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

• EF31 and UBS109 are more potent inhibitors of DNA methylation than curcumin.
• EF31 and UBS109 inhibit DNA methylation through NF-κB and HSP90 leading to downregulation of DNMT-1.
• EF31, UBS109 and curcumin induce expression of silenced p16, SPARC and E-cadherin.
• EF31 and UBS109 are promising agents for future therapeutic development 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.