title: Antiangiogenic effects of a novel synthetic curcumin analogue in pancreatic cancer.
abstract: Hypoxia-inducible factors (HIFs) and NF-κB play essential roles in cancer cell growth and metastasis by promoting angiogenesis. Heat shock protein 90 (Hsp90) serves as a regulator of HIF-1α and NF-κB protein. We hypothesized that curcumin and its analogues EF31 and UBS109 would disrupt angiogenesis in pancreatic cancer (PC) through modulation of HIF-1α and NF-κB. Conditioned medium from MIA PaCa-2 or PANC-1 cells exposed to curcumin and its analogues in vitro significantly impaired angiogenesis in an egg CAM assay and blocked HUVEC tube assembly in comparison to untreated cell medium. In vivo, EF31 and UBS109 blocked the vascularization of subcutaneous matrigel plugs developed by MIA PaCa-2 in mice. Significant inhibition of VEGF, angiopoietin 1, angiopoietin 2, platelet derived growth factor, COX-2, and TGFβ secretion was observed in PC cell lines treated with UBS109, EF31 or curcumin. Treatment with UBS109, EF31 or curcumin inhibited HSP90, NF-κB, and HIF-1α transcription in PC cell lines. UBS109 and EF31 inhibited HSP90 and HIF-1α expression even when elevated due to NF-κB (p65) overexpression. Finally, we demonstrate for the first time that curcumin analogues EF31 and UBS109 induce the downregulation of HIF-1α, Hsp90, COX-2 and VEGF in tumor samples from xenograft models compared to untreated xenografts. Altogether, these results suggest that UBS109 and EF31 are potent curcumin analogues with antiangiogenic activities.
authors.affiliation: Department of Hematology and Medical Oncology, Emory University, Atlanta, GA 30322, USA.
authors.forename: Ganji Purnachandra
authors.initials: GP
authors.lastname: Nagaraju
authors.affiliation: Department of Hematology and Medical Oncology, Emory University, Atlanta, GA 30322, USA.
authors.forename: Shijun
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Department of Hematology and Medical Oncology, Emory University, Atlanta, GA 30322, USA.
authors.forename: Jasmine E
authors.initials: JE
authors.lastname: Ko
authors.affiliation: Department of Hematology and Medical Oncology, Emory University, Atlanta, GA 30322, USA.
authors.forename: Nakkana
authors.initials: N
authors.lastname: Ashritha
authors.affiliation: Department of Hematology and Medical Oncology, Emory University, Atlanta, GA 30322, USA.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Kandimalla
authors.affiliation: Department of Chemistry, Emory University, Atlanta, GA 30322, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Snyder
authors.affiliation: Department of Hematology and Medical Oncology, Emory University, Atlanta, GA 30322, USA.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Shoji
authors.affiliation: Department of Hematology and Medical Oncology, Emory University, Atlanta, GA 30322, USA. Electronic address: belraye@emory.edu.
authors.forename: Bassel F
authors.initials: BF
authors.lastname: El-Rayes
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D042682:Angiopoietins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D010881:Piperidones / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C574747:3,5-bis(2-pyridinylmethylidene)-4-piperidone; D020533:Angiogenesis Inhibitors; D042682:Angiopoietins; D017077:Culture Media, Conditioned; D018841:HSP90 Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010881:Piperidones; D011725:Pyridines; D053773:Transforming Growth Factor beta1; C576828:UBS109; D042461:Vascular Endothelial Growth Factor A; D003474:Curcumin
keywords: Angiogenesis; Curcumin; EF31; Pancreatic cancer; UBS109