title: Downregulation of STAT3/NF-κB potentiates gemcitabine activity in pancreatic cancer cells.
abstract: There is an unmet need to develop new agents or strategies against therapy resistant pancreatic cancer (PanCA). Recent studies from our laboratory showed that STAT3 negatively regulates NF-κB and that inhibition of this crosstalk using Nexrutine® (Nx) reduces transcriptional activity of COX-2. Inhibition of these molecular interactions impedes pancreatic cancer cell growth as well as reduces fibrosis in a preclinical animal model. Nx is an extract derived from the bark of Phellodendron amurense and has been utilized in traditional Chinese medicine as antidiarrheal, astringent, and anti-inflammatory agent for centuries. We hypothesized that "Nx-mediated inhibition of survival molecules like STAT3 and NF-κB in pancreatic cancer cells will improve the efficacy of the conventional chemotherapeutic agent, gemcitabine (GEM)." Therefore, we explored the utility of Nx, one of its active constituents berberine and its derivatives, to enhance the effects of GEM. Using multiple human pancreatic cancer cells we found that combination treatment with Nx and GEM resulted in significant alterations of proteins in the STAT3/NF-κB signaling axis culminating in growth inhibition in a synergistic manner. Furthermore, GEM resistant cells were more sensitive to Nx treatment than their parental GEM-sensitive cells. Interestingly, although berberine, the Nx active component used, and its derivatives were biologically active in GEM sensitive cells they did not potentiate GEM activity when used in combination. Taken together, these results suggest that the natural extract, Nx, but not its active component, berberine, has the potential to improve GEM sensitivity, perhaps by down regulating STAT3/NF-κB signaling. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Gong
authors.affiliation: Department of Urology, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Amanda R
authors.initials: AR
authors.lastname: Muñoz
authors.affiliation: Department of Chemistry, Xavier University of Louisiana, New Orleans, Los Angeles.
authors.forename: Subramanya
authors.initials: S
authors.lastname: Pingali
authors.affiliation: Department of Chemistry, Xavier University of Louisiana, New Orleans, Los Angeles.
authors.forename: Florastina
authors.initials: F
authors.lastname: Payton-Stewart
authors.affiliation: Division of Medical Oncology, University of Colorado, Aurora, Colorado.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Chan
authors.affiliation: Division of Medical Oncology, University of Texas Health Science Center, San Antonio, Texas.|Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, Texas.|South Texas Veterans Health Care System, San Antonio, Texas.
authors.forename: James W
authors.initials: JW
authors.lastname: Freeman
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center, San Antonio, Texas.|Department of Urology, University of Texas Health Science Center, San Antonio, Texas.|Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, Texas.|Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Rita
authors.initials: R
authors.lastname: Ghosh
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center, San Antonio, Texas.|Department of Urology, University of Texas Health Science Center, San Antonio, Texas.|Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, Texas.|South Texas Veterans Health Care System, San Antonio, Texas.|Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Addanki P
authors.initials: AP
authors.lastname: Kumar
mesh_terms: D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001599:Berberine / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000276:immunology; D010179:Pancreas / Q000187:drug effects / Q000276:immunology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000276:immunology; D032102:Phellodendron / Q000737:chemistry; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects; D000093542:Gemcitabine
chemical_list: D000893:Anti-Inflammatory Agents; D000964:Antimetabolites, Antineoplastic; D016328:NF-kappa B; C512605:Nexrutine; D010936:Plant Extracts; D050796:STAT3 Transcription Factor; D001599:Berberine; D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: STAT3/NFκB; chemoresistance; gemcitabine; nexrutine; pancreatic cancer