Enhanced susceptibility of oral squamous cell carcinoma cell lines to FAS-mediated apoptosis by cisplatin and 5-fluorouracil

Int J Cancer. 2003 Sep 10;106(4):619-25. doi: 10.1002/ijc.11239.


Our study was conducted to investigate whether anticancer drugs, cisplatin (CDDP) and/or 5-fluorouracil (5-FU), can modulate Fas-mediated apoptosis in oral squamous cell carcinoma (OSCC) cell lines. When OSCC cell lines, NA and HSC-4, were treated with CDDP and/or 5-FU, Fas and its mRNA expression on the plasma membrane were enhanced. An increase in caspase-3 and -8 activities was then observed by the addition of agonistic anti-Fas antibody, CH-11. Apoptosis of OSCC cells treated with anticancer drugs were significantly enhanced by CH-11, whereas untreated cells were nearly resistant to apoptosis. Moreover, the combination of CDDP and 5-FU resulted in an increasing susceptibility to apoptosis. Caspase-3 and -8 inhibitors, but not caspase-9 inhibitor, reduced Fas-mediated apoptosis enhanced by the anticancer drugs. Furthermore, OSCC cells treated with anticancer drugs exhibited decreased cellular FADD-like interleukin 1-converting enzyme-inhibitory protein (c-FLIP) levels, whereas neither the Fas-associated death domain-containing protein (FADD) nor procaspase-8 changed the expression. Moreover, antisense oligonucleotide to c-FLIP confirmed that down-regulation of c-FLIP induced sensitization to Fas-mediated apoptosis. These results suggest that CDDP and 5-FU may enhance the susceptibility to Fas-mediated apoptosis through down-regulation of c-FLIP. From these findings, a new potential strategy may be developed to improve the efficacy of anticancer drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Annexin A5 / metabolism
  • Antimetabolites, Antineoplastic / pharmacology*
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Arabidopsis Proteins*
  • Blotting, Western
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology*
  • Carrier Proteins / metabolism
  • Caspase Inhibitors
  • Caspases / metabolism
  • Cisplatin / pharmacology*
  • DNA Primers / chemistry
  • Down-Regulation
  • Enzyme Inhibitors / metabolism
  • Fatty Acid Desaturases / metabolism
  • Flow Cytometry
  • Fluorouracil / pharmacology*
  • Humans
  • Intracellular Signaling Peptides and Proteins*
  • Mouth Neoplasms / metabolism
  • Mouth Neoplasms / pathology*
  • Oligonucleotides, Antisense / pharmacology
  • Polymerase Chain Reaction
  • RNA, Messenger / metabolism
  • RNA, Neoplasm / metabolism
  • Tumor Cells, Cultured / drug effects
  • fas Receptor / metabolism*


  • Annexin A5
  • Antimetabolites, Antineoplastic
  • Antineoplastic Agents
  • Arabidopsis Proteins
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • CFLAR protein, human
  • Carrier Proteins
  • Caspase Inhibitors
  • DNA Primers
  • Enzyme Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • Oligonucleotides, Antisense
  • RNA, Messenger
  • RNA, Neoplasm
  • fas Receptor
  • Fatty Acid Desaturases
  • Fad7 protein, Arabidopsis
  • Caspases
  • Cisplatin
  • Fluorouracil