Journal
INTERNATIONAL JOURNAL OF ONCOLOGY
Volume 44, Issue 3, Pages 959-969Publisher
SPANDIDOS PUBL LTD
DOI: 10.3892/ijo.2013.2229
Keywords
PIK-75; gemcitabine; NRF2; MRP5; synergism
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Funding
- National Institutes of Health [1R03CA152530]
- Lombardi Comprehensive Cancer Center, Georgetown University [P30-CA051008]
- National Research Foundation of Korea [R31-10069 WCU]
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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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