Maslinic acid potentiates the anti-tumor activity of tumor necrosis factor α by inhibiting NF-κB signaling pathway

Background: Tumor necrosis factor alpha (TNF alpha) has been used to treat certain tumors in clinic trials. However, the curative effect of TNF alpha has been undermined by the induced-NF-kappa B activation in many types of tumor. Maslinic acid (MA), a pharmacological safe natural product, has been known for its important effects as antioxidant, anti-inflammatory, and anti-viral activities. The aim of this study was to determine whether MA potentiates the anti-tumor activity of TNFa though the regulation of NF-kappa B activation. Results: In this study, we demonstrate that MA significantly enhanced TNF alpha-induced inhibition of pancreatic cancer cell proliferation, invasion, and potentiated TNF alpha-induced cell apoptosis by suppressing TNF alpha-induced NF-kappa B activation in a dose-and time-dependent manner. Addition of MA inhibited TNF alpha-induced I kappa B alpha degradation, p65 phosphorylation, and nuclear translocation. Furthermore, MA decreased the expression levels of NF-kappa B-Bregulated 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-kappa B-regulated anti-apoptotic gene expression, such as Survivin and Bcl-xl. Conclusions: Our data demonstrate that MA can potentiate the anti-tumor activities of TNF alpha and inhibit pancreatic tumor growth and invasion by activating caspase-dependent apoptotic pathway and by suppressing NF-kappa B activation and its downstream gene expression. Therefore, MA together with TNF alpha could be new promising agents in the treatment of pancreatic cancer.