Biochemical and Biophysical Research Communications
On the use of Europium (Eu) for designing new metal-based anticancer drugs
Graphical abstract
Introduction
The rational design of new drugs for chemotherapies and other kinds of treatments for human diseases is an important topic in pharmacology and related fields. In particular, metal-based compounds constitute a class of drugs largely employed in current chemotherapies [1,2], specially the platinum-based compound cisplatin and its derivatives [[3], [4], [5], [6]]. On the other hand, advances on drug development based on metals and semimetals such as Ruthenium, Osmium, Iridium, Iron, Cooper, Gold, Vanadium, Arsenic and others were recently reported [1]. Nevertheless, studies using rare earth elements are sparse, which opens up a huge range of possibilities for the design of new promising drugs using these elements.
Europium (Eu) is the most reactive rare earth metal, and a previous study performed with a particular Eu-based compound have achieved promising results concerning the development of Eu-based anticancer drugs [7]. Such compound, designed linking various aromatic rings to the Eu atom, interacts with DNA via hydrophobic groove binding with an equilibrium association binding constant on the order of 105 M−1, also exhibiting antimicrobial activity [7]. Nevertheless, since the aromatic rings alone can interact with DNA via hydrogen bonds, hydrophobic and π-π stacking interactions [8,9], it is difficult to discriminate the real effect of the Eu element in such compound. In addition, europium affinity of single-stranded DNA was also recently demonstrated [10].
In the present study, we investigate the effects of europium on double-stranded DNA using the simplest stable compound containing such element: the europium oxide Eu2O3. Pure europium cannot be used here because the element is very reactive and would rapidly oxidize in the sample chamber. To perform the study, we used force spectroscopy with optical tweezers and gel electrophoresis assays. Single molecule force spectroscopy is today recognized as the state-of-the-art technique for studies concerning the interactions between nucleic acids and ligands such as drugs and proteins, being able to provide information on the binding modes and on the physical chemistry of the interaction [[11], [12], [13]]. Gel electrophoresis, on the other hand, is a classic technique which allows one to observe the behavior of a large ensemble of nucleic acids molecules, thus complementing the single molecule analysis obtained from force spectroscopy. Our results show that Eu2O3 binds cooperatively to the double-helix with a high equilibrium association constant (on the order of 105 M−1), i. e., close to that found for many commercial anticancer drugs. Thus, the purpose of the present study is to show the potential of europium for interacting with nucleic acids and to motivate the development of new Eu-based anticancer drugs for chemotherapies.
Section snippets
Optical tweezers assays
The samples prepared for optical tweezers assays consist of λ-DNA molecules (48,502 base-pairs, New England Biolabs) end-labeled with biotin in a Phosphate Buffered Saline (PBS) solution with pH = 7.4. An end of the DNA molecules is attached to a streptavidin-coated polystyrene bead (Bangs Labs) and the other end to a streptavidin-coated coverslip, which is the support of our sample chamber. An o-ring glued in the coverslip surface contains the working solution (buffer and molecules). The
Force spectroscopy
In Fig. 1 we show the persistence length of the DNA-Eu2O3 complexes as a function of the Eu2O3 concentration in the sample, , for the two buffers used: PBS 1.4 mM (black circles) and PBS 154 mM (red squares). The fittings with our quenched-disorder statistical model, using the Hill isotherm, are also shown in the figure as solid lines.
Observe that the two data sets are indistinguishable within the error bars, showing that the interaction is independent on the ionic strength of the surrounding
Conclusions
We have investigated the action of europium oxide Eu2O3 on double-strand DNA molecules in single molecule force spectroscopy assays, showing that this compound presents a strong interaction with the biopolymer that is basically independent on the ionic strength used in the surrounding environment, i. e., the electrostatic character of the interaction is very weak. Among the main characteristics, Eu2O3 tends to bind in a cooperative way, forming bound clusters of ∼3 molecules, and presents a
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
This research was funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) grant number 403229/2016-2 and 400412/2014-4; Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) grant numbers 01927-16 and 01446-14; and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) - Finance Code 001.
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