The interaction of Fe(III), adriamycin and daunomycin with nucleotides and DNA and their effects on cell growth of fibroblasts (NIH-3T3)

Abstract

The interactions of the iron complexes of the anthracycline antitumour drugs daunomycin (DN) and adriamycin (ADM) with the mononucleotide AMP, herring sperm DNA, plasmic pBR322 and immortalized 3T3 fibroblasts were studied. By means of Mössbauer spectroscopy it was demonstrated that DNA is a powerful ferric iron chelator as compared with AMP, which is not able to compete with DN or acetohydroxamic acid for ferric iron. The difference between AMP and DNA is postulated to be based on the chelate effect. The Mössbauer spectra of the ternary Fe-anthracycline-DNA systems differ from Fe-anthracycline binary complexes, indicating rearrangement reactions. Dialysis experiments clearly disclose the formation of a ternary Fe-ADM-pBR322 complex, the topology of which differs substantially from intercalating ADM. The effect of Fe-ADM complexes (3:1) on the growth of immortalized mouse embryonal fibroblasts (NIH-3T3) was studied in comparison with ADM alone. No significant difference on the inhibition of cell growth was noticed, suggesting comparable cytotoxicity for the compounds. In contrast to literature data, no evidence was found for DNA cleavage by ferric ADM at molar ratios as high as 1/100 (ADM/base pair), even if the ternary systems were prepared in the light and in the presence of reducing or oxidizing agents. Based on our observations it seems that the cytotoxicity of both ADM and Fe-ADM oligomer is not based primarily on intercalation or direct interaction with DNA.

Oxidative stress and DNA damage in relation to transition metals overload in Abu-Qir Bay, Egypt

“…On the other hand, there was no correlation between copper and the number of AP sites. The above findings may be due to the nature of the DNA molecule as a powerful iron chelator [13]. In fact, iron has been documented as a key mediator of H 2 O 2 -induced DNA damage and development of hepatocellular carcinoma [35,15,28].…”

Contradistinction between doxorubicin and epirubicin: in-vivo metabolism, pharmacokinetics and toxicodynamics after single- and multiple-dosing in rats

“…It has been shown that the cardiotoxicity of doxorubicin may be due to early damage to the DNA, mediated by hydroxyl free radicals of the alcohol metabolite. This damage to DNA may ultimately result in a decreased synthesis of proteins that are critical for the proper functioning of the myocardium (Crooke et al 1983 ;Mimnaugh et al 1983 ;Muindi et al 1984 ;Sinha et al 1984 ;Monti et al 1995 ;Di Liegro et al 1996). The reduction in the net intensity of the 110-kDa SR Ca 2 + protein band after repeated dosing with doxorubicin may be explained on the basis of the effect of free radical formation and doxorubicinol and the related decrease in protein synthesis.…”

Synthesis, crystal structure from PXRD of a MnII(purp)2complex, interaction with DNA at different temperatures and pH and lack of stimulated ROS formation by the complex

“…5,10,11,14 Probably the other units present in anthracyclines assist hydroxy-9,10-anthraquinones in discharging its duties effectively. [19][20][21][22][23] The reason behind their formation is well known. This supports the general belief sugars play an important role in anticancer activity although a direct scientific justification is scarce.…”

“…[14][15][16] A study with carminic acid, having a sugar unit directly bound to a hydroxy-9,10-anthraquinone showed significant improvement in biophysical interactions and in experiments on cancer cells. [19][20][21][22][23] What is important is to show with suitably designed experiments that metal complexes (either of anthracyclines or of hydroxy-9,10-anthraquinones) are actually more effective cytotoxic agents than compounds from which they are prepared. Sugar(s), for example, is(are) believed to assist in drug binding to DNA and in recognition of cancer cells for which this moiety is often incorporated in a molecule during drug design.…”

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The formation of reactive oxygen species (ROS) by anthracycline anticancer drugs is essential for its antitumor activity but they also make these drugs cardiotoxic. 12,14,15,[20][21][22][23] Purpurin (1, 2, 4 trihydroxy-9,10-anthraquinone) resembling the core of anthracyclinesThe novel aspects of this study are the structure of the complex obtained from powder X-ray diffraction data since single crystals were not obtained, determination of thermodynamic parameters pertaining to interaction of purpurin and its complex with calf thymus DNA and lack of stimulated ROS formation by the complex. Interestingly, inspite of producing fewer ROS, some of the complexes are effective antitumor agents, often better than the parent anthracycline.

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