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 language | English |
|---|---|
| Pages (from-to) | 105137-105154 |
| Number of pages | 18 |
| Journal | Oncotarget |
| Volume | 8 |
| Issue number | 62 |
| DOIs | |
| Publication status | Published - Jan 1 2017 |
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Keywords
- Actin
- Anthraquinone
- Cell cycle
- DNA repair
- Topoisomerase
ASJC Scopus subject areas
- Oncology
Cite this
Molecular basis for the DNA damage induction and anticancer activity of asymmetrically substituted anthrapyridazone PDZ-7. / Misiak, Majus; Heldt, Mateusz; Szeligowska, Marlena; Mazzini, Stefania; Scaglioni, Leonardo; Grabe, Grzegorz J.; Serocki, Marcin; Lica, Jan; Switalska, Marta; Wietrzyk, Joanna; Beretta, Giovanni L.; Perego, Paola; Zietkowski, Dominik; Baginski, Maciej; Borowski, Edward; Skladanowski, Andrzej.
In: Oncotarget, Vol. 8, No. 62, 01.01.2017, p. 105137-105154.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Molecular basis for the DNA damage induction and anticancer activity of asymmetrically substituted anthrapyridazone PDZ-7
AU - Misiak, Majus
AU - Heldt, Mateusz
AU - Szeligowska, Marlena
AU - Mazzini, Stefania
AU - Scaglioni, Leonardo
AU - Grabe, Grzegorz J.
AU - Serocki, Marcin
AU - Lica, Jan
AU - Switalska, Marta
AU - Wietrzyk, Joanna
AU - Beretta, Giovanni L.
AU - Perego, Paola
AU - Zietkowski, Dominik
AU - Baginski, Maciej
AU - Borowski, Edward
AU - Skladanowski, Andrzej
PY - 2017/1/1
Y1 - 2017/1/1
N2 - 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.
AB - 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.
KW - Actin
KW - Anthraquinone
KW - Cell cycle
KW - DNA repair
KW - Topoisomerase
UR - http://www.scopus.com/inward/record.url?scp=85036512645&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85036512645&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.21806
DO - 10.18632/oncotarget.21806
M3 - Article
VL - 8
SP - 105137
EP - 105154
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 62
ER -