3-5-bis(2-pyridinylmethylidene)-4-piperidone and Colorectal-Neoplasms

The transcription factor NF-κB plays a central role in angiogenesis in colorectal cancer (CRC). Curcumin is a natural dietary product that inhibits NF-κB. The objective of this study is to evaluate the antiangiogenic effects of curcumin and two potent synthetic analogues (EF31 and UBS109) in CRC. IC

Topics: Angiogenesis Inhibitors; Animals; Chickens; Colon; Colorectal Neoplasms; Curcumin; Female; HCT116 Cells; HT29 Cells; Human Umbilical Vein Endothelial Cells; Humans; Mice, Nude; Neovascularization, Pathologic; NF-kappa B; Piperidones; Pyridines; Rats; Rectum; Signal Transduction; Vascular Endothelial Growth Factor A

Cell cycle progression and DNA synthesis are essential steps in cancer cell growth and resistance. Thymidylate synthase (TS) is a therapeutic target for 5FU. Curcumin is a potent inhibitor of NF-κB. EF31 and UBS109 are potent synthetic analogues of curcumin. We tested the hypothesis that inhibition of NF-κB translocation by curcumin and its analogs EF31 and UBS109 can inhibit cell cycle progression and downregulate TS levels in colorectal cancer (CRC) cell lines. Two CRC cell lines (HCT116 and HT-29) were either untreated (control) or treated with IC50 concentrations of curcumin, EF31 UBS109 led to G0/G1 cell cycle arrest. Treatment with curcumin, EF31 or UBS109 inhibited NF-κB, downregulated survival pathways and inhibited cell cycle progression. Arrest in the G0/G1 phase was associated with downregulation of the transcription factor E2F-1 and its target gene TS. NF-κB over-expression induced E2F-1 and TS protein and mRNA levels in both cell lines. EF31 and UBS109 treatment significantly decreased tumor growth in compared to untreated tumors. EF31 and UBS109 are promising agents for the prevention and treatment of CRC.

Topics: Animals; Cell Cycle Checkpoints; Cell Line, Tumor; Colorectal Neoplasms; Curcumin; Down-Regulation; Female; Humans; Mice; NF-kappa B; Piperidones; Protein Transport; Pyridines; Thymidylate Synthase