title: Curcumin potentiates antitumor activity of 5-fluorouracil in a 3D alginate tumor microenvironment of colorectal cancer.
abstract: BACKGROUND
  To overcome the limitations of animal-based experiments, 3D culture models mimicking the tumor microenvironment in vivo are gaining attention. Herein, we investigated an alginate-based 3D scaffold for screening of 5-fluorouracil (5-FU) or/and curcumin on malignancy of colorectal cancer cells (CRC).
  
  
  METHODS
  The potentiation effects of curcumin on 5-FU against proliferation and metastasis of HCT116 cell and its corresponding isogenic 5-FU-chemoresistant cells (HCT116R) were examined in a 3D-alginate tumor model.
  
  
  RESULTS
  CRC cells encapsulated in alginate were able to proliferate in 3D-colonospheres in a vivo-like phenotype and invaded from alginate. During cultivation of cells in alginate, we could isolate 3 stages of cells, (1) alginate proliferating (2) invasive and (3) adherent cells. Tumor-promoting factors (CXCR4, MMP-9, NF-κB) were significantly increased in the proliferating and invasive compared to the adherent cells, however HCT116R cells overexpressed factors in comparison to the parental HCT116, suggesting an increase in malignancy behavior. In alginate, curcumin potentiated 5-FU-induced decreased capacity for proliferation, invasion and increased more sensitivity to 5-FU of HCT116R compared to the HCT116 cells. IC50 for HCT116 to 5-FU was 8nM, but co-treatment with 5 μM curcumin significantly reduced 5-FU concentrations in HCT116 and HCT116R cells (0.8nM, 0.1nM, respectively) and these effects were accompanied by down-regulation of NF-κB activation and NF-κB-regulated gene products.
  
  
  CONCLUSIONS
  Our results demonstrate that the alginate provides an excellent tumor microenvironment and indicate that curcumin potentiates and chemosensitizes HCT116R cells to 5-FU-based chemotherapy that may be useful for the treatment of CRC and to overcome drug resistance.
authors.affiliation: Institute of Anatomy, Ludwig-Maximilian-University Munich, Pettenkoferstrasse 11, D-80336, Munich, Germany. mehdi.shakibaei@med.uni-muenchen.de.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Shakibaei
authors.affiliation: Institute of Anatomy, Ludwig-Maximilian-University Munich, Pettenkoferstrasse 11, D-80336, Munich, Germany. patricia_kraehe@gmx.de.
authors.forename: Patricia
authors.initials: P
authors.lastname: Kraehe
authors.affiliation: Department of Anatomy and Cell Biology, Ludwig-Maximilian-University Munich, D-80336, Munich, Germany. Bastian.Popper@med.uni-muenchen.de.
authors.forename: Bastian
authors.initials: B
authors.lastname: Popper
authors.affiliation: Investigating Institute of Molecular Biological System Transfer, Tehran, 1417863171, Iran. pshayan@ut.ac.ir.|Department of Parasitology, Faculty of Veterinary Medicine, University of Tehran, Tehran, 141556453, Iran. pshayan@ut.ac.ir.
authors.forename: Parviz
authors.initials: P
authors.lastname: Shayan
authors.affiliation: Gastrointestinal Cancer Research Laboratory, Division of Gastroenterology, Baylor Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA. AjayG@BaylorHealth.edu.
authors.forename: Ajay
authors.initials: A
authors.lastname: Goel
authors.affiliation: Institute of Anatomy, Ludwig-Maximilian-University Munich, Pettenkoferstrasse 11, D-80336, Munich, Germany. constanze.buhrmann@med.uni-muenchen.de.
authors.forename: Constanze
authors.initials: C
authors.lastname: Buhrmann
mesh_terms: D000464:Alginates / Q000737:chemistry; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D003474:Curcumin / Q000008:administration & dosage*; D004357:Drug Synergism; D005472:Fluorouracil / Q000008:administration & dosage*; D020723:Glucuronic Acid / Q000737:chemistry; D045325:HCT116 Cells; D006603:Hexuronic Acids / Q000737:chemistry; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D051379:Mice; D009361:Neoplasm Invasiveness; D019718:Receptors, CXCR4 / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D059016:Tumor Microenvironment / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000464:Alginates; C527276:CXCR4 protein, human; D006603:Hexuronic Acids; D019718:Receptors, CXCR4; D020723:Glucuronic Acid; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D003474:Curcumin; D005472:Fluorouracil