Inhibition of NRF2 by PIK-75 augments sensitivity of pancreatic cancer cells to gemcitabine

被引：69

作者：

Duong, Hong-Quan ^{[1
,3
,4
]}

Yi, Yong Weon ^{[1
,3
,4
]}

Kang, Hyo Jin ^{[1
]}

Hong, Young Bin ^{[1
]}

Tang, Wenxi ^{[5
]}

Wang, Antai ^{[5
,6
]}

Seong, Yeon-Sun ^{[3
,4
]}

Bae, Insoo ^{[1
,2
,3
,4
]}

机构：

[1] Georgetown Univ, Dept Oncol, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA

[2] Georgetown Univ, Dept Radiat Med, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA

[3] Dankook Univ, Dept Nanobiomed Sci, Cheonan, South Korea

[4] Dankook Univ, WCU World Class Univ Res Ctr Nanobiomed Sci, Cheonan, South Korea

[5] Columbia Univ, Dept Biostat, New York, NY USA

[6] Columbia Univ, Herbert Irving Comprehens Canc Ctr, New York, NY USA

来源：

INTERNATIONAL JOURNAL OF ONCOLOGY | 2014年 / 44卷 / 03期

基金：

美国国家卫生研究院; 新加坡国家研究基金会;

关键词：

PIK-75; gemcitabine; NRF2; MRP5; synergism; NF-E2-RELATED FACTOR-2 NRF2; GENE-EXPRESSION; TRANSCRIPTION FACTOR; LUNG-CANCER; ADENOCARCINOMA CELLS; NUCLEAR EXPORT; RESISTANCE; KINASE; PATHWAY; GROWTH;

D O I：

10.3892/ijo.2013.2229

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

We describe the potential benefit of PIK-75 in combination of gemcitabine to treat pancreatic cancer in a preclinical mouse model. The effect of PIK-75 on the level and activity of NRF2 was characterized using various assays including reporter gene, quantitative PCR, DNA-binding and western blot analyses. Additionally, the combinatorial effect of PIK-75 and gemcitabine was evaluated in human pancreatic cancer cell lines and a xenograft model. PIK-75 reduced NRF2 protein levels and activity to regulate its target gene expression through proteasome-mediated degradation of NRF2 in human pancreatic cancer cell lines. PIK-75 also reduced the gemcitabine-induced NRF2 levels and the expression of its downstream target MRP5. Co-treatment of PIK-75 augmented the antitumor effect of gemcitabine both in vitro and in vivo. Our present study provides a strong mechanistic rationale to evaluate NRF2 targeting agents in combination with gemcitabine to treat pancreatic cancers.

引用

页码：959 / 969

页数：11

共 50 条

[1]

[Anonymous], 2013, CANC FACTS FIG 2013

[2]

Inhibition of the Nrf2 transcription factor by the alkaloid trigonelline renders pancreatic cancer cells more susceptible to apoptosis through decreased proteasomal gene expression and proteasome activity [J].