title: Inhibition of NF-κB translocation by curcumin analogs induces G0/G1 arrest and downregulates thymidylate synthase in colorectal cancer.
abstract: 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.
authors: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA; Department of Microbiology, Banasthali University, Banasthali, Rajasthan 304022, India.
authors: Balney
authors: B
authors: Rajitha
authors: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA.
authors: Astrid
authors: A
authors: Belalcazar
authors: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA; Department of Biotechnology, Berhampur University, Bhanjavihar, Odisha 760007, India.
authors: Ganji Purnachandra
authors: GP
authors: Nagaraju
authors: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA.
authors: Walid L
authors: WL
authors: Shaib
authors: Department of Chemistry, Emory University, Atlanta, Georgia 30322, USA.
authors: James P
authors: JP
authors: Snyder
authors: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA.
authors: Mamoru
authors: M
authors: Shoji
authors: Department of Biotechnology, Berhampur University, Bhanjavihar, Odisha 760007, India.
authors: Subasini
authors: S
authors: Pattnaik
authors: Department of Microbiology, Banasthali University, Banasthali, Rajasthan 304022, India.
authors: Afroz
authors: A
authors: Alam
authors: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA. Electronic address: belraye@emory.edu.
authors: Bassel F
authors: BF
authors: El-Rayes
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003474:Curcumin / Q000031:analogs & derivatives / Q000494:pharmacology*; D015536:Down-Regulation; D005260:Female; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D010881:Piperidones / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*
chemical_list: C574747:3,5-bis(2-pyridinylmethylidene)-4-piperidone; D016328:NF-kappa B; D010881:Piperidones; D011725:Pyridines; C576828:UBS109; D013940:Thymidylate Synthase; D003474:Curcumin
keywords: Curcumin; EF31; UBS109; colorectal cancer; nuclear factor kappa B