Platinum-Based Drugs and DNA Interactions Studied by Single-Molecule and Bulk Measurements

Domenico Salerno, Giovanni L. Beretta, Giuliano Zanchetta, Simone Brioschi, Matteo Cristofalo, Natalia Missana, Luca Nardo, Valeria Cassina, Alessia Tempestini, Roberto Giovannoni, Maria Grazia Cerrito, Nadia Zaffaroni, Tommaso Bellini, Francesco Mantegazza

Research output: Contribution to journalArticle

Abstract

Platinum-containing molecules are widely used as anticancer drugs. These molecules exert cytotoxic effects by binding to DNA through various mechanisms. The binding between DNA and platinum-based drugs hinders the opening of DNA, and therefore, DNA duplication and transcription are severely hampered. Overall, impeding the above-mentioned important DNA mechanisms results in irreversible DNA damage and the induction of apoptosis. Several molecules, including multinuclear platinum compounds, belong to the family of platinum drugs, and there is a body of research devoted to developing more efficient and less toxic versions of these compounds. In this study, we combined different biophysical methods, including single-molecule assays (magnetic tweezers) and bulk experiments (ultraviolet absorption for thermal denaturation) to analyze the differential stability of double-stranded DNA in complex with either cisplatin or multinuclear platinum agents. Specifically, we analyzed how the binding of BBR3005 and BBR3464, two representative multinuclear platinum-based compounds, to DNA affects its stability as compared with cisplatin binding. Our results suggest that single-molecule approaches can provide insights into the drug-DNA interactions that underlie drug potency and provide information that is complementary to that generated from bulk analysis; thus, single-molecule approaches have the potential to facilitate the selection and design of optimized drug compounds. In particular, relevant differences in DNA stability at the single-molecule level are demonstrated by analyzing nanomechanically induced DNA denaturation. On the basis of the comparison between the single-molecule and bulk analyses, we suggest that transplatinated drugs are able to locally destabilize small portions of the DNA chain, whereas other regions are stabilized.

Original languageEnglish
Pages (from-to)2151-2161
Number of pages11
JournalBiophysical Journal
Volume110
Issue number10
DOIs
Publication statusPublished - May 24 2016

ASJC Scopus subject areas

  • Biophysics

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    Salerno, D., Beretta, G. L., Zanchetta, G., Brioschi, S., Cristofalo, M., Missana, N., Nardo, L., Cassina, V., Tempestini, A., Giovannoni, R., Cerrito, M. G., Zaffaroni, N., Bellini, T., & Mantegazza, F. (2016). Platinum-Based Drugs and DNA Interactions Studied by Single-Molecule and Bulk Measurements. Biophysical Journal, 110(10), 2151-2161. https://doi.org/10.1016/j.bpj.2016.02.030