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| Status |
Public on Nov 22, 2012 |
| Title |
Role of Aldoketoreductases and Other Doxorubicin Pharmacokinetic Genes in Doxorubicin Resistance, DNA binding, and Subcellular Localization |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Objective: To assess the role of aldoketoreductases and other doxorubicin pharmacokinetic or pharmacogenomic genes in doxorubicin cytotoxicity, resistance, DNA binding activity, and subcellular localization, Methods: We conducted a whole genome microarray study to identify differences in between doxorubicin-sensitive MCF-7cc cells and doxorubicin-resistant MCF-7Dox2-12 cells in terms of their expression of genes related to doxorubicin pharmacokinetics or pharmacodynamics. Targets were then validated by pharmacologic inhibition in conjunction with drug metabolite profiling, drug localization, drug cytotoxicity, and drug DNA binding studies. Results: 2063 differentially expressed transcripts were identified, including 17% and 43% of genes or gene families associated with doxorubicin pharmacokinetics or pharmacodynamics (p values of significance of 0.05 and <0.0001, respectively). The largest changes in the expression of genes associated with doxorubicin pharmacokinetics and pharmacodynamics were chiefly among the aldo-keto reductases (AKRs) Akr1c2, Akr1c3 and Akr1b10 which convert doxorubicin to doxorubicinol. We observed that doxorubicinol exhibits dramatically reduced drug toxicity, reduced drug DNA-binding activity, and altered drug subcellular localization to lysosomes. Pharmacologic inhibition of these AKRs in MCF-7Dox2-12 cells restored drug cytotoxicity, and drug localization to the nucleus. Conclusion: These findings demonstrate the utility of using curated pharmacokinetic and pharmacodynamic knowledgebases to identify highly relevant genes associated with doxorubicin resistance. The products of one or more of these genes could effectively be shown to alter the drug’s properties, while inhibiting them restored drug DNA binding, cytotoxicity, and subcellular localization.
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| Overall design |
Doxorubicin resistant cell lines of breast MCF-7 cells were generated for gene expression profilling. Two colour microarray of Agilent whole human genome nucleotide arrays was conducted with four labelling replicates of both forward and reverse labellings plus another set of 8 arrays with forward labelling. Sixteen arrays were used for this experiments. The co-cultured control cells MCF-7cc12 was generated by parallel selection process in the absence of drug.
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| Contributor(s) |
Heibein AD, Guo B, Sprowl JA, MacLean DA, Parissenti AM |
| Citation(s) |
22938713 |
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| Submission date |
Feb 11, 2011 |
| Last update date |
Feb 22, 2018 |
| Contact name |
Baoqing Guo |
| E-mail(s) |
bguo@amric.ca
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| Phone |
705 522 6237
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| Organization name |
Advanced Medical Research Institute of Canada
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| Department |
Tumor Biology
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| Street address |
41 Ramsey Lake Road
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| City |
Sudbury |
| State/province |
ON |
| ZIP/Postal code |
P3E 5J1 |
| Country |
Canada |
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| Platforms (1) |
| GPL4133 |
Agilent-014850 Whole Human Genome Microarray 4x44K G4112F (Feature Number version) |
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| Samples (16)
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| GSM673809 |
MCF-7Dox2-12 vs MCF-7cc12 forward labeling set 1 replicate 1 |
| GSM673810 |
MCF-7Dox2-12 vs MCF-7cc12 forward labeling set 1 replicate 2 |
| GSM673811 |
MCF-7Dox2-12 vs MCF-7cc12 forward labeling set 1 replicate 3 |
| GSM673812 |
MCF-7Dox2-12 vs MCF-7cc12 forward labeling set 1 replicate 4 |
| GSM673813 |
MCF-7Dox2-12 vs MCF-7cc12 forward labeling set 1 replicate 5 |
| GSM673814 |
MCF-7Dox2-12 vs MCF-7cc12 forward labeling set 1 replicate 6 |
| GSM673815 |
MCF-7Dox2-12 vs MCF-7cc12 forward labeling set 1 replicate 7 |
| GSM673816 |
MCF-7Dox2-12 vs MCF-7cc12 forward labeling set 1 replicate 8 |
| GSM673817 |
MCF-7Dox2-12 vs MCF-7cc12 forward labeling set 2 replicate 1 |
| GSM673818 |
MCF-7Dox2-12 vs MCF-7cc12 forward labeling set 2 replicate 2 |
| GSM673819 |
MCF-7Dox2-12 vs MCF-7cc12 reverse labeling set 2 replicate 3 |
| GSM673820 |
MCF-7Dox2-12 vs MCF-7cc12 reverse labeling set 2 replicate 4 |
| GSM673821 |
MCF-7Dox2-12 vs MCF-7cc12 forward labeling set 3 replicate 1 |
| GSM673822 |
MCF-7Dox2-12 vs MCF-7cc12 forward labeling set 3 replicate 2 |
| GSM673823 |
MCF-7Dox2-12 vs MCF-7cc12 reverse labeling set 3 replicate 3 |
| GSM673824 |
MCF-7Dox2-12 vs MCF-7cc12 reverse labeling set 3 replicate 4 |
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| Relations |
| BioProject |
PRJNA137203 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE27254_MCF-7Dox2-12_vs_MCF-7cc_4-way_ANOVA_analysis.txt.gz |
1.9 Mb |
(ftp)(http) |
TXT |
| GSE27254_RAW.tar |
250.7 Mb |
(http)(custom) |
TAR (of TXT) |
| Processed data included within Sample table |
| Processed data are available on Series record |
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