当前位置:
X-MOL 学术
›
J. Cell. Biochem.
›
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.)
Cytotoxic effect of carbohydrate derivatives of digitoxigenin involves modulation of plasma membrane Ca2+-ATPase
Journal of Cellular Biochemistry ( IF 4 ) Pub Date : 2021-09-22 , DOI: 10.1002/jcb.30150 Jéssica Martins de Moura Valadares 1 , Sumit O Bajaj 2 , Hongyan Li 2 , Hua-Yu L Wang 2 , Simone Cavalcante Silva 2 , Israel José Pereira Garcia 1 , Duane Gischewiski Pereira 1 , Pedro Azalim 3 , Luis Eduardo Menezes Quintas 3 , François Noël 3 , Vanessa Faria Cortes 1 , George Augustine O'Doherty 2 , Leandro Augusto Barbosa 1
Journal of Cellular Biochemistry ( IF 4 ) Pub Date : 2021-09-22 , DOI: 10.1002/jcb.30150 Jéssica Martins de Moura Valadares 1 , Sumit O Bajaj 2 , Hongyan Li 2 , Hua-Yu L Wang 2 , Simone Cavalcante Silva 2 , Israel José Pereira Garcia 1 , Duane Gischewiski Pereira 1 , Pedro Azalim 3 , Luis Eduardo Menezes Quintas 3 , François Noël 3 , Vanessa Faria Cortes 1 , George Augustine O'Doherty 2 , Leandro Augusto Barbosa 1
Affiliation
Cardiac glycosides, such as digoxin and digitoxin, are compounds that interact with Na+/K+-ATPase to induce anti-neoplastic effects; however, these cardiac glycosides have narrow therapeutic index. Thus, semi-synthetic analogs of digitoxin with modifications in the sugar moiety has been shown to be an interesting approach to obtain more selective and more effective analogs than the parent natural product. Therefore, the aim of this study was to assess the cytotoxic potential of novel digitoxigenin derivatives, digitoxigenin-α-L-rhamno-pyranoside (1) and digitoxigenin-α-L-amiceto-pyranoside (2), in cervical carcinoma cells (HeLa) and human diploid lung fibroblasts (Wi-26-VA4). In addition, we studied the anticancer mechanisms of action of these compounds by comparing its cytotoxic effects with the potential to modulate the activity of three P-type ATPases; Na+/K+-ATPase, sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), and plasma membrane Ca2+-ATPase (PMCA). Briefly, the results showed that compounds 1 and 2 were more cytotoxic and selectivity for HeLa tumor cells than the nontumor cells Wi-26-VA4. While the anticancer cytotoxicity in HeLa cells involves the modulation of Na+/K+-ATPase, PMCA and SERCA, the modulation of these P-type ATPases was completely absent in Wi-26-VA4 cells, which suggest the importance of their role in the cytotoxic effect of compounds 1 and 2 in HeLa cells. Furthermore, the compound 2 inhibited directly erythrocyte ghosts PMCA and both compounds were more cytotoxic than digitoxin in HeLa cells. These results provide a better understanding of the mode of action of the synthetic cardiac glycosides and highlights 1 and 2 as potential anticancer agents.
中文翻译:
洋地黄毒苷碳水化合物衍生物的细胞毒性作用涉及质膜 Ca2+-ATP 酶的调节
强心苷,如地高辛和洋地黄毒苷,是与 Na + /K + -ATPase 相互作用以诱导抗肿瘤作用的化合物;然而,这些强心苷的治疗指数较窄。因此,已证明在糖部分进行修饰的洋地黄毒苷的半合成类似物是获得比母体天然产物更具选择性和更有效的类似物的有趣方法。因此,本研究的目的是评估新型洋地黄毒苷衍生物、洋地黄毒苷-α-L-鼠李糖苷 ( 1 ) 和洋地黄毒苷-α-L-氨基吡喃糖苷 ( 2 ) 的细胞毒性潜力), 在宫颈癌细胞 (HeLa) 和人二倍体肺成纤维细胞 (Wi-26-VA4) 中。此外,我们通过比较其细胞毒性作用与调节三种 P 型 ATP 酶活性的潜力,研究了这些化合物的抗癌作用机制;Na + /K + -ATP 酶、肌细胞/内质网 Ca 2+ -ATP 酶 (SERCA) 和质膜 Ca 2+ -ATP 酶 (PMCA)。简而言之,结果表明化合物1和2对 HeLa 肿瘤细胞的细胞毒性和选择性高于非肿瘤细胞 Wi-26-VA4。而 HeLa 细胞的抗癌细胞毒性涉及 Na + / K +的调节-ATP 酶、PMCA 和 SERCA,这些 P 型 ATP 酶的调节在 Wi-26-VA4 细胞中完全不存在,这表明它们在 HeLa 细胞中化合物1和2的细胞毒性作用中的作用的重要性。此外,化合物2直接抑制红细胞血影 PMCA,并且这两种化合物在 HeLa 细胞中的细胞毒性均高于洋地黄毒苷。这些结果有助于更好地了解合成强心苷的作用方式,并突出显示1和2作为潜在的抗癌剂。
更新日期:2021-09-22
中文翻译:
洋地黄毒苷碳水化合物衍生物的细胞毒性作用涉及质膜 Ca2+-ATP 酶的调节
强心苷,如地高辛和洋地黄毒苷,是与 Na + /K + -ATPase 相互作用以诱导抗肿瘤作用的化合物;然而,这些强心苷的治疗指数较窄。因此,已证明在糖部分进行修饰的洋地黄毒苷的半合成类似物是获得比母体天然产物更具选择性和更有效的类似物的有趣方法。因此,本研究的目的是评估新型洋地黄毒苷衍生物、洋地黄毒苷-α-L-鼠李糖苷 ( 1 ) 和洋地黄毒苷-α-L-氨基吡喃糖苷 ( 2 ) 的细胞毒性潜力), 在宫颈癌细胞 (HeLa) 和人二倍体肺成纤维细胞 (Wi-26-VA4) 中。此外,我们通过比较其细胞毒性作用与调节三种 P 型 ATP 酶活性的潜力,研究了这些化合物的抗癌作用机制;Na + /K + -ATP 酶、肌细胞/内质网 Ca 2+ -ATP 酶 (SERCA) 和质膜 Ca 2+ -ATP 酶 (PMCA)。简而言之,结果表明化合物1和2对 HeLa 肿瘤细胞的细胞毒性和选择性高于非肿瘤细胞 Wi-26-VA4。而 HeLa 细胞的抗癌细胞毒性涉及 Na + / K +的调节-ATP 酶、PMCA 和 SERCA,这些 P 型 ATP 酶的调节在 Wi-26-VA4 细胞中完全不存在,这表明它们在 HeLa 细胞中化合物1和2的细胞毒性作用中的作用的重要性。此外,化合物2直接抑制红细胞血影 PMCA,并且这两种化合物在 HeLa 细胞中的细胞毒性均高于洋地黄毒苷。这些结果有助于更好地了解合成强心苷的作用方式,并突出显示1和2作为潜在的抗癌剂。