Compensation of DNA stabilization and destabilization effects caused by cisplatin is partially disturbed in alkaline medium.
Binding of the antitumor compound cisplatin to DNA locally distorts the double helix. These distortions correlate with a decrease in DNA melting temperature (Tm). However, the influence of cisplatin on DNA stability is more complex because it decreases the DNA charge density. In this way, cisplatin increases the melting temperature and partially compensates for the destabilizing influence of structural distortions. The stabilization is stronger at low Na+ ion concentration. Due to this compensation, the total decrease in the DNA melting temperature after cisplatin binding is much lower than the decrease caused by the distortions themselves, especially at low [Na+]. It is shown in this study that, besides Na+ concentration, pH also strongly influences the value of a change in the melting temperature caused by cisplatin. In alkaline medium (pH=10.5-10.8), a fall in the melting temperature caused by platination is enhanced several times with respect to neutral medium. Such a stronger drop in Tm is explained by a decrease in pK values of base pairs caused by lowering the charge density under platination that facilitates proton release. At neutral pH, the proton release is low for both control and platinated DNA and does not influence the melting behavior. Therefore, lowering in the charge density under platination, besides stabilization, gives additional destabilization just in alkaline medium. Destabilization caused by structural distortions due to this pH induced compensation of stabilizing effect is more pronounced. In the presence of carbonate ion, destabilization caused by high pH value is strengthened. As a decrease in DNA charge density, interstrand crosslinking caused by cisplatin also increases the DNA stability due to loss in the entropy of the melted state. However, computer modeling of DNA stability demonstrates that interstrand crosslinks formed by cisplatin do not stabilize long DNA. It is shown that the increase in Tm caused by interstrand crosslinking itself is compensated for by a local destabilization of the double helix at the sites of location of interstrand crosslinks formed by cisplatin.
Galyuk
Elena N
EN
Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, 5/2, Kuprevich St., 220141, Minsk, Belarus.
Fridman
Alexander S
AS
Vorob'ev
Vladimir I
VI
Haroutiunian
Samvel G
SG
Sargsyan
Shushanik A
SA
Hauruk
Maryna M
MM
Lando
Dmitri Y
DY
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D020029:Base Pairing / Q000187:drug effects / Q000502:physiology; D002417:Cattle; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology*; D003432:Cross-Linking Reagents / Q000378:metabolism / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D009691:Nucleic Acid Denaturation / Q000187:drug effects
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D004247:DNA; C427203:calf thymus DNA; D002945:Cisplatin