Molecular basis for the DNA damage induction and anticancer activity of asymmetrically substituted anthrapyridazone PDZ-7 - Publication - Bridge of Knowledge

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Molecular basis for the DNA damage induction and anticancer activity of asymmetrically substituted anthrapyridazone PDZ-7

Abstract

nthrapyridazones, imino analogues of anthraquinone, constitute a family of compounds with remarkable anti-cancer activity. To date, over 20 derivatives were studied, of which most displayed nanomolar cytotoxicity towards broad spectrum of cancer cells, including breast, prostate and leukemic ones. BS-154, the most potent derivative, had IC50 values close to 1 nM, however, it was toxic in animal studies. Here, we characterize another anthrapyridazone, PDZ-7, which retains high cytotoxicity while being well tolerated in mice. PDZ-7 is also active in vivo against anthracycline-resistant tumor in a mouse xenograft model and induces DNA damage in proliferating cells, preferentially targeting cells in S and G2 phases of the cell cycle. Activation of Mre11-Rad50-Nbs1 (MRN) complex and phosphorylation of H2AX suggest double-stranded DNA breaks as a major consequence of PDZ-7 treatment. Consistent with this, PDZ-7 treatment blocked DNA synthesis and resulted in cell cycle arrest in late S and G2 phases. Analysis of topoisomerase IIα activity and isolation of the stabilized covalent topoisomerase IIα - DNA complex in the presence of PDZ-7 suggests that this compound is a topoisomerase IIα poison. Moreover, PDZ-7 interfered with actin polymerization, thereby implying its action as a dual inhibitor of processes critical for dividing cells. Using nuclear magnetic resonance (NMR) spectroscopy we show that PDZ-7 interacts with DNA double helix and quadruplex DNA structure. Taken together, our results suggest that PDZ-7 is a unique compound targeting actin cytoskeleton and DNA.

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Category:
Articles
Type:
artykuł w czasopiśmie wyróżnionym w JCR
Published in:
Oncotarget no. 10, pages 105137 - 105154,
ISSN: 1949-2553
Language:
English
Publication year:
2017
Bibliographic description:
Misiak M., Heldt M., Szeligowska M., Mazzini S., Scaglioni L., Grabe G., Serocki M., Lica J., Świtalska M., Wietrzyk J., Beretta G., Perego P., Ziętkowski D., Bagiński M., Borowski E., Składanowski A.: Molecular basis for the DNA damage induction and anticancer activity of asymmetrically substituted anthrapyridazone PDZ-7// Oncotarget. -Vol. 10, nr. 8 (2017), s.105137-105154
DOI:
Digital Object Identifier (open in new tab) 10.18632/oncotarget.21806
Verified by:
Gdańsk University of Technology

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