title: 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.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
authors.forename: Hong-Quan
authors.initials: HQ
authors.lastname: Duong
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
authors.forename: Yong Weon
authors.initials: YW
authors.lastname: Yi
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
authors.forename: Hyo Jin
authors.initials: HJ
authors.lastname: Kang
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
authors.forename: Young Bin
authors.initials: YB
authors.lastname: Hong
authors.affiliation: Department of Biostatistics, Columbia University, New York, NY, USA.
authors.forename: Wenxi
authors.initials: W
authors.lastname: Tang
authors.affiliation: Department of Biostatistics, Columbia University, New York, NY, USA.
authors.forename: Antai
authors.initials: A
authors.lastname: Wang
authors.affiliation: Department of Nanobiomedical Science and WCU (World Class University) Research Center of Nanobiomedical Science, Dankook University, Cheonan, Republic of Korea.
authors.forename: Yeon-Sun
authors.initials: YS
authors.lastname: Seong
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
authors.forename: Insoo
authors.initials: I
authors.lastname: Bae
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D006835:Hydrazones / Q000008:administration & dosage*; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D013449:Sulfonamides / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D006835:Hydrazones; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C549211:PIK 75; D013449:Sulfonamides; D003841:Deoxycytidine; D000093542:Gemcitabine