Novotna Romana, Wsol Vladimir, Xiong Guangming, Maser Edmund
Department of Biochemical Sciences, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, CZ-50005 Hradec Kralove, Czech Republic.
Toxicol Lett. 2008 Sep;181(1):1-6. doi: 10.1016/j.toxlet.2008.06.858. Epub 2008 Jun 21.
Resistance towards anticancer drugs is a general problem upon chemotherapy. Among the mechanisms of resistance, metabolic inactivation by carbonyl reduction is a major cause of chemotherapy failure that applies to drugs bearing a carbonyl moiety. Oracin is a promising anticancer drug which is presently in phase II clinical trials. Pharmacokinetic studies have revealed that oracin undergoes metabolic inactivation by carbonyl reduction. In the present study, we provide evidence that AKR1C3, a member of the aldo-keto reductase (AKR) superfamily, catalyzes the inactivation of oracin. Moreover, AKR1C3 does also mediate C13 carbonyl reduction of doxorubicin to its inactive hydroxy metabolite doxorubicinol. Doxorubicinol, however, has also been considered responsible for the cardiomyopathy observed upon doxorubicin chemotherapy. Since AKR1C3 is overexpressed in hormone-dependent malignancies like prostate and breast cancer, coadministration of AKR1C3 inhibitors might enhance the chemotherapeutic efficacy of oracin and doxorubicin, and simultaneously reduce the risk of cardiomyopathy upon doxorubicin treatment.
对抗癌药物产生耐药性是化疗过程中普遍存在的问题。在耐药机制中，羰基还原导致的代谢失活是化疗失败的主要原因之一，适用于带有羰基部分的药物。奥拉辛是一种很有前景的抗癌药物，目前正处于II期临床试验阶段。药代动力学研究表明，奥拉辛会通过羰基还原发生代谢失活。在本研究中，我们提供证据表明，醛酮还原酶（AKR）超家族成员AKR1C3催化奥拉辛的失活。此外，AKR1C3也介导阿霉素的C13羰基还原为其无活性的羟基代谢物阿霉素醇。然而，阿霉素醇也被认为是阿霉素化疗时观察到的心肌病的病因。由于AKR1C3在前列腺癌和乳腺癌等激素依赖性恶性肿瘤中过度表达，联合使用AKR1C3抑制剂可能会提高奥拉辛和阿霉素的化疗效果，同时降低阿霉素治疗时发生心肌病的风险。
