Analysis of ATP-Binding Cassette Transporter Expression in Drug-Selected Cell Lines by a Microarray Dedicated to Multidrug Resistance
Discovery of the multidrug resistance protein 1 (MDR1), an ATP-binding cassette (ABC) transporter able to transport many anticancer drugs, was a clinically relevant breakthrough in multidrug resistance research. Although the overexpression of ABC transporters such as P-glycoprotein/ABCB1, MRP1/ABCC1...
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Published in | Molecular pharmacology Vol. 66; no. 6; pp. 1397 - 1405 |
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Main Authors | , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Pharmacology and Experimental Therapeutics
01.12.2004
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Subjects | |
Online Access | Get full text |
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Summary: | Discovery of the multidrug resistance protein 1 (MDR1), an ATP-binding cassette (ABC) transporter able to transport many anticancer
drugs, was a clinically relevant breakthrough in multidrug resistance research. Although the overexpression of ABC transporters
such as P-glycoprotein/ABCB1, MRP1/ABCC1, and MXR/ABCG2 seems to be a major cause of failure in the treatment of cancer, acquired
resistance to multiple anticancer drugs may also be multifactorial, involving alteration of detoxification processes, apoptosis,
DNA repair, drug uptake, and overexpression of other ABC transporters. As a tool for the study of such phenomena, we designed
and created a microarray platform, the ABC-ToxChip, to evaluate relative levels of transcriptional activation among genes
involved in the various mechanisms of resistance. In the ABC-ToxChip, a comprehensive set of genes important in toxicological
responses (represented by 2200 cDNA probes) is complemented with probes specifically matching ABC transporters as well as
oligonucleotides representing 18,000 unique human genes. By comparing the transcriptional profiles of KB-3-1 and DU-145 parental
cells with resistant derivatives selected in colchicine (KB-8-5), and 9-nitro-camptothecin (RCO.1), respectively, we demonstrate
that ABC transporters (ABCB1/MDR1 and ABCC2/MRP2, respectively) show dramatic overexpression, whereas the glutathione S -transferase gene GST-Pi shows the strongest decrease in expression among the 20,000 genes studied. The results were confirmed
by quantitative reverse transcription-polymerase chain reaction and immunohistochemistry. The custom-designed ABC-Tox microarray
presented here will be helpful to elucidate mechanisms leading to anticancer drug resistance. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 |
ISSN: | 0026-895X 1521-0111 |
DOI: | 10.1124/mol.104.005009 |