Abstract
Pharmacodynamic interactions of three anthracycline antibiotics namely doxorubicin (DXH), epirubicin (EpiDXH) and daunorubicin (DNR) with DNA in the absence and presence of ascorbic acid (AA) as natural additive were monitored under physiological conditions (pH = 7.4, 4.7 and T = 309.5K). Route–1 (Anthracycline–AA–DNA) and Route–2 (Anthracycline–DNA–AA) were adopted to see the interactional behavior by cyclic voltammetry (CV) and UV-visible spectroscopy. In comparison to Route–2; voltammetric and spectral responses as well as binding constant (Kb) and Gibb’s free energy change (ΔG) values revealed strongest and more favorable interaction of anthracycline–AA complex with DNA via Route–1. Kb, s (binding site sizes) and ΔG evaluated from experimental (CV, UV-Vis) and theoretical (molecular docking) findings showed enhanced binding strength of tertiary complexes as compared to binary drug–DNA complexes. The results were found comparatively better at pH 7.4. Consistency was observed in binding parameters evaluated from experimental and theoretical techniques. Diffusion coefficients (Do) and heterogeneous electron transfer rate constant (ks,h) confirmed the formation of complexes via slow diffusion kinetics. Percent cell inhibition (%Cinh) of anthracyclines for non-small cell cancer cell lines (NSCCLs) H-1299 and H-157 were evaluated higher in the presence of AA which further complimented experimental and theoretical results.
Highlights
The clinical importance of anthracycline antibiotics is obvious and many new analogues and derivatives of anthracyclines antibiotics have been formulated for clinically trials [1,2,3]
Voltammetric behavior of anthracyclines and ascorbic acid at PH 4.7 are given as S1–S3 Figs. and electrochemical parameters at pH 7.4 and 4.7 are tabulated in S1 and S2 Tables provided in supplementary material
Results revealed that binding propensity of anthracyclines with DNA was comparatively high when ascorbic acid (AA) was added to anthracycline before addition of DNA (Route–1; anthracycline–AA–DNA) than after DNA addition (Route–2; anthracycline–DNA–AA)
Summary
The clinical importance of anthracycline antibiotics is obvious and many new analogues and derivatives of anthracyclines antibiotics have been formulated for clinically trials [1,2,3]. Molecular structures of anthracyclines contain a planar aglycone ring coupled with an amino-sugar which exhibits a variety of biological effects [5,6,7]. DNA is one of the targets of clinically used anticancer drugs including anthracyclines. Experimental and theoretical studies reported on anthracyclines for their binding with DNA have shown the possibilities of reversible binding interactions i.e., intercalation between the DNA base pairs via planar anthracycline ring and interaction of amino-sugar moiety with the negatively charged phosphate groups in the DNA minor groove that could lead to change in the shape of the DNA double helix and hinders DNA replication and RNA transcription [8,9,10,11,12,13]. Despite of anthracyclines being potent anticancer therapeutic agents, their clinical usefulness is limited due to their dose related cardiotoxicity [14]
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