Role of aldo-keto reductases and other doxorubicin pharmacokinetic genes in doxorubicin resistance, DNA binding, and subcellular localization

BMC Cancer

Research Article

Allan D Heibein¹  David A MacLean²  Amadeo M Parissenti³  Jason A Sprowl⁴  Baoqing Guo⁵ 

[1]Graduate Program in Biology, Laurentian University, Sudbury, ON, Canada

[2]Graduate Program in Biology, Laurentian University, Sudbury, ON, Canada

[3]Division of Medical Sciences, Northern Ontario School of Medicine, Sudbury, ON, Canada

[4]Graduate Program in Biology, Laurentian University, Sudbury, ON, Canada

[5]Regional Cancer Program, Sudbury Regional Hospital, P3E 5J1, Sudbury, ON, Canada

[6]Graduate Program in Biomolecular Science, Laurentian University, Sudbury, ON, Canada

[7]Division of Medical Sciences, Northern Ontario School of Medicine, Sudbury, ON, Canada

[8]Divison Of Oncology, Faculty of Medicine, University of Ottawa, Ottawa, Canada

[9]Graduate Program in Biomolecular Science, Laurentian University, Sudbury, ON, Canada

[10]Regional Cancer Program, Sudbury Regional Hospital, P3E 5J1, Sudbury, ON, Canada

关键词: Doxorubicin;    Resistance;    Gene profiling;    PharmGKB;    Pharmacokinetics;    Aldo-keto reductases;    Cytotoxicity;    Lysosome;    DNA-binding;    Drug localization;   

DOI  :  10.1186/1471-2407-12-381

 received in 2012-01-19, accepted in 2012-08-17,  发布年份 2012

来源: Springer

【 摘 要 】

BackgroundSince proteins involved in chemotherapy drug pharmacokinetics and pharmacodynamics have a strong impact on the uptake, metabolism, and efflux of such drugs, they likely play critical roles in resistance to chemotherapy drugs in cancer patients.MethodsTo investigate this hypothesis, we conducted a whole genome microarray study to identify difference in the expression of genes between isogenic doxorubicin-sensitive and doxorubicin-resistant MCF-7 breast tumour cells. We then assessed the degree of over-representation of doxorubicin pharmacokinetic and pharmacodynamic genes in the dataset of doxorubicin resistance genes.ResultsOf 27,958 Entrez genes on the array, 7.4 per cent or 2,063 genes were differentially expressed by ≥ 2-fold between wildtype and doxorubicin-resistant cells. The false discovery rate was set at 0.01 and the minimum p value for significance for any gene within the “hit list” was 0.01. Seventeen and 43 per cent of doxorubicin pharmacokinetic genes were over-represented in the hit list, depending upon whether the gene name was identical or within the same gene family, respectively. The most over-represented genes were within the 1C and 1B families of aldo-keto reductases (AKRs), which convert doxorubicin to doxorubicinol. Other genes convert doxorubicin to other metabolites or affect the influx, efflux, or cytotoxicity of the drug. In further support of the role of AKRs in doxorubicin resistance, we observed that, in comparison to doxorubicin, doxorubincol exhibited dramatically reduced cytotoxicity, reduced DNA-binding activity, and strong localization to extra nuclear lysosomes. Pharmacologic inhibition of the above AKRs in doxorubicin-resistant cells increased cellular doxorubicin levels, restored doxorubicin cytotoxicity and re-established doxorubicin localization to the nucleus. The properties of doxorubicinol were unaffected.ConclusionsThese findings demonstrate the utility of using curated pharmacokinetic and pharmacodynamic knowledge bases to identify highly relevant genes associated with doxorubicin resistance. The induction of one or more of these genes was found to be correlated with changes in the drug’s properties, while inhibiting one specific class of these genes (the AKRs) increased cellular doxorubicin content and restored drug DNA binding, cytotoxicity, and subcellular localization.

【 授权许可】

Unknown   
© Heibein et al.; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.