的主要障碍。核因子红细胞2相关因子2（nuclear factor erythroid 2-related factor 2，Nrf 2）作为一种氧化应激反应性转录因子，调控细胞保护基因的表达。nrf 2不仅在化学预防中起关键作用，而且还有助于化学抗性。在本研究中，我们发现地高辛通过抑制SW 1990/Gem和Panc-1/Gem细胞中的Nrf 2信号而显著逆转吉西他滨的耐药性。进一步的研究表明地高辛在转录水平上调控Nrf 2。在体内研究中，我们发现地高辛和吉西他滨联合治疗在SW 1990/Gem-sh对照细胞来源的异种移植物中比单独吉西他滨治疗更显著地抑制肿瘤生长。同时，SW 1990/Gem-shNrf 2细胞衍生的异种移植物对吉西他滨和联合治疗的反应相似，表明地高辛使吉西他滨耐药的人胰腺癌对吉西他滨敏感，吉西他滨是Nrf 2依赖性的。这些结果表明，地高辛可能作为一种有前途的辅助增敏剂，通过抑制Nrf 2信号转导逆转吉西他滨耐药胰腺癌对吉西他滨的化疗耐药性。
Chemoresistance is a major therapeutic obstacle in the treatment of human pancreatic ductal adenocarcinoma (PDAC). As an oxidative stress responsive transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the expression of cytoprotective genes. Nrf2 not only plays a critical role in chemoprevention, but also contributes to chemoresistance. In this study, we found that digoxin markedly reversed drug resistance of gemcitabine by inhibiting Nrf2 signaling in SW1990/Gem and Panc-1/Gem cells. Further research revealed that digoxin regulated Nrf2 at transcriptional level. In in vivo study, we found that digoxin and gemcitabine in combination inhibited tumor growth more substantially when compared with gemcitabine treatment alone in SW1990/Gem-shControl cells-derived xenografts. In the meantime, SW1990/Gem-shNrf2 cells-derived xenografts responded to gemcitabine and combination treatment similarly, suggesting that digoxin sensitized gemcitabine-resistant human pancreatic cancer to gemcitabine, which was Nrf2 dependent. These results demonstrated that digoxin might be used as a promising adjuvant sensitizer to reverse chemoresistance of gemcitabine-resistant pancreatic cancer to gemcitabine via inhibiting Nrf2 signaling.
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影响因子：
7.4
作者：
Moon, Eui Jung;Giaccia, Amato
通讯作者：
Giaccia, Amato
影响因子：
--
作者：
Hu, Xiu-Feng;Yao, Jun;Feng, Xiao-Shan
通讯作者：
Feng, Xiao-Shan
DOI：
10.1891/9780826121646.0002
发表时间：
2018-09
期刊：
Cancer Rehabilitation
影响因子：
--
作者：
K. Miller;R. Siegel;R. Khan;A. Jemal
通讯作者：
K. Miller;R. Siegel;R. Khan;A. Jemal
低氧诱导因子1通过诱导碳酸酐酶IX表达来促进肺癌的化学耐药性。
影响因子：
4
作者：
Sowa T;Menju T;Chen-Yoshikawa TF;Takahashi K;Nishikawa S;Nakanishi T;Shikuma K;Motoyama H;Hijiya K;Aoyama A;Sato T;Sonobe M;Harada H;Date H
通讯作者：
Date H
影响因子：
2.5
作者：
No JH;Kim YB;Song YS
通讯作者：
Song YS