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

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

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)959-969
Number of pages11
JournalInternational Journal of Oncology
Volume44
Issue number3
DOIs
StatePublished - Mar 2014

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Keywords

  • Gemcitabine
  • MRP5
  • NRF2
  • PIK-75
  • Synergism

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