Anthracycline antibiotics. Interaction with DNA and nucleosomes and inhibition of DNA synthesis

Abstract

We report studies of the interaction of four anthracycline antibiotics, iremycin (IM), daunomycin (DM), aclacinomycin A (AM), and violamycin B1 (VM), with naked DNA, nucleosomal core particles, and 175 base pair (bp) nucleosomes lacking histone H1. In all cases the binding strength increases in the order IM less than DM approximately AM less than VM. The binding substrates increased in affinity for the drugs in the following order: core particles less than 175-bp nucleosomes less than DNA. The apparent DNA length increment per drug bound decreases in the progression IM greater than DM greater than AM greater than VM, the same serial order as is characterized by increasing binding affinity. Dichroism amplitude measurements show that for all drugs the long-wavelength absorbance transition moment is tilted by 26-29 degrees relative to the plane perpendicular to the helix axis; this angle probably corresponds to the long axis tilt of the intercalated chromophore. Finally, it was found that the ability of the drugs to inhibit DNA synthesis by Escherichia coli DNA polymerase I increases in the same order as their binding affinity.

Daunomycin-induced Unfolding and Aggregation of Chromatin

“…Consistent with our data, however, their studies have also shown that binding of daunomycin to 175 bp (histone H1-depleted) of nucleosomes is strongly reduced relative to its affinity for free DNA (14). Their findings also agree with our results that the affinity of daunomycin for different nucleohistone complexes increases in the following order: nucleosome core particle Ͻ 175 bp nucleosome Ͻ DNA (38). Thus it appears as if the affinity of the drug for the chromatin complexes decreases with the decrease of the number of base pairs in the DNA region flanking the DNA coils protected by the histone octamer.…”

The anthracycline antibiotics: antitumor drugs that alter chromatin structure

“…(37)(38)(39)(40) It was shown that the affinity of daunomycin for different nucleohistone complexes is in the following order: DNA > 175 bp H1/H5 depleted nucleosomes > nucleosome core particles. (14,38) These results are in agreement with those observed for the interaction of daunomycin with chromatin containing either the full native linker histones (H1 and H5) or depleted of these histones. (21) Addition of daunomycin to 175 bp H1-depleted nucleosomes or 146 bp nucleosome core particles stabilizes their low melting transition temperature, which corresponds to the regions of the nucleosomal DNA less tightly bound to the histone octamer at the flanking ends of the particle.…”

“…(10,11) Although there is still some controversy about their mode of action, the anticancer activity or cytotoxic effects may involve the interaction with nuclear components, especially DNA and type II topoisomerases; they may also participate in the inhibition of DNA and RNA synthesis. (9,(12)(13)(14) Characterization of the binding sites of antitumor drugs in the cell is important because it can provide clues required for further drug design to enhance drug efficacy. This review focuses its attention on progress made on the understanding of the interaction of anthracycline antibiotics adriamycin and daunomycin with different chromatin components.…”

Effects of solute conditions on the relative affinities of the oligonucleotides d(G‐C)5 and d(A‐T)5 for the anthracycline drug 2‐fluoro‐4‐demethoxydaunomycin

“…When used clinically, it is likely that daunomycin and adriamycin act on DNA in the form of its chromatin complex [16]. For this reason a study of the effects of free lysine and arginine on 2FD binding preference between d(G-C)s and d(A-T)s was undertaken, the aim having been to establish whether anthracycline binding site selectivity might be affected by DNA-histone association.…”