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Induction of 1C aldoketoreductases and other drug dose-dependent genes upon acquisition of anthracycline resistance

Veitch, Zachary W.a c; Guo, Baoqingc; Hembruff, Stacey L.c; Bewick, Adam J.c; Heibein, Allan D.a; Eng, Jameie; Cull, Stephanieb; Maclean, David A.b d; Parissenti, Amadeo M.a c d e

Pharmacogenetics and Genomics: June 2009 - Volume 19 - Issue 6 - p 477-488
doi: 10.1097/FPC.0b013e32832c484b

Objectives Recent studies suggest that tumor cells overexpressing aldoketoreductases (AKRs) exhibit increased resistance to DNA damaging agents such as anthracyclines. AKRs may induce resistance to the anthracycline doxorubicin by catalyzing its conversion to the less toxic 13-hydroxy metabolite doxorubicinol. However, it has not been established whether during selection for anthracycline resistance, AKR overexpression in tumor cells can be correlated with the onset or magnitude of drug resistance and with appreciable conversion of anthracyclines to 13-hydroxy metabolites.

Methods and findings Through microarray and quantitative polymerase chain reaction studies involving rigid selection criteria and both correlative discriminate statistics and time-course models, we have identified several genes whose expression can be correlated with the onset and/or magnitude of anthracycline resistance, including AKR1C2 and AKR1C3. Also associated with the onset or magnitude of anthracycline resistance were genes involved in drug transport (ABCB1, ABCC1), cell signaling and transcription (RDC1, CXCR4), cell proliferation or apoptosis (BMP7, CAV1), protection from reactive oxygen species (AKR1C2, AKR1C3, FTL, FTH, TXNRD1, MT2A), and structural or immune system proteins (IFI30, STMN1). As expected, doxorubicin-resistant and epirubicin-resistant cells exhibited higher levels of doxorubicinol than wild-type cells, although at insufficient levels to account for significant drug resistance. Nevertheless, an inhibitor of Akr1c2 (5β-cholanic acid) almost completely restored sensitivity to doxorubicin in ABCB1-deficient doxorubicin-resistant cells, while having no effect on ABCB1-expressing epirubicin-resistant cells.

Conclusion Taken together, we show for the first time that a variety of genes (particularly redox genes such as AKR1C2 and AKR1C3) can be temporally and causally correlated with the acquisition of anthracycline resistance in breast tumor cells.

aDepartment of Biology

bSchool of Human Kinetics, Laurentian University

cTumor Biology Research Program, Sudbury Regional Hospital

dDivision of Medical Sciences, Northern Ontario School of Medicine, Sudbury

eDepartment of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada

Correspondence to Dr Amadeo M. Parissenti, PhD, Chair in Cancer Research, Regional Cancer Program, Sudbury Regional Hospital, Sudbury, ON P3E 5J1 Canada

Tel: +1 705 522 6237 x2719; fax: +1 705 523 7326;


Received 5 November 2008 Accepted 31 March 2009

© 2009 Lippincott Williams & Wilkins, Inc.