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.
Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blotting, Western
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Cadherins / genetics
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Cadherins / metabolism
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Curcumin / analogs & derivatives*
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Curcumin / pharmacology
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Cytosine / metabolism
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DNA (Cytosine-5-)-Methyltransferase 1
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DNA (Cytosine-5-)-Methyltransferases / genetics
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DNA (Cytosine-5-)-Methyltransferases / metabolism
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DNA Methylation / drug effects*
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Dose-Response Relationship, Drug
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Female
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Gene Expression Regulation, Neoplastic / drug effects
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HSP90 Heat-Shock Proteins / genetics
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HSP90 Heat-Shock Proteins / metabolism
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Humans
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Immunohistochemistry
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Mice
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Mice, Nude
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Osteonectin / genetics
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Osteonectin / metabolism
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Pancreatic Neoplasms / drug therapy*
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Pancreatic Neoplasms / genetics
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Pancreatic Neoplasms / metabolism
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Piperidones / pharmacology*
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Pyridines
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Reverse Transcriptase Polymerase Chain Reaction
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Xenograft Model Antitumor Assays*
Substances
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3,5-bis(2-pyridinylmethylidene)-4-piperidone
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Cadherins
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HSP90 Heat-Shock Proteins
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Osteonectin
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Piperidones
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Pyridines
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SPARC protein, human
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UBS109
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Cytosine
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DNA (Cytosine-5-)-Methyltransferase 1
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DNA (Cytosine-5-)-Methyltransferases
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Curcumin