title: Curcumin chemosensitizes 5-fluorouracil resistant MMR-deficient human colon cancer cells in high density cultures.
abstract: OBJECTIVE
  Treatment of colorectal cancer (CRC) remains a clinical challenge, as more than 15% of patients are resistant to 5-Fluorouracil (5-FU)-based chemotherapeutic regimens, and tumor recurrence rates can be as high as 50-60%. Cancer stem cells (CSC) are capable of surviving conventional chemotherapies that permits regeneration of original tumors. Therefore, we investigated the effectiveness of 5-FU and plant polyphenol (curcumin) in context of DNA mismatch repair (MMR) status and CSC activity in 3D cultures of CRC cells.
  
  
  METHODS
  High density 3D cultures of CRC cell lines HCT116, HCT116+ch3 (complemented with chromosome 3) and their corresponding isogenic 5-FU-chemo-resistant derivative clones (HCT116R, HCT116+ch3R) were treated with 5-FU either without or with curcumin in time- and dose-dependent assays.
  
  
  RESULTS
  Pre-treatment with curcumin significantly enhanced the effect of 5-FU on HCT116R and HCR116+ch3R cells, in contrast to 5-FU alone as evidenced by increased disintegration of colonospheres, enhanced apoptosis and by inhibiting their growth. Curcumin and/or 5-FU strongly affected MMR-deficient CRC cells in high density cultures, however MMR-proficient CRC cells were more sensitive. These effects of curcumin in enhancing chemosensitivity to 5-FU were further supported by its ability to effectively suppress CSC pools as evidenced by decreased number of CSC marker positive cells, highlighting the suitability of this 3D culture model for evaluating CSC marker expression in a close to vivo setting.
  
  
  CONCLUSIONS
  Our results illustrate novel and previously unrecognized effects of curcumin in enhancing chemosensitization to 5-FU-based chemotherapy on DNA MMR-deficient and their chemo-resistant counterparts by targeting the CSC sub-population. (246 words in abstract).
authors.affiliation: Institute of Anatomy, Ludwig-Maximilian-University Munich, Germany.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Shakibaei
authors.affiliation: Institute of Anatomy, Ludwig-Maximilian-University Munich, Germany.
authors.forename: Constanze
authors.initials: C
authors.lastname: Buhrmann
authors.affiliation: Institute of Anatomy, Ludwig-Maximilian-University Munich, Germany.
authors.forename: Patricia
authors.initials: P
authors.lastname: Kraehe
authors.affiliation: Investigating Institute of Molecular Biological System Transfer, Tehran, Iran.
authors.forename: Parviz
authors.initials: P
authors.lastname: Shayan
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Laboratory for Tissue Engineering, German Heart Institute Berlin, Berlin, Germany.
authors.forename: Cora
authors.initials: C
authors.lastname: Lueders
authors.affiliation: Gastrointestinal Cancer Research Laboratory, Division of Gastroenterology, Baylor Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas, United States of America.
authors.forename: Ajay
authors.initials: A
authors.lastname: Goel
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002452:Cell Count; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics*; D003474:Curcumin / Q000494:pharmacology*; D053843:DNA Mismatch Repair / Q000187:drug effects* / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005472:Fluorouracil / Q000494:pharmacology* / Q000633:toxicity; D045325:HCT116 Cells; D006801:Humans; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D018874:Spheroids, Cellular; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D003474:Curcumin; D005472:Fluorouracil