title: Maslinic acid potentiates the anti-tumor activity of tumor necrosis factor alpha by inhibiting NF-kappaB signaling pathway.
abstract: BACKGROUND
  Tumor necrosis factor alpha (TNFalpha) has been used to treat certain tumors in clinic trials. However, the curative effect of TNFalpha has been undermined by the induced-NF-kappaB activation in many types of tumor. Maslinic acid (MA), a pharmacological safe natural product, has been known for its important effects as anti-oxidant, anti-inflammatory, and anti-viral activities. The aim of this study was to determine whether MA potentiates the anti-tumor activity of TNFalpha though the regulation of NF-kappaB activation.
  
  
  RESULTS
  In this study, we demonstrate that MA significantly enhanced TNFalpha-induced inhibition of pancreatic cancer cell proliferation, invasion, and potentiated TNFalpha-induced cell apoptosis by suppressing TNFalpha-induced NF-kappaB activation in a dose- and time-dependent manner. Addition of MA inhibited TNFalpha-induced IkappaBalpha degradation, p65 phosphorylation, and nuclear translocation. Furthermore, MA decreased the expression levels of NF-kappaB-regulated genes, including genes involved in tumor cell proliferation (Cyclin D1, COX-2 and c-Myc), apoptosis (Survivin, Bcl-2, Bcl-xl, XIAP, IAP-1), invasion (MMP-9 and ICAM-1), and angiogenesis (VEGF). In athymic nu/nu mouse model, we further demonstrated that MA significantly suppressed pancreatic tumor growth, induced tumor apoptosis, and inhibited NF-kappaB-regulated anti-apoptotic gene expression, such as Survivin and Bcl-xl.
  
  
  CONCLUSIONS
  Our data demonstrate that MA can potentiate the anti-tumor activities of TNFalpha and inhibit pancreatic tumor growth and invasion by activating caspase-dependent apoptotic pathway and by suppressing NF-kappaB activation and its downstream gene expression. Therefore, MA together with TNFalpha could be new promising agents in the treatment of pancreatic cancer.
authors.affiliation: The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Chenghai
authors.initials: C
authors.lastname: Li
authors.forename: Zhengfeng
authors.initials: Z
authors.lastname: Yang
authors.forename: Chunyan
authors.initials: C
authors.lastname: Zhai
authors.forename: Wenwei
authors.initials: W
authors.lastname: Qiu
authors.forename: Dali
authors.initials: D
authors.lastname: Li
authors.forename: Zhengfang
authors.initials: Z
authors.lastname: Yi
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Tang
authors.forename: Min
authors.initials: M
authors.lastname: Qian
authors.forename: Jian
authors.initials: J
authors.lastname: Luo
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000096:biosynthesis / Q000187:drug effects*; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction / Q000187:drug effects*; D014315:Triterpenes / Q000008:administration & dosage*; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays; D009828:Oleanolic Acid / Q000031:analogs & derivatives
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D014315:Triterpenes; D014409:Tumor Necrosis Factor-alpha; C412811:maslinic acid; D009828:Oleanolic Acid