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

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.

• Authors: Hong-Quan Duong, Yong Weon Yi, Hyo Jin Kang, Young Bin Hong, Wenxi Tang, Antai Wang, Yeon-Sun Seong, Insoo Bae
• Journal: International journal of oncology (Int J Oncol) Vol. 44 Issue 3 Pg. 959-69 (Mar 2014) ISSN: 1791-2423 [Electronic] Greece
• PMID: 24366069 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Hydrazones
• NF-E2-Related Factor 2
• NFE2L2 protein, human
• PIK 75
• Sulfonamides
• Deoxycytidine
• Gemcitabine

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage)
• Cell Line, Tumor
• Deoxycytidine (administration & dosage, analogs & derivatives)
• Humans
• Hydrazones (administration & dosage)
• Mice
• NF-E2-Related Factor 2 (antagonists & inhibitors, genetics)
• Pancreatic Neoplasms (drug therapy, genetics, pathology)
• Sulfonamides (administration & dosage)
• Xenograft Model Antitumor Assays
• Gemcitabine