Veitch Zachary W, Guo Baoqing, Hembruff Stacey L, Bewick Adam J, Heibein Allan D, Eng Jamei, Cull Stephanie, Maclean David A, Parissenti Amadeo M
Department of Biology, Laurentian University, Northern Ontario School of Medicine, Sudbury, Canada.
Pharmacogenet Genomics. 2009 Jun;19(6):477-88. doi: 10.1097/FPC.0b013e32832c484b.
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.
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.
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.
最近的研究表明，过表达醛酮还原酶（AKRs）的肿瘤细胞对阿霉素等DNA损伤剂表现出更高的抗性。AKRs可能通过催化阿霉素转化为毒性较低的13-羟基代谢产物阿霉素醇，从而诱导对阿霉素的抗性。然而，在选择阿霉素抗性的过程中，肿瘤细胞中AKR的过表达是否与耐药性的发生或程度以及阿霉素向13-羟基代谢产物的显著转化相关，尚未得到证实。
通过微阵列和定量聚合酶链反应研究，涉及严格的选择标准以及相关判别统计和时间进程模型，我们鉴定出了几个基因，其表达与阿霉素抗性的发生和/或程度相关，包括AKR1C2和AKR1C3。与阿霉素抗性的发生或程度相关的还有参与药物转运的基因（ABCB1、ABCC1）、细胞信号传导和转录（RDC1、CXCR4）、细胞增殖或凋亡（BMP7、CAV1）、抗氧化应激的基因（AKR1C2、AKR1C3、FTL、FTH、TXNRD1、MT2A）以及结构或免疫系统蛋白（IFI30、STMN1）。正如预期的那样，耐阿霉素和耐表柔比星的细胞比野生型细胞表现出更高水平的阿霉素醇，尽管其水平不足以解释显著的耐药性。然而，Akr1c2的抑制剂（5β-胆酸）几乎完全恢复了ABCB1缺陷的耐阿霉素细胞对阿霉素的敏感性，而对表达ABCB1的耐表柔比星细胞没有影响。
综上所述，我们首次表明，多种基因（特别是氧化还原基因，如AKR1C2和AKR1C3）在时间和因果关系上与乳腺肿瘤细胞获得阿霉素抗性相关。
