Molecular basis for the DNA damage induction and anticancer activity of asymmetrically substituted anthrapyridazone PDZ-7
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Majus Misiak1, Mateusz Heldt1,*, Marlena Szeligowska1,*, Stefania Mazzini2, Leonardo Scaglioni2, Grzegorz J. Grabe3, Marcin Serocki1, Jan Lica1, Marta Switalska5, Joanna Wietrzyk5, Giovanni L. Beretta4, Paola Perego4, Dominik Zietkowski6, Maciej Baginski1, Edward Borowski1,6,** and Andrzej Skladanowski1
1Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, Gdansk University of Technology, Gdansk, Poland
2Department of Food, Environmental and Nutritional Sciences, Division of Chemistry and Molecular Biology, University of Milan, Milan, Italy
3Department of Medicine, Faculty of Medicine, Imperial College London, London, UK
4Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
5Department of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
6BS-154 sp. z o.o., Gdansk, Poland
*These authors have contributed equally to this work
**Prof. Edward Borowski passed away on August 17, 2016
Majus Misiak, email: [email protected]
Keywords: actin; anthraquinone; cell cycle; DNA repair; topoisomerase
Received: April 07, 2017 Accepted: September 23, 2017 Published: October 10, 2017
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 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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