Department of Biochemical Sciences, Faculty of Pharmacy, Charles University, Akademika Heyrovskeho 1203, Hradec Kralove, CZ-50005, Czech Republic.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Akademika Heyrovskeho 1203, Hradec Kralove, CZ-50005, Czech Republic.
Chem Biol Interact. 2019 Apr 1;302:101-107. doi: 10.1016/j.cbi.2019.01.026. Epub 2019 Jan 28.
Buparlisib is a pan-class I phosphoinositide 3-kinase (PI3K) inhibitor and is currently under clinical evaluation for the treatment of different cancers. Because PI3K signalling is related to cell proliferation and resistance to chemotherapy, new therapeutic approaches are focused on combining PI3K inhibitors with other anti-cancer therapeutics. Carbonyl-reducing enzymes catalyse metabolic detoxification of anthracyclines and reduce their cytotoxicity. In the present work, the effects of buparlisib were tested on six human recombinant carbonyl-reducing enzymes: AKR1A1, AKR1B1, AKR1B10, AKR1C3, and AKR7A2 from the aldo-keto reductase superfamily and CBR1 from the short-chain dehydrogenase/reductase superfamily, all of which participate in the metabolism of daunorubicin. Buparlisib exhibited the strongest inhibitory effect on recombinant AKR1C3, with a half-maximal inhibitory concentration (IC) of 9.5 μM. Its inhibition constant K was found to be 14.0 μM, and the inhibition data best fitted a mixed-type mode with α = 0.6. The same extent of inhibition was observed at the cellular level in the human colorectal carcinoma HCT 116 cell line transfected with a plasmid encoding the AKR1C3 transcript (IC = 7.9 μM). Furthermore, we performed an analysis of flexible docking between buparlisib and AKR1C3 and found that buparlisib probably occupies a part of the binding site for a cofactor most likely via the trifluoromethyl group of buparlisib interacting with catalytic residue Tyr55. In conclusion, our results show a novel PI3K-independent effect of buparlisib that may improve therapeutic efficacy and safety of daunorubicin by preventing its metabolism by AKR1C3.
布帕利西布是一种全 I 类磷酸肌醇 3-激酶（PI3K）抑制剂，目前正在临床评估用于治疗不同类型的癌症。由于 PI3K 信号与细胞增殖和化疗耐药性有关，新的治疗方法侧重于将 PI3K 抑制剂与其他抗癌治疗药物联合使用。羰基还原酶催化蒽环类药物的代谢解毒，降低其细胞毒性。在本工作中，研究人员测试了布帕利西布对 6 个人重组羰基还原酶的影响：醛酮还原酶超家族的 AKR1A1、AKR1B1、AKR1B10、AKR1C3 和 AKR7A2，以及短链脱氢酶/还原酶超家族的 CBR1，它们均参与柔红霉素的代谢。布帕利西布对重组 AKR1C3 的抑制作用最强，半抑制浓度（IC）为 9.5μM。其抑制常数 K 为 14.0μM，抑制数据最好拟合混合模式，α为 0.6。在转染编码 AKR1C3 转录本的质粒的人结直肠癌细胞系 HCT 116 中，在细胞水平上观察到相同程度的抑制（IC=7.9μM）。此外，我们对布帕利西布与 AKR1C3 之间的柔性对接进行了分析，发现布帕利西布可能通过其三氟甲基与催化残基 Tyr55 相互作用，占据结合部位的一部分，该结合部位可能与辅因子结合。总之，我们的研究结果表明，布帕利西布具有一种新型的 PI3K 非依赖性作用，通过防止 AKR1C3 代谢柔红霉素，可能提高柔红霉素的治疗效果和安全性。
