Abstract
To facilitate a systematic study of chemoresistance across diverse classes of anticancer drug candidates, we performed correlation analyses between cytotoxic drug potency and gene expression in 60 tumor cell lines (NCI-60; NCI—National Cancer Institute). Ellipticine analogs displayed a range of correlation coefficients (r) with MDR1 (ABCB1, encoding multidrug resistance (MDR) protein MDR1 or P-glycoprotein). To determine MDR1 interactions of five ellipticines with diverse MDR1-r values, we employed MDR1-transport and cytotoxicity assays, using MDR1 inhibitors and siRNA-mediated MDR1 downregulation, in MDR1-overexpressing cells. Ellipticines with negative correlations—indicative of MDR1-mediated resistance—were shown to be MDR1 substrates, whereas those with neutral or positive correlations served as MDR1 inhibitors, which escape MDR1-mediated chemoresistance. Correlation with additional genes in the NCI-60 confirmed topoisomerases as ellipticine targets, but suggested distinct mechanisms of action and chemoresistance among them, providing a guide for selecting optimal drug candidates.
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Abbreviations
- NCI:
-
the National Cancer Institute
- 5-FU:
-
5-fluorouracil
- Pgp:
-
P-glycoprotein
- MDR:
-
multidrug resistance
- ABC:
-
ATP-binding cassette
- siRNA:
-
small interfering RNA
- RNAi:
-
RNA interference
- SRB:
-
sulforhodamine B
- CsA:
-
Cyclosporin A
- R-123:
-
rhodamine-123
- DNR:
-
daunorubicin
- PCA:
-
principal component analysis
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Acknowledgements
This study was supported by NIH grant GM61390 and by funds from the Ohio State University.
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Supplementary Information accompanies the paper on The Pharmacogenomics Journal website (http://www.nature.com/tpj).
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Huang, Y., Blower, P., Yang, C. et al. Correlating gene expression with chemical scaffolds of cytotoxic agents: ellipticines as substrates and inhibitors of MDR1. Pharmacogenomics J 5, 112–125 (2005). https://doi.org/10.1038/sj.tpj.6500297
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DOI: https://doi.org/10.1038/sj.tpj.6500297
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