Potentiation of induction of apoptosis by sequential treatment with cisplatin followed by 5-fluorouracil in human oral cancer cells.
We examined the mechanism involved in the induction of apoptosis in human oral cancer (B88) cells with 5-fluorouracil (5-FU) and cisplatin (CDDP) combination. Three different combination treatment sequences were evaluated: i) 5-FU administered simultaneously with CDDP for 72 h (sequence I); ii) CDDP administered for 24 h before 5-FU treatment for 48 h (sequence II); and iii) 5-FU administered for 24 h before CDDP treatment for 48 h (sequence III). When combining the two drugs at doses 40% of their respective cytotoxicity, the growth-suppressing ratios were 49, 55, and 40% in sequences I, II, and III, respectively. Caspase 3 was significantly activated in sequence II as compared to its level of activation in sequence I or III. The mitochondrial release of cytochrome c was much greater in sequence II than in sequence III. In addition, activation of caspase 8 was most strongly activated in sequence II as compared with sequences I and III. Activation of caspase-9 was also observed in sequence II, and, to a lesser extent, in sequence III. Finally, although Bcl-2 was reduced in sequence II, no significant change was observed in sequence III. Accordingly, the data presented here demonstrate that sequence II showing a significant increase in the induction of apoptosis of cancer cells, is superior to sequences I and III.
Azuma
Masayuki
M
Second Department of Oral and Maxillofacial Surgery, Tokushima University School of Dentistry, Tokushima 770-8504, Japan. azumasa@dent.tokushima-u.ac.jp
Harada
Koji
K
Supriatno
Tamatani
Tetsuya
T
Motegi
Katsumi
K
Ashida
Yuki
Y
Sato
Mitsunobu
M
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology* / Q000556:secondary; D020169:Caspases / Q000378:metabolism; D002945:Cisplatin / Q000008:administration & dosage; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D008928:Mitochondria / Q000187:drug effects; D009062:Mouth Neoplasms / Q000378:metabolism / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D019253:Proto-Oncogene Proteins c-bcl-2; D045304:Cytochromes c; D020169:Caspases; D002945:Cisplatin; D005472:Fluorouracil