title: Docosahexaenoic acid enhances the susceptibility of human colorectal cancer cells to 5-fluorouracil.
abstract: OBJECTIVE
  Powerful growth-inhibitory action has been shown for n-3 polyunsaturated fatty acids against colon cancer cells. We have previously described their ability to inhibit proliferation of colon epithelial cells in patients at high risk of colon cancer. In the work reported here we investigated the ability of docosahexaenoic acid (DHA) to potentiate the antineoplastic activity of 5-fluorouracil (5-FU) in p53-wildtype (LS-174 and Colo 320) and p53-mutant (HT-29 and Colo 205) human colon cancer cells.
  
  
  METHODS
  When in combination with DHA, 5-FU was used at concentrations ranging from 0.1 to 1.0 microM, much lower than those currently found in plasma patients after infusion of this drug. Similarly, the DHA concentrations (< or =10 microM) used in combination with 5-FU were lower than those widely used in vitro and known to cause peroxidative effects in vivo.
  
  
  RESULTS
  Whereas the cells showed different sensitivity to the growth-inhibitory action of 5-FU, DHA reduced cell growth independently of p53 cellular status. DHA synergized with 5-FU in reducing colon cancer cell growth. The potentiating effect of DHA was attributable to the enhancement of the proapoptotic effect of 5-FU. DHA markedly increased the inhibitory effect of 5-FU on the expression of the antiapoptotic proteins BCL-2 and BCL-XL, and induced overexpression of c-MYC which has recently been shown to drive apoptosis and, when overexpressed, to sensitize cancer cells to the action of proapoptotic agents, including 5-FU.
  
  
  CONCLUSIONS
  Our results indicate that DHA strongly increases the antineoplastic effects of low concentrations of 5-FU. Overall, the results suggest that combinations of low doses of the two compounds could represent a chemotherapeutic approach with low toxicity.
authors.affiliation: Institute of General Pathology, Catholic University, L.go F. Vito, 1, 00168, Rome, Italy. g.calviello@rm.unicatt.it
authors.forename: Gabriella
authors.initials: G
authors.lastname: Calviello
authors.forename: Fiorella
authors.initials: F
authors.lastname: Di Nicuolo
authors.forename: Simona
authors.initials: S
authors.lastname: Serini
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Piccioni
authors.forename: Alma
authors.initials: A
authors.lastname: Boninsegna
authors.forename: Nicola
authors.initials: N
authors.lastname: Maggiano
authors.forename: Franco O
authors.initials: FO
authors.lastname: Ranelletti
authors.forename: Paola
authors.initials: P
authors.lastname: Palozza
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000473:pathology*; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D014407:Tumor Cells, Cultured
chemical_list: D000964:Antimetabolites, Antineoplastic; D004281:Docosahexaenoic Acids; D005472:Fluorouracil