期刊
EUROPEAN JOURNAL OF PHARMACOLOGY
卷 658, 期 2-3, 页码 98-107出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejphar.2011.02.015
关键词
MHY336; Topoisomerase II inhibitor; Apoptosis; p53; Prostate cancer
资金
- Korea government [20090083538]
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 mu M) than in DIJ145 (IC(50) = 2.94 mu M) and PD cells (IC(50) = 3.72 mu M). Furthermore, MHY336 treatment induced similar levels of cytotoxicity compared to doxorubicin treatment (IC(50) = 1.55 mu M) 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 PO 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. Crown Copyright (C) 2011 Published by Elsevier B.V. All rights reserved.
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