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

Majus Misiak, Mateusz Heldt, Marlena Szeligowska, Stefania Mazzini, Leonardo Scaglioni, Grzegorz J. Grabe, Marcin Serocki, Jan Lica, Marta Switalska, Joanna Wietrzyk, Giovanni L. Beretta, Paola Perego, Dominik Zietkowski, Maciej Baginski, Edward Borowski, Andrzej Skladanowski

Research output: Contribution to journalArticlepeer-review

Abstract

Anthrapyridazones, 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 anthracyclineresistant 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 doublestranded 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.

Original languageEnglish
Pages (from-to)105137-105154
Number of pages18
JournalOncotarget
Volume8
Issue number62
DOIs
Publication statusPublished - Jan 1 2017

Keywords

  • Actin
  • Anthraquinone
  • Cell cycle
  • DNA repair
  • Topoisomerase

ASJC Scopus subject areas

  • Oncology

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