Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Tiantan Xili, 100050, Beijing, China.
HTA Co., Ltd., CAEA Center of Excellence on Nuclear Technology Applications for Engineering and Industrialization of Radiopharmaceuticals, CNNC Engineering Research Center of Radiopharmaceuticals, 102413, Beijing, China.
Eur J Pharmacol. 2024 Nov 15;983:176968. doi: 10.1016/j.ejphar.2024.176968. Epub 2024 Sep 2.
Compound 5p is a 4β-N-substituted podophyllotoxin derivative, which exhibited potent activity toward drug-resistant K562/A02 cells and decreased MDR-1 mRNA expression. Here, we further investigated its detail mechanism and tested its antitumor activity. 5p exerted catalytic inhibition of topoisomerase IIα, and didn't show the inhibitor of topoisomerase I. 5p exhibited the inhibitory effect on microtubule polymerization. 5p showed potent anti-proliferation against breast cancer, oral squamous carcinoma, and their drug-resistant cell lines, with resistance index of 0.61 and 0.86, respectively. 5p downregulated the expression levels of P-gp in KB cells and BCRP in MCF7/ADR cells in dose-dependent manner. Moreover, 5p induced KB and KB cells arrest at G/M phase by up-regulating the expression of γ-H2AX, p-Histone H3 and cyclin B1. 5p induced apoptosis and pyroptosis by increased the expression levels of cleaved-PARP, cleaved-caspase3, N-GSDME as well as LDH release in KB and KB cells. In addition, 5p efficiently impaired tumor growth in KB and KB xenograft mice. Conclusively, this work elucidated the dual inhibitor of topoisomerase II and microtubule of 5p and its mechanism of overcoming the multidrug resistance, indicating that 5p exerts the antitumor potentiality.
化合物 5p 是一种 4β-N-取代的鬼臼毒素衍生物，对耐药 K562/A02 细胞具有很强的活性，并降低了 MDR-1 mRNA 的表达。在这里，我们进一步研究了它的详细机制，并测试了它的抗肿瘤活性。5p 对拓扑异构酶 IIα 具有催化抑制作用，而对拓扑异构酶 I 没有抑制作用。5p 对微管聚合有抑制作用。5p 对乳腺癌、口腔鳞状细胞癌及其耐药细胞系表现出强烈的增殖抑制作用，其耐药指数分别为 0.61 和 0.86。5p 以剂量依赖的方式下调 KB 细胞中 P-gp 和 MCF7/ADR 细胞中 BCRP 的表达水平。此外，5p 通过上调 γ-H2AX、p-Histone H3 和 cyclin B1 的表达，使 KB 和 KB 细胞阻滞在 G/M 期。5p 通过增加 cleaved-PARP、cleaved-caspase3、N-GSDME 的表达水平以及 LDH 的释放，诱导 KB 和 KB 细胞发生凋亡和焦亡。此外，5p 有效地抑制了 KB 和 KB 异种移植小鼠的肿瘤生长。总之，这项工作阐明了 5p 作为拓扑异构酶 II 和微管的双重抑制剂及其克服多药耐药的机制，表明 5p 具有抗肿瘤潜力。
