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 IC50values 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 G2phases 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 G2phases. Analysis of topoisomerase IIÎ± activity and isolation of the stabilized covalent topoisomerase IIÎ± - DNA complex in the presence of PDZ-7 suggests that this compound is a topoisomerase IIÎ± 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.
Molecular basis for the DNA damage induction and anticancer activity of asymmetrically substituted anthrapyridazone PDZ-7 / M. Majus, H. Mateusz, S. Marlena, S. Mazzini, L. Scaglioni, G. Grzegorz J., S. Marcin, L. Jan, S. Marta, W. Joanna, B. Giovanni L., P. Perego, Z. Dominik, B. Maciej, B. Edward, S. Andrzej. - In: ONCOTARGET. - ISSN 1949-2553. - 8:62(2017 Dec 01), pp. 105137-105154.
|Titolo:||Molecular basis for the DNA damage induction and anticancer activity of asymmetrically substituted anthrapyridazone PDZ-7|
|Parole Chiave:||actin; anthraquinone; cell cycle; DNA repair; topoisomerase; oncology|
|Settore Scientifico Disciplinare:||Settore CHIM/06 - Chimica Organica|
|Data di pubblicazione:||1-dic-2017|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.18632/oncotarget.21806|
|Appare nelle tipologie:||01 - Articolo su periodico|