Abstract
BackgroundThe role of telomerase activation in the expression and/or maintenance of drug resistance is not clearly understood. Therefore, we investigated the relationships, among the telomerase activity, telomere length and the expression of multidrug resistance genes in colorectal cancer cell lines cultivated with anti-cancer drugs.MethodsLoVo and DLD-1 cells were continuously grown in the presence of both CDDP and 5-FU for up to 100 days. Cell proliferation, telomerase activity, telomere length and the expression of multidrug resistance genes were serially monitored as the PDL increased.ResultsThe expression of multidrug resistance genes tended to increase as the PDL increased. However, an abnormal aneuploid clone was not detected as far as the cells were monitored by a DNA histogram analysis. Tumor cells showing resistance to anti-cancer drugs revealed a higher cell proliferation rate. The telomere length gradually increased with a progressive PDL. The telomerase activity reached a maximum level at 15 PDL in LoVo cells and at 27 PDL in DLD-1 cells. An increase in the mRNA expression of the telomerase components, especially in hTERT and in hTR, was observed at the same PDLs.ConclusionsThese results suggest that a high telomerase activity and an elongation of telomeres both appear to help maintain and/or increase drug resistance in colorectal cancer cells. Cancer cells with long telomeres and a high proliferative activity may thus be able to better survive exposure to anti-cancer drugs. This is presumably due to an increased chromosome stability and a strong expression of both mdr-1 and MRP genes.
Highlights
The role of telomerase activation in the expression and/or maintenance of drug resistance is not clearly understood
We investigated the long-term effects of CDDP and 5-FU, both of which are often used as anticancer drugs in the actual clinical treatment of the colorectal cancers, on two colorectal adenocarcinoma cell lines, LoVo and DLD-1
Cell proliferative activity was evaluated based on the relationship between the number of cultivated days and the population doubling level (PDL) (Fig. 1)
Summary
The role of telomerase activation in the expression and/or maintenance of drug resistance is not clearly understood. We investigated the relationships, among the telomerase activity, telomere length and the expression of multidrug resistance genes in colorectal cancer cell lines cultivated with anti-cancer drugs. Once tumor cells acquire telomerase activity, the telomere length has been shown to be maintained [8,9,10,11]. In such cases, abnormal chromosomes are considered to be stably passaged to the daughter carcinoma cells. There have been numerous papers focusing on the role of telomerase activation in the progression of cancer cells, but the relationship between telomerase activation and drug resistance has not yet been clearly explained
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