Publications Repository - Gdańsk University of Technology

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.

Authors

• Majus Misiak link open in new tab ,
• Mateusz Heldt link open in new tab ,
• Marlena Szeligowska link open in new tab ,
• dr Stefania Mazzini,
• dr Leonardo Scaglioni,
• dr Grzegorz Jan Grabe,
• dr inż. Marcin Serocki link open in new tab ,
• mgr Jan Jakub Lica link open in new tab ,
• Marta Świtalska,
• Joanna Wietrzyk,
• Giovanni Beretta,
• Paola Perego,
• Dominik Ziętkowski,
• prof. dr hab. inż. Maciej Bagiński link open in new tab ,
• prof. dr hab. inż. Edward Borowski link open in new tab ,
• prof. dr hab. inż. Andrzej Składanowski link open in new tab