Identification of copper(II) binding sites in actinomycin D, a cytostatic drug--correlation of coordination with DNA damage.
Actinomycin D (AD) is a potent anticancer drug widely applied in therapy, which however exhibits very high toxicity in humans. As the character of donors present in the AD molecule seems to be very favorable for Cu(II) ions, we undertook the coordination study on the Cu(II)-AD system. Potentiometric experiments proved a formation of very stable complexes and with the use of spectroscopic methods the identification of the binding sites was made. The values of potential energy minima, provided by theoretical modeling, confirmed the feasibility of formation of the complexes in water solution. We also demonstrated a significant effect of Cu(II) ions on AD interactions with DNA. The strand-nicking activity was observed. This process could be correlated with the speciation of complex forms. We also found out that in the presence of H2O2, low levels of Cu(II)-AD complexes induce the formation of considerable amounts of linearised plasmid. In consequence, the hypothesis is proposed that the physiologically available cupric ions may participate in the drug-induced toxic effects.
Szczepanik
Wojciech
W
Faculty of Chemistry, University of Wrocław, F.Joliot-Curie 14, Wrocław 50-383, Poland.
Kaczmarek
Piotr
P
Jezowska-Bojczuk
Małgorzata
M
D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D002942:Circular Dichroism; D003300:Copper / Q000737:chemistry* / Q000378:metabolism; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D004249:DNA Damage; D003609:Dactinomycin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D064420:Drug-Related Side Effects and Adverse Reactions; D004587:Electrophoresis, Agar Gel; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008958:Models, Molecular; D008962:Models, Theoretical; D015394:Molecular Structure; D010957:Plasmids / Q000187:drug effects / Q000235:genetics; D011199:Potentiometry; D011522:Protons; D012996:Solutions / Q000737:chemistry; D013057:Spectrum Analysis / Q000379:methods; D014867:Water / Q000737:chemistry
D000903:Antibiotics, Antineoplastic; D011522:Protons; D012996:Solutions; D014867:Water; D003609:Dactinomycin; D003300:Copper; D004247:DNA; D006861:Hydrogen Peroxide