WRC-213, an l-methionine-conjugated mitoxantrone derivative, displays anticancer activity with reduced cardiotoxicity and drug resistance: Identification of topoisomerase II inhibition and apoptotic machinery in prostate cancers
Journal
Biochemical Pharmacology
Journal Volume
75
Journal Issue
4
Pages
847-856
Date Issued
2008
Author(s)
Abstract
Anthracyclines and anthracenediones are well-known cancer chemotherapeutic agents but their uses are limited with cardiotoxicity and drug resistance. Several l- and d-form amino acids were introduced into the anthraquinone skeleton and numerous derivatives were synthesized for the evaluation of anticancer activity. The screening tests showed that WRC-213, an l-methionine conjugation, was the most effective derivative to inhibit proliferative effect of human androgen-independent prostate cancer PC-3 cells (IC50 = 50 nM). In an extension evaluation, WRC-213 displayed a potent anti-proliferative activity in various cancer cell lines, including non-small cell lung cancer A549, androgen-independent prostate cancer DU145, colorectal cancer HT-29, breast cancer MCF-7 and hepatocellular carcinoma Hep3B and HepG2. It induced cell-cycle arrest at S and G2, but not mitotic phase, in PC-3 cells. The comet assay revealed that induction of DNA damage and inhibition of topoisomerase II were the primary insults. After the checkpoint arrest of the cell-cycle, WRC-213 induced the mitochondria-mediated intrinsic apoptotic pathway, including Mcl-1 cleavage, Bcl-2 down-regulation and activation of caspase-9/caspase-3 cascades. Survivin degradation and caspase-2 activation also contributed to WRC-213-induced apoptosis. Moreover, the assessment of cytotoxicity in H9c2 cardiomyocytes and drug resistance in NCI/ADR-RES cells demonstrated that WRC-213 showed much lower cardiotoxicity and P-glycoprotein-related resistance than those of mitoxantrone, etoposide and doxorubicin. In conclusion, it is suggested that WRC-213 is a potential topoisomerase II inhibitor with reduced cardiotoxicity and drug resistance. It inhibits topoisomerase II activity and induces chromosomal DNA strand breaks, leading to S and G2 arrest of the cell-cycle and activation of mitochondria-mediated apoptotic pathways. ? 2007 Elsevier Inc. All rights reserved.
SDGs
Other Subjects
androgen; caspase 2; caspase 3; caspase 9; DNA; DNA topoisomerase (ATP hydrolysing); doxorubicin; etoposide; glycoprotein P; methionine derivative; mitoxantrone; protein bcl 2; protein mcl 1; survivin; unclassified drug; wrc 213; antineoplastic activity; apoptosis; article; breast cancer; cancer cell; cancer cell culture; cancer screening; cardiotoxicity; cell activation; cell cycle arrest; cell cycle G2 phase; cell cycle S phase; cell proliferation; cell strain MCF 7; chromosome; colorectal cancer; comet assay; controlled study; cytotoxicity; degradation; DNA damage; DNA strand breakage; down regulation; drug activity; drug conjugation; drug inhibition; drug resistance; enzyme activation; enzyme activity; enzyme inhibition; heart muscle cell; human; human cell; IC 50; liver cell carcinoma; lung non small cell cancer; male; mitochondrion; priority journal; prostate cancer; Antineoplastic Agents; Apoptosis; Blotting, Western; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Comet Assay; DNA Damage; DNA Topoisomerases, Type II; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Flow Cytometry; Humans; Male; Methionine; Mitoxantrone; Molecular Structure; Myocytes, Cardiac; Prostatic Neoplasms
Type
journal article