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首页> 外文期刊>Biochemical Pharmacology >Roscovitine and purvalanol A effectively reverse anthracycline resistance mediated by the activity of aldo-keto reductase 1C3 (AKR1C3): A promising therapeutic target for cancer treatment
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Roscovitine and purvalanol A effectively reverse anthracycline resistance mediated by the activity of aldo-keto reductase 1C3 (AKR1C3): A promising therapeutic target for cancer treatment

机译：Roscovitine和Purvalanol A有效地逆转蒽环旋转型抗性由Aldo-Keto还原酶1C3（AKR1C3）的活性介导：癌症治疗的有希望的治疗靶标

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摘要

Members of the short-chain dehydrogenase/reductase (SDR) and aldo-keto reductase (AKR) superfamilies mediate the reduction of anthracyclines to their less potent C-13 alcohol metabolites. This reductive metabolism has been recognized as one of the most important factors that trigger anthracycline resistance in cancer cells. In our study, two purine analogues, purvalanol A and roscovitine, were identified as effective inhibitors of aldo-keto reductase 1C3 (AKR1C3), an enzyme that is overexpressed in many cancer types and is also a key player in tumour cell resistance to anthracyclines. Purvalanol A and roscovitine potently inhibited human recombinant AKR1C3 (Ki?=?5.5?μM and 1.4?μM, respectively) and displayed similar activity in experiments with intact cells. Ligand-protein docking calculations suggested that both inhibitors occupied a part of the cofactor-binding site. Furthermore, we demonstrated that the combination of daunorubicin with purvalanol A or roscovitine exhibited a synergistic effect in AKR1C3 overexpressing cells. Based on these findings, it is possible to presume that purvalanol A and roscovitine may have the potential to enhance the therapeutic effectiveness and safety of anthracyclines via inhibition of AKR1C3.
机译：短链脱氢酶/还原酶（SDR）和Aldo-keto还原酶（AKR）Superfamilies的成员介导蒽环酰胺的减少到它们较小的C-13醇代谢物。这种还原新陈代谢被认为是引发癌细胞中蒽环素抗性的最重要因素之一。在我们的研究中，将两种嘌呤类似物，purvalanol A和Roscovitine鉴定为Aldo-keto还原酶1c3（akr1c3）的有效抑制剂，在许多癌症类型中过表达的酶，也是肿瘤细胞抗性的关键球员。 Purvalanol A和Roscovitine Potly抑制人重组AkR1C3（分别分别在具有完整细胞的实验中显示出类似的活性。配体 - 蛋白对接计算表明，两种抑制剂都占据了辅因子结合位点的一部分。此外，我们证明了具有purvalanol A或Roscovitine的Daunorubicin的组合在AKR1C3过表达细胞中表现出协同作用。基于这些发现，可以假设purvalanol a和roscovitine可能具有通过抑制Akr1c3来增强蒽环类的治疗效果和安全性。

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