Functional analysis of the gene expression profiles of colorectal cancer cell lines in relation to oxaliplatin and cisplatin cytotoxicity.
The objective was to relate the gene expression profiles of colorectal cancer cells in culture to the in vitro cytotoxicity of cisplatin and oxaliplatin. We studied the gene expression profiles of six human colorectal cancer cell lines, using the Atlas Plastic Human 8K Microarray from Clontech, and related it to the in vitro cytotoxicities of oxaliplatin and cisplatin obtained by inhibition of exponential growth of cells. We calculated the Pearson's coefficients of correlation (r) between gene expression and drug IC50. A functional analysis was performed using the Gene Ontology Consortium database. Results were validated on a series of representative genes by real-time quantitative PCR. Validation of the significance of the coefficients of correlation was also performed using a leave-one-out analysis. We identified 394 genes whose expression was significantly correlated (P<0.05) to oxaliplatin cytotoxicity and 40 with cisplatin cytotoxicity. Three major functions were preferentially involved in oxaliplatin activity: protein synthesis, cell energetics and response to oxidative stress. No significant correlation was observed between oxaliplatin or cisplatin cytotoxicity and the expression of genes involved in DNA repair, cell proliferation or cell adhesion. A strongly significant correlation was found between the microarray and the rt-PCR approaches (r=0.968, P<10(-6)). The leave-one-out analysis showed that the same functions still appeared significantly involved in the activity of both drugs. Based on the functional analysis, we hypothesized that oxaliplatin would specifically form protein adducts during synthesis, thus exposing their thiol groups, which are known to be especially vulnerable to reactive oxygen species.
Meynard
Delphine
D
Laboratoire de Pharmacologie des Agents Anticancéreux, Institut Bergonié, CNRS FRE 2618, Université Victor Segalen Bordeaux 2, 33076 Bordeaux-cedex, France.
Le Morvan
Valérie
V
Bonnet
Jacques
J
Robert
Jacques
J
D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D002945:Cisplatin