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

Duong,Hong-Quan; Yi,Yong Weon; Kang,Hyo Jin; Hong,Young Bin; Tang,Wenxi; Wang,Antai; Seong,Yeon-Sun; Bae,Insoo

doi:10.3892/ijo.2013.2229

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

Authors:
- Hong-Quan Duong
- Yong Weon Yi
- Hyo Jin Kang
- Young Bin Hong
- Wenxi Tang
- Antai Wang
- Yeon-Sun Seong
- Insoo Bae
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Affiliations: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA, Department of Biostatistics, Columbia University, New York, NY, USA, Department of Nanobiomedical Science and WCU (World Class University) Research Center of Nanobiomedical Science, Dankook University, Cheonan, Republic of Korea
Published online on: December 23, 2013 https://doi.org/10.3892/ijo.2013.2229
Pages: 959-969

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Abstract

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.

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