ABSTRACT
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 (5beta-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.
Subject(s)
Antibiotics, Antineoplastic/pharmacology , Doxorubicin/pharmacology , Hydroxysteroid Dehydrogenases/genetics , 3-Hydroxysteroid Dehydrogenases/genetics , Aldo-Keto Reductase Family 1 Member C3 , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Cell Line, Tumor , Drug Resistance, Neoplasm/genetics , Enzyme Inhibitors , Female , Gene Expression Regulation, Neoplastic , Humans , Hydroxyprostaglandin Dehydrogenases/genetics , Hydroxysteroid Dehydrogenases/antagonists & inhibitors , Oligonucleotide Array Sequence AnalysisABSTRACT
Genome profiling approaches such as cDNA microarray analysis and quantitative reverse transcription polymerase chain reaction are playing ever-increasing roles in the classification of human cancers and in the discovery of biomarkers for the prediction of prognosis in cancer patients. Increasing research efforts are also being directed at identifying set of genes whose expression can be correlated with response to specific drugs or drug combinations. Such genes hold the prospect of tailoring chemotherapy regimens to the individual patient, based on tumour or host gene expression profiles. This review outlines recent advances and challenges in using genome profiling for the identification of tumour or host genes whose expression correlates with response to chemotherapy drugs both in vitro and in clinical studies. Genetic predictors of response to a variety of anticancer agents are discussed, including the anthracyclines, taxanes, topoisomerase I and II inhibitors, nucleoside analogs, alkylating agents, and vinca alkaloids.
