Altered expression of cell proliferation-related and interferon-stimulated genes in colon cancer cells resistant to SN38

Irinotecan is a topoisomerase I inhibitor widely used as an anticancer agent in the treatment of metastatic colon cancer. However, its efficacy is often limited by the development of resistance. We have isolated a colon carcinoma cell line, HCT116-SN6, which displays a 6-fold higher resistance to SN38, the active metabolite of irinotecan. In this paper, we studied the molecular mechanisms that cause resistance to SN38 in the HCT116-SN6 cell line. First, we analyzed proliferation, cell cycle distribution, apoptosis, topoisomerase I expression and activity in SN38-resistant (HCT116-SN6) and sensitive (HCT116-s cells). We showed that the SN38-induced apoptosis and the SN38-activated cell cycle checkpoints leading to G2/M cell cycle arrest were similar in both cell lines. Topoisomerase I expression and catalytic activity were also unchanged. Then, we compared mRNA expression profiles in the two cell lines using the Affymetrix Human Genome GeneChip® arrays U133A and B. Microarray analysis showed that among the...