denbinobin and Pancreatic-Neoplasms

Human pancreatic carcinoma is a highly malignant cancer. Previous studies have shown that the decoy receptor 3 (DcR3) for Fas ligand (FasL) plays significant roles in tumour progression and immune suppression. In the present study, we evaluated the anti-cancer activity of a natural compound, denbinobin (5-hydroxy-3,7-dimethoxy-1,4-phenanthraquinone), through decreasing DcR3 levels in human pancreatic adenocarcinoma cell lines.. We used immunoprecipitation and ELISA assays to examine DcR3 levels, and used FACS to determine the percentage of cells with a sub-G1 DNA content.. AsPC-1 and BxPC-3 human pancreatic cancer cells express high levels of DcR3. Denbinobin concentration-dependently decreased DcR3 levels in BxPC-3 cells. MTT and flow cytometry assays indicated that BxPC-3 was FasL-resistant because high concentrations (100 ng.mL(-1)) of soluble FasL did not inhibit cell growth. However, combinations of denbinobin (3 micromol.L(-1)) with lower concentrations of soluble FasL (10, 30 and 50 ng.mL(-1)) or membrane-bound FasL, were synergistic on cell growth inhibition and apoptosis. Exogenous excess DcR3 reversed this synergistic effect. We observed no significant increase in the levels of surface Fas, cleaved forms of caspase-8, -3, -9, Bax, Bid, Bcl-xL, cytochrome c or mitochondrial membrane potentials following denbinobin treatment. However, denbinobin treatment increased the levels of apoptosis-inducing factor.. Denbinobin and FasL trigger a synergistic cytotoxic effect in human pancreatic adenocarcinoma cells. Denbinobin mediated a decrease in levels of DcR3, which played a major role in this synergistic effect, and also increased caspase-independent apoptosis, via apoptosis-inducing factor.

Topics: Adenocarcinoma; Anthraquinones; Antineoplastic Agents, Phytogenic; Apoptosis; Apoptosis Inducing Factor; Cell Line, Tumor; Cell Survival; Drug Synergism; Fas Ligand Protein; Humans; Pancreatic Neoplasms; Phenanthrenes; Receptors, Tumor Necrosis Factor, Member 6b

The bane of anti-cancer therapy is usually the development of resistance to apoptosis in malignant cells. Identification of strategies to re-sensitize cancer cells to apoptosis has now become a top priority in anti-cancer research. Denbinobin is a novel, naturally occurring phenathroquinone isolated from orchids of the genus Dendrobium that has remarkable anti-cancer activities demonstrated both in vitro and in vivo. Recently denbinobin has been shown to diminish the levels of expression of the decoy receptor-3 and also to act synergistically with Fas ligand to induce apoptosis in a pancreatic adenocarcinoma cell line. There is hope that denbinobin could be developed as an adjuvant in combination therapies aimed at killing cancers that rely on decoy receptors to evade the host's immune surveillance.

Topics: Adenocarcinoma; Anthraquinones; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Line, Tumor; Drug Synergism; Fas Ligand Protein; Humans; Pancreatic Neoplasms; Phenanthrenes; Receptors, Tumor Necrosis Factor, Member 6b; Tumor Escape