Novel synthetic curcumin analogues EF31 and UBS109 are potent DNA hypomethylating agents in pancreatic cancer.
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.
Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, United States.
Ganji Purnachandra
GP
Nagaraju
Shijun
S
Zhu
Jing
J
Wen
Alton B
AB
Farris
Volkan N
VN
Adsay
Roberto
R
Diaz
James P
JP
Snyder
Shoji
S
Mamoru
Bassel F
BF
El-Rayes
D000818:Animals; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology; D003596:Cytosine / Q000378:metabolism; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D015676:Osteonectin / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D010881:Piperidones / Q000494:pharmacology*; D011725:Pyridines; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays
C574747:3,5-bis(2-pyridinylmethylidene)-4-piperidone; D015820:Cadherins; D018841:HSP90 Heat-Shock Proteins; D015676:Osteonectin; D010881:Piperidones; D011725:Pyridines; C577241:SPARC protein, human; C576828:UBS109; D003596:Cytosine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D003474:Curcumin
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