cDNA microarray-based identification of genes and pathways associated with oxaliplatin resistance

Abstract

In order to identify genes whose expression is associated with resistance to the chemotherapeutic agent oxaliplatin, transcripts differentially expressed between an oxaliplatin sensitive and a stably resistant subline were compared in six independent replicates using Stanford cDNA microarrays for five cell lines. "Significance analysis of microarrays" (SAM) was used to identify genes whose expression was statistically significantly different in the sensitive versus resistant members of each cell line pair. The biochemical pathways of the Kyoto Encyclopedia of Genes and Genomes (KEGG) database were searched to identify those pathways in which the number of SAM-identified genes exceeded the number expected. This identified four pathways in which upregulated genes were significantly associated with resistance in two of the cell line pairs, and two pathways in which the association was found in three cell line pairs. The search also identified 12 pathways in which downregulated genes were associated with resistance in two cell line pairs and one pathway in which the association reached statistical significance in three cell line pairs. Pathways identified included the ribosome pathway, the Huntington's disease pathway that includes caspase 8, and the ATP synthesis pathways. Determination of the chromosomal location of each SAM-identified gene revealed several locales within which genes lay in close proximity, including three genes (APACD, IF-2, and REV1L) located on chromosome 2 that lie immediately adjacent to each other and were significantly upregulated in three of five cell line pairs. Biochemical pathway and chromosomal mapping of genes identified by SAM as differentially expressed in related cell line pairs points to mechanisms and chromosomal sites not previously suspected of association with the oxaliplatin-resistant phenotype.

Pharmacogenomic approach for the identification of novel determinants of acquired resistance to oxaliplatin in colorectal cancer

“…We used four colorectal cancer cell lines and we were able to induce resistance to oxaliplatin, a drug widely used in the standard treatment of this tumor. The resulting oxaliplatin-resistant cells were not subcloned, similarly to most of the published works based on microarray analysis by using in vitro models (10,13,26). The four colorectal cancer cell lines, which showed genotypic differences such as p53 status and RER phenotype, were analyzed jointly.…”

“…Thereby, our approach allows emphasizing the involvement of selected genes in general mechanisms of oxaliplatin resistance acquisition and avoids processes due to individual characteristics of a particular cell line. It is important to point out that this is one of the few studies on drug resistance that include more than one resistant cell line (26) and all of them are of the same tumor type (13).…”

“…Besides the presence of DNA amplifications at GARP locus (11q13. [5][6][7][8][9][10][11][12][13][14] in breast cancer (49), to our knowledge, the possible involvement of these genes in metabolism or resistance to chemotherapeutic agents has not been described. Actually, the little information existing about these genes set them as new oxaliplatin-related targets of study.…”

“…It is a multifactor process that has been related to decreased drug accumulation, increased detoxification and repair, enhanced tolerance to damage, alteration in pathways involved in cell cycle kinetics, and apoptosis inactivation (3,13). Platinum-resistant cells are characterized by reduced cellular drug accumulation and decreased DNA adducts formation.…”

Cell fusion promotes chemoresistance in metastatic colon carcinoma

“…1,2 Clinical studies have also revealed that expression of these pumps was rarely observed and did not necessarily correlate with the outcome in colon cancer. 3 Therefore, these proteins cannot completely account for the appearance of a MDR phenotype of colon cancer and other mechanisms must be involved in this process. 5-Fluorouracil (5-FU), leucovorin and oxaliplatin (Oxa) represent a therapeutic regime (FOLFOX) commonly used in the treatment of patients with advanced colon cancer.…”