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

BMC Cancer

Amadeo M Parissenti¹  David A MacLean⁴  Jason A Sprowl³  Baoqing Guo²  Allan D Heibein⁵ 

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

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

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

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

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

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

Others  :  1080227
DOI  :  10.1186/1471-2407-12-381

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

【 摘 要 】

Background

Since 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.

Methods

To 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.

Results

Of 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.

Conclusions

These 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】

   
2012 Heibein et al.; licensee BioMed Central Ltd.

【 图 表 】

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