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地高辛通过抑制 Nrf2 信号通路使吉西他滨耐药的胰腺癌细胞对吉西他滨敏感。

Digoxin sensitizes gemcitabine-resistant pancreatic cancer cells to gemcitabine via inhibiting Nrf2 signaling pathway.

机构信息

State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Jiangsu, Nanjing 210009, China.

State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Jiangsu, Nanjing 210009, China.

出版信息

Redox Biol. 2019 Apr;22:101131. doi: 10.1016/j.redox.2019.101131. Epub 2019 Jan 30.

DOI:10.1016/j.redox.2019.101131
PMID:30735911
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6365940/
Abstract

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.

摘要

化学耐药性是人类胰腺导管腺癌（PDAC）治疗的主要治疗障碍。作为一种氧化应激反应转录因子，核因子红细胞 2 相关因子 2（Nrf2）调节细胞保护基因的表达。Nrf2 不仅在化学预防中起关键作用，而且有助于化学耐药性。在这项研究中，我们发现地高辛通过抑制 SW1990/Gem 和 Panc-1/Gem 细胞中的 Nrf2 信号显着逆转了吉西他滨的耐药性。进一步的研究表明，地高辛在转录水平上调节 Nrf2。在体内研究中，我们发现与单独使用吉西他滨相比，地高辛和吉西他滨联合治疗在 SW1990/Gem-shControl 细胞衍生的异种移植物中更有效地抑制了肿瘤生长。同时，SW1990/Gem-shNrf2 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类胰腺癌对吉西他滨敏感，这依赖于 Nrf2。这些结果表明，地高辛可能被用作一种有前途的佐剂增敏剂，通过抑制 Nrf2 信号来逆转吉西他滨耐药的胰腺癌对吉西他滨的耐药性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bc2/6365940/d7c552cf7be2/mmc7.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bc2/6365940/23bd7c769283/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bc2/6365940/1f0e4209ab2e/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bc2/6365940/66f4df108249/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bc2/6365940/7a55b1253dc8/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bc2/6365940/3fb0dd19c52e/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bc2/6365940/818cc1333944/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bc2/6365940/b59897d5c535/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bc2/6365940/7c18b2e089b1/gr8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bc2/6365940/9f4e1e4649b7/gr9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bc2/6365940/308ee45ca483/mmc1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bc2/6365940/43ce68497d93/mmc2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bc2/6365940/d1f52d6d414a/mmc3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bc2/6365940/e858ba024e3c/mmc4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bc2/6365940/3cc1c25e336d/mmc5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bc2/6365940/39b405cf7332/mmc6.jpg
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