Maslinic acid potentiates the anti-tumor activity of tumor necrosis factor alpha by inhibiting NF-kappaB signaling pathway.
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.
Li
Chenghai
C
The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
Yang
Zhengfeng
Z
Zhai
Chunyan
C
Qiu
Wenwei
W
Li
Dali
D
Yi
Zhengfang
Z
Wang
Lei
L
Tang
Jie
J
Qian
Min
M
Luo
Jian
J
Liu
Mingyao
M
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
D000970:Antineoplastic Agents; D016328:NF-kappa B; D014315:Triterpenes; D014409:Tumor Necrosis Factor-alpha; C412811:maslinic acid; D009828:Oleanolic Acid