Repression of cell cycle-related proteins by oxaliplatin but not cisplatin in human colon cancer cells.
Oxaliplatin (Eloxatin) is a third-generation platinum derivative with an in vitro and in vivo spectrum of activity distinct from that of cisplatin, especially in colon cancer cells. Here, we studied the molecular basis of this difference on the HCT-116 human colon carcinoma cell line (mismatch repair-deficient, wild-type functional p53). Oxaliplatin inhibited HCT-116 cell proliferation with greater efficacy than cisplatin. At comparable concentrations, cisplatin slowed down the replication phase and activated the G2-M checkpoint, whereas oxaliplatin activated the G1-S checkpoint and completely blocked the G2-M transition. With the aim of finding oxaliplatin-specific target genes and mechanisms differing from those of cisplatin, we established the transcriptional signatures of both products on HCT-116 cells using microarray technology. Based on hierarchical clustering, we found that (a) many more genes were modulated by oxaliplatin compared with cisplatin and (b) among the 117 modulated genes, 79 were regulated similarly by both drugs and, in sharp contrast, 38 genes were dose dependently down-regulated by oxaliplatin and, conversely, up-regulated or unaffected by cisplatin. Interestingly, several cell cycle-related genes encoding proteins involved in DNA replication and G2-M progression belong to this latter group. RNA modulations, confirmed at the protein level, were in accordance with oxaliplatin- and cisplatin-induced cell cycle variations. Beyond the identification of genes affected by both drugs, the identified oxaliplatin-specific target genes could be useful as predictive markers for evaluating and comparing the efficacy and molecular pharmacology of platinum drugs.
Voland
Carole
C
Oncology Department, Sanofi-Synthelabo Recherche, F-34184 Montpellier Cedex 04, France.
Bord
Annie
A
Péleraux
Annick
A
Pénarier
Géraldine
G
Carrière
Dominique
D
Galiègue
Sylvaine
S
Cvitkovic
Esteban
E
Jbilo
Omar
O
Casellas
Pierre
P
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D045325:HCT116 Cells; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D014158:Transcription, Genetic / Q000187:drug effects
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D002945:Cisplatin