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A novel epoxypropoxy flavonoid derivative and topoisomerase II inhibitor, MHY336, induces apoptosis in prostate cancer cells.
- Source :
-
European journal of pharmacology [Eur J Pharmacol] 2011 May 11; Vol. 658 (2-3), pp. 98-107. Date of Electronic Publication: 2011 Mar 01. - Publication Year :
- 2011
-
Abstract
- 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.<br /> (Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.)
- Subjects :
- Antineoplastic Agents chemical synthesis
Antineoplastic Agents chemistry
Antineoplastic Agents pharmacology
Biocatalysis drug effects
Cell Cycle drug effects
Cell Line, Tumor
Cell Proliferation drug effects
Down-Regulation drug effects
Flavonoids chemical synthesis
Flavonoids pharmacology
Free Radical Scavengers chemical synthesis
Free Radical Scavengers chemistry
Free Radical Scavengers pharmacology
Humans
Male
Molsidomine analogs & derivatives
Molsidomine pharmacology
Oxidative Stress drug effects
Prostatic Neoplasms metabolism
Reactive Oxygen Species metabolism
Topoisomerase II Inhibitors chemical synthesis
Tumor Suppressor Protein p53 metabolism
Up-Regulation drug effects
Apoptosis drug effects
DNA Topoisomerases, Type II metabolism
Flavonoids chemistry
Prostatic Neoplasms pathology
Topoisomerase II Inhibitors chemistry
Topoisomerase II Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1879-0712
- Volume :
- 658
- Issue :
- 2-3
- Database :
- MEDLINE
- Journal :
- European journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 21376033
- Full Text :
- https://doi.org/10.1016/j.ejphar.2011.02.015