Electrochemical behaviour of anticancer drug lomustine and in situ evaluation of its interaction with DNA

[Display omitted] •Electrochemical behavior of lomustine (CCNU) and its degradation in aqueous solution.•CCNU in situ interaction with DNA studied with voltammetric techniques and comet assays.•CCNU led to dsDNA condensation, breakage, and oxidative damage. Electrochemical techniques were used to in...

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Published in:Journal of pharmaceutical and biomedical analysis 2019-11, Vol.176, p.112786-112786, Article 112786
Main Authors: de Carvalho, Paulina Andréa V., Campelo Lopes, Ilanna, Silva, Elizaura Hyeda C., Bruzaca, Evellin Enny S., Alves, Hugo José, Lima, Mayara Ingrid S., Tanaka, Auro Atsushi
Format: Article
Language:English
Subjects:
Antineoplastic Agents, Alkylating - chemistry
Antineoplastic Agents, Alkylating - pharmacology
Biosensing Techniques
biosensor
Diffusion
DNA
DNA - chemistry
DNA - drug effects
DNA Breaks, Single-Stranded - drug effects
Drug Stability
Electrochemical Techniques
Electrodes
lomustine
Lomustine - chemistry
Lomustine - pharmacology
nitrosurea
Nucleic Acid Conformation - drug effects
Water
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Summary:[Display omitted] •Electrochemical behavior of lomustine (CCNU) and its degradation in aqueous solution.•CCNU in situ interaction with DNA studied with voltammetric techniques and comet assays.•CCNU led to dsDNA condensation, breakage, and oxidative damage. Electrochemical techniques were used to investigate the behavior of lomustine (CCNU) and its degradation in aqueous solution at a glassy carbon electrode (GCE). The in situ interaction of CCNU and chemically degraded CCNU (cdCCNU) with dsDNA was then investigated in dsDNA incubated solutions, using dsDNA electrochemical biosensors and comet assays. CCNU undergoes electrochemical reduction in two irreversible, diffusion-controlled, and pH-dependent redox processes, each with transfer of two electrons and one proton. At pH ≥ 10.1, the peak potential for the two processes was essentially pH-independent and involved only one electron. A mechanism was proposed for the reduction of CCNU in a neutral medium. In addition, it was found that CCNU underwent spontaneous degradation during incubation in aqueous solution, without the formation of electroactive degradation products. The degradation process was faster in basic media. Moreover, this pro-drug interacted with the DNA. Its metabolite(s) initially caused condensation of the double helix chains, followed by the unwinding of these chains. In addition, free guanine (Gua) was released from the dsDNA and oxidative damage to the DNA by the CCNU metabolite(s) was evidenced from the detection of 8-oxoGua and 2,8-oxoAde. These results were confirmed by the poly(dA)- and poly(dG)-polyhomonucleotide biosensors, which revealed the oxidative damage caused to both bases (guanine and adenine) of the dsDNA by the CCNU metabolite(s). The comet assay indicated breaks in the single strand DNA, complementing the results of the studies using differential pulse voltammetry. Conformational changes of dsDNA caused by CCNU and cdCCNU were confirmed using comet assays.
ISSN:0731-7085
1873-264X
DOI:10.1016/j.jpba.2019.112786