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First published on January 24, 2006; DOI: 10.1124/mol.105.018036

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Received for publication August 23, 2005.
Revised January 9, 2006.
Accepted for publication January 20, 2006.

Merbarone Induces Activation of Caspase-Activated DNase and Excision of Chromosomal DNA Loops from the Nuclear Matrix

Yoko Otake 1, Alice Mims 1, Daniel J Fernandes 1*

1 Medical University of South Carolina

* Address correspondence to: E-mail: fernand{at}musc.edu

Abstract

Studies were carried out to address possible cellular mechanisms by which merbarone, a catalytic inhibitor of DNA topoisomerase II, can block tumor cell growth without inducing extensive DNA cleavage. Merbarone induced the release of high molecular weight DNA fragments from the nuclear matrix of HL-60 leukemia cells, which preceded the internucleosomal-size DNA fragmentation characteristic of late stage apoptosis. The chromatin fragments were enriched in a matrix attachment region (MAR) sequence compared to a non-MAR sequence, and were similar in size to DNA loops extracted from nuclear matrices. However, merbarone did not directly induce the excision of high molecular weight DNA fragments from the nuclear matrix by promoting topoisomerase II catalyzed DNA cleavage, since the drug inhibited topoisomerase II-mediated cleavage in isolated nuclear matrix preparations. Instead merbarone induced rapid activation of the mitochondrial apoptosis pathway, which included the following temporal sequence of events: dissipation of the mitochondrial transmembrane potential within 30 min, release of mitochondrial cytochrome c, and activation of caspase-activated DNase by cleavage of its inhibitor ICAD. The excision of high molecular weight DNA was inhibited at least 80 % in merbarone treated cells preincubated with the pan-caspase inhibitor, z-VAD-fmk and in caspase-resistant Jurkat cells (ICAD/DM) that express a mutant form of ICAD. These results provide evidence that merbarone can induce rapid disorganization of DNA in tumor cells having a functional mitochondrial apoptosis pathway without inducing extensive DNA cleavage.


Key words: Apoptosis, DNA damage and repair, Mechanisms of cell killing/apoptosis, Topoisomerases


This article has been cited by other articles:


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 Molecular Cancer TherapeuticsHome page
F. Wu, S. Chiocca, W. T. Beck, and Y.-Y. Mo
Gam1-associated alterations of drug responsiveness through activation of apoptosis
Mol. Cancer Ther., June 1, 2007; 6(6): 1823 - 1830.
[Abstract] [Full Text] [PDF]


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