title: Role of caspases in 5-FU and selenium-induced growth inhibition of colorectal cancer cells.
abstract: BACKGROUND
  The mechanisms that could explain the poor sensitivity to 5-FU in certain colorectal cancer (CRC) cells were investigated and whether or not cotreatment with low doses of selenium would offer a therapeutic benefit was explored.
  
  
  METHODS
  Four CRC cell lines (Caco2, RKO, DLD1 and HT-29) with defined tumor signatures and seven different chemical forms of selenium were tested.
  
  
  RESULTS
  5-FU partially inhibited the HT-29 and RKO cells, but had a weak effect on the DLD1 and almost none on the Caco2 cells. Selenous acid and sodium selenite induced growth inhibition of the DLD1, RKO and HT-29 cells, with a marginal effect on the Caco2 cells. The Caco2 cells with mutant p53, failure to activate caspase-8, -9, -7 and -3 and with hypermethylated caspase-8 were resistant to 5-FU. Conversely, RKO cells expressing wildtype p53, proteolytically activated caspase-8, -9, -7 and -3 and unmethylated caspase-8 were more responsive to 5-FU and selenous acid-induced apoptosis.
  
  
  CONCLUSIONS
  Combination treatment with selenous acid may offer an efficacious strategy to overcome 5-FU resistance in certain CRC cells.
authors.affiliation: Division of Cancer Research and Training, Department of Medicine, Charles Drew University of Medicine and Science, Los Angeles, CA 90059, USA.
authors.forename: Aye Aye
authors.initials: AA
authors.lastname: Thant
authors.forename: Yanyuan
authors.initials: Y
authors.lastname: Wu
authors.forename: Jane
authors.initials: J
authors.lastname: Lee
authors.forename: Dhruva Kumar
authors.initials: DK
authors.lastname: Mishra
authors.forename: Heather
authors.initials: H
authors.lastname: Garcia
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
authors.forename: Jaydutt V
authors.initials: JV
authors.lastname: Vadgama
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D018938:Caco-2 Cells; D020169:Caspases / Q000378:metabolism*; D048708:Cell Growth Processes / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology*; D019073:HT29 Cells; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008745:Methylation; D016566:Organoselenium Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D018036:Selenium Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D016566:Organoselenium Compounds; D018036:Selenium Compounds; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D020169:Caspases; D005472:Fluorouracil