Abstract
The binding between anticancer drugs and double-stranded DNA (dsDNA) is a key issue to understand their mechanism of action, and many chemical methods have been explored on this task. Molecular docking techniques successfully predict the affinity of small molecules into the DNA binding sites. In turn, various DNA-targeted drugs are electroactive; in this regard, their electrochemical behavior may change according to the nature and strength of interaction with DNA. A carbon paste electrode (CPE) modified with calf thymus ds-DNA (CPDE) and computational methods were used to evaluate the drug–DNA intercalation of doxorubicin (DOX), daunorubicin (DAU), idarubicin (IDA), dacarbazine (DAR), mitoxantrone (MIT), and methotrexate (MTX), aiming to evaluate eventual correlations. CPE and CPDE were immersed in pH 7 0.1 mM solutions of each drug with different incubation times. As expected, the CPDE response for all DNA-targeted drugs was higher than that of CPE, evidencing the drug–DNA interaction. A peak current increase of up to 10-fold was observed; the lowest increase was seen for MTX, and the highest increase for MIT. Although this increase in the sensitivity is certainly tied to preconcentration effects of DNA, the data did not agree entirely with docking studies, evidencing the participation of other factors, such as viscosity, interfacial electrostatic interactions, and coefficient of diffusion.
Highlights
Intercalating drugs are classical antineoplastic agents that have DNA as the target binding site, and the interaction strength dictates the anticancer efficacy [1,2,3,4,5,6]
A forgotten approach is the concomitant evaluation of different anticancer drugs, which evaluates how much the analytical data would match with drug potency and docking studies
The optimized DNA-based biosensor, carbon paste electrode modified with double-stranded DNA (CPDE), was employed for the evaluation of the connection between the preconcentration effect of DNA and the proposed mechanism of action for different electroactive anticancer drugs: the anthracenedione, MIT, the anthracyclines, DOX, IDA, and DAU, representing the drugs whose action mechanism is the intercalation between DNA bases, the antimetabolite, MTX, the alkylating pro-drug with no in vitro activity, DAR, and the tricyclic antidepressant, CBP, representing the nonintercalating drugs
Summary
Intercalating drugs are classical antineoplastic agents that have DNA as the target binding site, and the interaction strength dictates the anticancer efficacy [1,2,3,4,5,6]. Despite the fact that the intercalation with DNA can lead to inhibition of mRNA transcription and duplication, many intercalating drugs act by dual or multiple mechanisms. DOX, DAU, and IDA act by inhibiting topoisomerase II, leading to the formation of double-stranded breaks of DNA [7,8,9,10,11,12,13,14,15]. MTX, a broad-spectrum anticancer drug, binds to and inhibits the enzyme dihydrofolate reductase, resulting in inhibition of purine nucleotide and thymidylate synthesis and, subsequently, inhibition of DNA and RNA syntheses. Though MTX is mostly classified as an antifolate agent, electrochemical assays have showed its potential for DNA intercalation [4,16]
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