The determinants of sensitivity and acquired resistance to gemcitabine differ in non–small cell lung cancer: a role of ABCC5 in gemcitabine sensitivity
We examined the expression levels of the multidrug resistance protein 5 ( ABCC5 ) gene in non–small cell lung cancer (NSCLC) cell lines to clarify the relationship with the sensitivity to gemcitabine. The expression levels of ABCC5 were inversely correlated with gemcitabine sensitivity significantly...
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Published in | Molecular cancer therapeutics Vol. 5; no. 7; pp. 1800 - 1806 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Association for Cancer Research
01.07.2006
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Subjects | |
Online Access | Get full text |
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Summary: | We examined the expression levels of the multidrug resistance protein 5 ( ABCC5 ) gene in non–small cell lung cancer (NSCLC) cell lines to clarify the relationship with the sensitivity to gemcitabine. The
expression levels of ABCC5 were inversely correlated with gemcitabine sensitivity significantly ( r = 0.628; P < 0.01) in 17 NSCLC cells, whereas the expression of ABCC5 in the gemcitabine-resistant NSCLC cell line H23/GEM-R was the same as that in parental NCI-H23 cells. Treatment with the
ABCC5 inhibitor zaprinast altered the sensitivity to gemcitabine in ABCC5-expressing NSCLC cells. In addition, decreasing
the expression of ABCC5 by small interfering RNA altered the cytotoxicity to gemcitabine. These results indicate that modulation of ABCC5 activity
could be used to increase the gemcitabine sensitivity in NSCLC. Previously, we found a decreased expression of deoxycytidine
kinase in H23/GEM-R cells, and further investigation in this study showed an increased expression of ribonucleotide reductase
subunit 1 in H23/GEM-R cells. We therefore also examined the effect of modifying the expression of both genes on gemcitabine
resistance. We found that using small interfering RNA to decrease the expression of ribonucleotide reductase subunit 1 resulted in a decreased resistance to gemcitabine in H23/GEM-R cells. Furthermore, pretreatment with pemetrexed resulted
in an increased deoxycytidine kinase expression concomitant with the alteration of the resistance to gemcitabine in H23/GEM-R cells. The determinants for sensitivity
and the acquired resistance in gemcitabine are quite different; nonetheless, modification of these factors may increase the
efficacy of gemcitabine in the treatment of NSCLC. [Mol Cancer Ther 2006;5(7):1800–6] |
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ISSN: | 1535-7163 1538-8514 |
DOI: | 10.1158/1535-7163.MCT-06-0025 |