Although novel anticancer drugs are being developed intensively, anthracyclines remain the gold standard in the treatment of acute myeloid leukaemia (AML). The reductive conversion of daunorubicin (Dau) to less active daunorubicinol (Dau-ol) is an important mechanism that contributes to the development of pharmacokinetic anthracycline resistance. Dau is a key component in many AML regimes, in which it is combined with many drugs, including all-trans-retinoic acid (ATRA), cytarabine, cladribine and prednisolone. In the present study, we investigated the influence of these anticancer drugs on the reductive Dau metabolism mediated by the aldo–keto reductases AKR1A1, 1B10, 1C3, and 7A2 and carbonyl reductase 1 (CBR1). In incubation experiments with recombinant enzymes, cladribine and cytarabine did not significantly inhibit the activity of the tested enzymes. Prednisolone inhibited AKR1C3 with an IC₅₀ of 41.73 µM, while ATRA decreased the activity of AKR1B10 (IC₅₀ = 78.33 µM) and AKR1C3 (IC₅₀ = 1.17 µM). Subsequent studies showed that AKR1C3 inhibition mediated by ATRA exhibited tight binding (Ki^app = 0.54 µM). Further, the combination of 1 µM ATRA with different concentrations of Dau demonstrated synergistic effects in HCT116 and KG1a human cells expressing AKR1C3. Our results suggest that ATRA-mediated inhibition of AKR1C3 can contribute to the mechanisms that are hidden beyond the beneficial clinical outcome of the ATRA–Dau combination.

尽管正在大力开发新型抗癌药物，但蒽环类药物仍是治疗急性髓细胞性白血病（AML）的金标准。柔红霉素（Dau）向活性较低的柔红霉素（Dau-ol）的还原性转化是促进药代动力学蒽环类药物耐药性发展的重要机制。Dau是许多AML方案中的关键组成部分，其中Dau与多种药物（包括全反式）结合使用-视黄酸（ATRA），阿糖胞苷，克拉屈滨和泼尼松龙。在本研究中，我们研究了这些抗癌药物对由醛-酮还原酶AKR1A1、1B10、1C3和7A2和羰基还原酶1（CBR1）介导的还原Dau代谢的影响。在用重组酶进行的温育实验中，克拉屈滨和阿糖胞苷并未显着抑制所测试酶的活性。泼尼松龙抑制AKR1C3，IC ₅₀为41.73 µM，而ATRA降低AKR1B10（IC ₅₀  = 78.33 µM）和AKR1C3（IC ₅₀  = 1.17 µM）的活性。随后的研究表明，由ATRA介导的AKR1C3抑制表现出紧密结合（Ki ^app = 0.54 µM）。此外，将1 µM ATRA与不同浓度的Dau混合使用可在表达AKR1C3的HCT116和KG1a人类细胞中发挥协同作用。我们的结果表明，ATRA介导的AKR1C3抑制作用可能是隐藏在ATRA-Dau组合的有益临床结果之外的机制。