title: Novel synthetic curcumin analogs as potent antiangiogenic agents in colorectal cancer.
abstract: 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. IC50values for curcumin, EF31, and UBS109 were determined in the HCT116 and HT-29 cell lines. HUVEC tube formation, egg CAM assay, and matrigel plug assays revealed decreased angiogenesis in cell lines treated with curcumin, EF31, or UBS109. Curcumin and its analogues significantly inhibited VEGF-A synthesis and secretion in both cell lines in association with loss of HIF-1α, COX-2, and p-STAT-3 expression. Nuclear NF-κB expression was inhibited by curcumin, EF31, and UBS109. Transfection of p65-NF-κB in HCT116 and HT-29 cells resulted in increased expression of HIF-1α, COX-2, STAT-3, and VEGF-A. Treatment with curcumin, EF31, or UBS109 inhibited these effects in transfected cell lines. In mice carrying HCT116 and HT-29 cell xenografts, EF31 and UBS109 inhibited subcutaneous tumor growth and potentiated the effects of oxaliplatin and 5-FU. Tumors from treated animals revealed inhibition of HIF-1α, COX-2, p-STAT-3, and VEGF expression. Our findings suggest that inhibition of NF-κB leading to decreased transcription and expression of HIF-1α, COX-2, STAT-3, and VEGF is a rational approach for antiangiogenic therapy in CRC. The distinctive properties of EF31 and UBS109 make them promising therapeutic agents for development in CRC as single agents or as part of combination chemotherapy regimens. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia.|Department of Microbiology, Banasthali University, Banasthali, Rajasthan, India.
authors.forename: Balney
authors.initials: B
authors.lastname: Rajitha
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia.|Department of Biotechnology, Berhampur University, Bhanjavihar, Odisha, India.
authors.forename: Ganji Purnachandra
authors.initials: GP
authors.lastname: Nagaraju
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Walid L
authors.initials: WL
authors.lastname: Shaib
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Olatunji B
authors.initials: OB
authors.lastname: Alese
authors.affiliation: Department of Chemistry, Emory University, Atlanta, Georgia.
authors.forename: James P
authors.initials: JP
authors.lastname: Snyder
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Shoji
authors.affiliation: Department of Biotechnology, Berhampur University, Bhanjavihar, Odisha, India.
authors.forename: Subasini
authors.initials: S
authors.lastname: Pattnaik
authors.affiliation: Department of Microbiology, Banasthali University, Banasthali, Rajasthan, India.
authors.forename: Afroz
authors.initials: A
authors.lastname: Alam
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Bassel F
authors.initials: BF
authors.lastname: El-Rayes
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002645:Chickens; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D045325:HCT116 Cells; D019073:HT29 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010881:Piperidones / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D012007:Rectum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C574747:3,5-bis(2-pyridinylmethylidene)-4-piperidone; D020533:Angiogenesis Inhibitors; D016328:NF-kappa B; D010881:Piperidones; D011725:Pyridines; C576828:UBS109; D042461:Vascular Endothelial Growth Factor A; D003474:Curcumin
keywords: angiogenesis; colorectal cancer; curcumin