Novel synthetic curcumin analogues EF31 and UBS109 are potent DNA hypomethylating agents in pancreatic cancer

Cancer Lett. 2013 Dec 1;341(2):195-203. doi: 10.1016/j.canlet.2013.08.002. Epub 2013 Aug 7.

Abstract

DNA methylation is a rational therapeutic target in pancreatic cancer. The activity of novel curcumin analogues EF31 and UBS109 as demethylating agents were investigated. MiaPaCa-2 and PANC-1 cells were treated with vehicle, curcumin, EF31 or UBS109. EF31 and UBS109 resulted in significantly higher inhibition of proliferation and cytosine methylation than curcumin. Demethylation was associated with re-expression of silenced p16, SPARC, and E-cadherin. EF31 and UBS109 inhibited HSP-90 and NF-κB leading to downregulation of DNA methyltransferase-1 (DNMT-1) expression. Transfection experiments confirmed this mechanism of action. Similar results were observed in vitro when subcutaneous tumors (MiaPaCa-2) were treated with EF31 and UBS109.

Keywords: 4′-6-diamidino-2-phenylindole; Curcumin; DAPI; DNA methylation; DNA methyltransferase-1; DNMT-1; EF31; HSP90; Pancreatic cancer; SPARC; UBS109; heat shock protein 90; secreted protein acidic and rich in cysteine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cadherins / genetics
  • Cadherins / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Curcumin / analogs & derivatives*
  • Curcumin / pharmacology
  • Cytosine / metabolism
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • DNA Methylation / drug effects*
  • Dose-Response Relationship, Drug
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • HSP90 Heat-Shock Proteins / genetics
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Immunohistochemistry
  • Mice
  • Mice, Nude
  • Osteonectin / genetics
  • Osteonectin / metabolism
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism
  • Piperidones / pharmacology*
  • Pyridines
  • Reverse Transcriptase Polymerase Chain Reaction
  • Xenograft Model Antitumor Assays*

Substances

  • 3,5-bis(2-pyridinylmethylidene)-4-piperidone
  • Cadherins
  • HSP90 Heat-Shock Proteins
  • Osteonectin
  • Piperidones
  • Pyridines
  • SPARC protein, human
  • UBS109
  • Cytosine
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases
  • Curcumin