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

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.

• Authors: Ganji Purnachandra Nagaraju, Shijun Zhu, Jing Wen, Alton B Farris, Volkan N Adsay, Roberto Diaz, James P Snyder, Shoji Mamoru, Bassel F El-Rayes
• Journal: Cancer letters (Cancer Lett) Vol. 341 Issue 2 Pg. 195-203 (Dec 01 2013) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 23933177 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• 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

Topics

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