Antiangiogenic effects of a novel synthetic curcumin analogue in pancreatic cancer

Cancer Lett. 2015 Feb 28;357(2):557-65. doi: 10.1016/j.canlet.2014.12.007. Epub 2014 Dec 9.

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.

Keywords: Angiogenesis; Curcumin; EF31; Pancreatic cancer; UBS109.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / pharmacology*
  • Angiopoietins / genetics
  • Angiopoietins / metabolism
  • Animals
  • Blotting, Western
  • Cell Line
  • Cell Line, Tumor
  • Chick Embryo
  • Chorioallantoic Membrane / blood supply
  • Chorioallantoic Membrane / drug effects
  • Culture Media, Conditioned / pharmacology
  • Curcumin / analogs & derivatives*
  • Curcumin / pharmacology
  • Female
  • Gene Expression / drug effects
  • HSP90 Heat-Shock Proteins / genetics
  • HSP90 Heat-Shock Proteins / metabolism
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / physiology
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Mice, Nude
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / prevention & control
  • Neovascularization, Physiologic / drug effects
  • Pancreatic Neoplasms / blood supply
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / pathology
  • Piperidones / pharmacology*
  • Pyridines / pharmacology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / metabolism
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • 3,5-bis(2-pyridinylmethylidene)-4-piperidone
  • Angiogenesis Inhibitors
  • Angiopoietins
  • Culture Media, Conditioned
  • HSP90 Heat-Shock Proteins
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Piperidones
  • Pyridines
  • Transforming Growth Factor beta1
  • UBS109
  • Vascular Endothelial Growth Factor A
  • Curcumin