Molecular Inflammation Research Institute for Aging Intervention and College of Pharmacy, Pusan National University, San 30, Jangjeon-dong, Geumjeong-gu, Busan 609–735, South Korea.
Eur J Pharmacol. 2011 May 11;658(2-3):98-107. doi: 10.1016/j.ejphar.2011.02.015. Epub 2011 Mar 1.
Here, we reported the synthesis of a novel topoisomerase II inhibitor, MHY336, which that has strong topoisomerase-mediated anticancer activity but fewer side effects than other topoisomerase II inhibitors. The catalytic activity of MHY336 on the topoisomerase II enzyme was the same as that of the etoposide. In a cell-free system, MHY336 exhibited a potent activity on scavenging of reactive oxygen species against 3-morpholinosydnonimine hydrochloride (SIN-1)-induced oxidative stress. An in vitro cell-based assay demonstrated that MHY336 significantly inhibited the proliferation of three prostate cancer cell lines, LNCaP, PC-3, and DU145 cells. Notably, the cytotoxicity of MHY336 was more potent in LNCaP cells (IC(50)=1.39 μM) than in DU145 (IC(50)=2.94 μM) and PC3 cells (IC(50)=3.72 μM). Furthermore, MHY336 treatment induced similar levels of cytotoxicity compared to doxorubicin treatment (IC(50)=1.55 μM) in LNCap cells. Also, MHY336 significantly down-regulated topoisomerase II alpha expression and up-regulated p53 expression in LNCaP cells (wild-type p53), whereas it up-regulated the topoisomerase II alpha protein in both DU145 and PC3 cells (p53 mutated or deleted). MHY336 induced G2/M or S phase arrest in LNCaP cells through a well-documented topoisomerase II-dependent mechanism. Further studies using Annexin V-FITC binding assay, DAPI staining, and Western blot analyses illustrated that MHY336 markedly induced apoptotic cell death via the mitochondria-mediated intrinsic pathway in LNCaP cells. These results suggest that MHY336 is an attractive chemotherapeutic agent because of its topoisomerase II-mediated anti-tumour activity in human prostate cancer.
在这里，我们报道了一种新型拓扑异构酶 II 抑制剂 MHY336 的合成，它具有很强的拓扑异构酶介导的抗癌活性，但副作用比其他拓扑异构酶 II 抑制剂少。MHY336 对拓扑异构酶 II 酶的催化活性与依托泊苷相同。在无细胞体系中，MHY336 对 3-吗啉基-sydnonimine 盐酸盐（SIN-1）诱导的氧化应激具有很强的清除活性氧的活性。体外细胞试验表明，MHY336 能显著抑制三种前列腺癌细胞系 LNCaP、PC-3 和 DU145 的增殖。值得注意的是，MHY336 对 LNCaP 细胞的细胞毒性（IC50=1.39 μM）比 DU145 细胞（IC50=2.94 μM）和 PC3 细胞（IC50=3.72 μM）更强。此外，MHY336 处理在 LNCap 细胞中诱导的细胞毒性与阿霉素处理（IC50=1.55 μM）相似。此外，MHY336 显著下调 LNCaP 细胞中拓扑异构酶 IIα的表达，并上调 p53 的表达（野生型 p53），而在 DU145 和 PC3 细胞中则上调拓扑异构酶 IIα 蛋白（p53 突变或缺失）。MHY336 通过一种已被充分证实的拓扑异构酶 II 依赖性机制，诱导 LNCaP 细胞的 G2/M 或 S 期阻滞。进一步的 Annexin V-FITC 结合试验、DAPI 染色和 Western blot 分析表明，MHY336 通过线粒体介导的内在途径显著诱导 LNCaP 细胞的凋亡性细胞死亡。这些结果表明，MHY336 是一种有吸引力的化疗药物，因为它在人类前列腺癌中具有拓扑异构酶 II 介导的抗肿瘤活性。
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