BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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. KEY RESULTS: 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. CONCLUSIONS AND IMPLICATIONS: 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.
BACKGROUND AND PURPOSE:Humanpancreatic 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 humanpancreatic adenocarcinoma cell lines. EXPERIMENTAL APPROACH: 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. KEY RESULTS: AsPC-1 and BxPC-3 humanpancreatic 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. CONCLUSIONS AND IMPLICATIONS: Denbinobin and FasL trigger a synergistic cytotoxic effect in humanpancreatic 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.
Authors: C Bai; B Connolly; M L Metzker; C A Hilliard; X Liu; V Sandig; A Soderman; S M Galloway; Q Liu; C P Austin; C T Caskey Journal: Proc Natl Acad Sci U S A Date: 2000-02-01 Impact factor: 11.205
Authors: Thi Sau Migone; Jun Zhang; Xia Luo; Li Zhuang; Cecil Chen; Bugen Hu; June S Hong; James W Perry; Su Fang Chen; Joe X H Zhou; Yun Hee Cho; Stephen Ullrich; Palanisamy Kanakaraj; Jeffrey Carrell; Ernest Boyd; Henrik S Olsen; Gang Hu; Laurie Pukac; Ding Liu; Jian Ni; Sunghee Kim; Reiner Gentz; Ping Feng; Paul A Moore; Steve M Ruben; Ping Wei Journal: Immunity Date: 2002-03 Impact factor: 31.745
Authors: A Elnemr; T Ohta; A Yachie; M Kayahara; H Kitagawa; T Fujimura; I Ninomiya; S Fushida; G I Nishimura; K Shimizu; K Miwa Journal: Int J Oncol Date: 2001-02 Impact factor: 5.650
Authors: W Roth; S Isenmann; M Nakamura; M Platten; W Wick; P Kleihues; M Bähr; H Ohgaki; A Ashkenazi; M Weller Journal: Cancer Res Date: 2001-03-15 Impact factor: 12.701
Authors: W von Bernstorff; R A Spanjaard; A K Chan; D C Lockhart; N Sadanaga; I Wood; M Peiper; P S Goedegebuure; T J Eberlein Journal: Surgery Date: 1999-01 Impact factor: 3.982