当前位置: X-MOL 学术J. Membr. Biol. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Implications of Synthetic Modifications of the Cardiotonic Steroid Lactone Ring on Cytotoxicity
The Journal of Membrane Biology ( IF 2.4 ) Pub Date : 2021-06-14 , DOI: 10.1007/s00232-021-00186-x
Gisele Capanema de Oliveira 1 , Sayonarah Carvalho Rocha 1 , Miliane Alves da Silva Lopes 2 , Natasha Paixão 2 , Silmara Lúcia Grego Alves 3 , Marco Túlio Corrêa Pessoa 1, 4 , François Noël 2 , Luis Eduardo M Quintas 2 , Leandro Augusto Barbosa 1 , José Augusto Ferreira Perez Villar 3 , Vanessa Faria Cortes 1
Affiliation  

Na,K-ATPase (NKA) and cardiotonic steroids (CTS) have shown potent cytotoxic and anticancer effects. Here, we have synthesized a series of CTS digoxin derivatives (γ-benzylidene) with substitutions in the lactone ring and evaluated the cytotoxicity caused by digoxin derivatives in tumor and non-tumor cells lines, as well as their effects on NKA. The cytotoxicity assay was determined in HeLa, A549, and WI-26 VA4 after they were treated for 48 h with increased concentrations of CTS. The effects of CTS on NKA activity and immunoblotting of α1 and β1 isoforms were evaluated at IC50 concentrations in A549 cell membrane. NKA activity from mouse brain cortex was also measured. The majority of CTS exhibited low cytotoxicity in tumor and non-tumor cells, presenting IC50 values at micromolar concentrations, while digoxin showed cytotoxicity at nanomolar concentrations. BD-15 presented the lowest IC50 value (8 µM) in A549 and reduced its NKA activity in 28%. In contrast, BD-7 was the compound that most inhibited NKA (56% inhibition) and presented high IC50 value for A549. In mouse cortex, only BD-15 modulated the enzyme activity in a concentration-dependent inhibition curve. These results demonstrate that the cytotoxicity of these compounds is not related to NKA inhibition. The substitutions in the lactone ring of digoxin led to an increase in the cytotoxic concentration in tumor cells, which may not be interesting for cancer, but it has the advantage of increasing the therapeutic margin of these molecules when compared to classic CTS, and can be used safely in research for other diseases.

Graphic Abstract



中文翻译:

强心类固醇内酯环的合成修饰对细胞毒性的影响

Na,K-ATPase (NKA) 和强心类固醇 (CTS) 已显示出有效的细胞毒性和抗癌作用。在这里,我们合成了一系列内酯环取代的 CTS 地高辛衍生物(γ-亚苄基),并评估了地高辛衍生物在肿瘤和非肿瘤细胞系中的细胞毒性及其对 NKA 的影响。用增加的 CTS 浓度处理 48 小时后,在 HeLa、A549 和 WI-26 VA4 中测定细胞毒性测定。在 A549 细胞膜中以 IC 50浓度评估 CTS 对 NKA 活性和 α1 和 β1 同种型免疫印迹的影响。还测量了来自小鼠大脑皮层的 NKA 活性。大多数 CTS 在肿瘤和非肿瘤细胞中表现出低细胞毒性,IC 50微摩尔浓度下的值,而地高辛在纳摩尔浓度下显示出细胞毒性。BD-15 在 A549 中具有最低的 IC 50值 (8 µM),并将其 NKA 活性降低了 28%。相比之下,BD-7 是最能抑制 NKA(56% 抑制)并呈现高 IC 50的化合物A549 的价值。在小鼠皮质中,只有 BD-15 在浓度依赖性抑制曲线中调节酶活性。这些结果表明这些化合物的细胞毒性与NKA抑制无关。地高辛内酯环的取代导致肿瘤细胞中细胞毒性浓度的增加,这可能对癌症没有意义,但与经典 CTS 相比,它具有增加这些分子的治疗范围的优势,并且可以安全地用于其他疾病的研究。

图形摘要

更新日期:2021-06-15
down
wechat
bug