Acosta Javier, Pérez Elena, Sánchez-Murcia Pedro A, Fillat Cristina, Fernández-Lucas Jesús
Applied Biotechnology Group, European University of Madrid, c/ Tajo s/n, Villaviciosa de Odón, 28670 Madrid, Spain.
Division of Physiological Chemistry, Otto-Loewi Research Center, Medical University of Graz, Neue Stiftingtalstraße 6/III, A-8010 Graz, Austria.
Biomolecules. 2021 Jan 18;11(1):120. doi: 10.3390/biom11010120.
Herein we report the first proof for the application of type II 2'-deoxyribosyltransferase from (NDT) in suicide gene therapy for cancer treatment. To this end, we first confirm the hydrolytic ability of NDT over the nucleoside-based prodrugs 2'-deoxy-5-fluorouridine (dFUrd), 2'-deoxy-2-fluoroadenosine (dFAdo), and 2'-deoxy-6-methylpurine riboside (d6MetPRib). Such activity was significantly increased (up to 30-fold) in the presence of an acceptor nucleobase. To shed light on the strong nucleobase dependence for enzymatic activity, different molecular dynamics simulations were carried out. Finally, as a proof of concept, we tested the NDT/dFAdo system in human cervical cancer (HeLa) cells. Interestingly, NDT/dFAdo showed a pronounced reduction in cellular viability with inhibitory concentrations in the low micromolar range. These results open up future opportunities for the clinical implementation of nucleoside 2'-deoxyribosyltransferases (NDTs) in cancer treatment.
在此，我们报告了来自[具体来源未提及]的II型2'-脱氧核糖基转移酶（NDT）在癌症治疗的自杀基因疗法中的首次应用证据。为此，我们首先证实了NDT对基于核苷的前药2'-脱氧-5-氟尿苷（dFUrd）、2'-脱氧-2-氟腺苷（dFAdo）和2'-脱氧-6-甲基嘌呤核糖苷（d6MetPRib）的水解能力。在存在受体核碱基的情况下，这种活性显著增加（高达30倍）。为了阐明酶活性对核碱基的强烈依赖性，我们进行了不同的分子动力学模拟。最后，作为概念验证，我们在人宫颈癌（HeLa）细胞中测试了NDT/dFAdo系统。有趣的是，NDT/dFAdo在低微摩尔范围内的抑制浓度下显示出细胞活力的显著降低。这些结果为核苷2'-脱氧核糖基转移酶（NDTs）在癌症治疗中的临床应用开辟了未来的机会。
