title: Platinum-Based Drugs and DNA Interactions Studied by Single-Molecule and Bulk Measurements.
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.
authors.affiliation: School of Medicine, Università di Milano-Bicocca, Monza, Italy. Electronic address: domenico.salerno@unimib.it.
authors.forename: Domenico
authors.initials: D
authors.lastname: Salerno
authors.affiliation: Dipartimento di Oncologia Sperimentale e Medicina Molecolare, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy.
authors.forename: Giovanni L
authors.initials: GL
authors.lastname: Beretta
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina Translazionale, Università degli Studi di Milano, Segrate, Italy.
authors.forename: Giuliano
authors.initials: G
authors.lastname: Zanchetta
authors.affiliation: School of Medicine, Università di Milano-Bicocca, Monza, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Brioschi
authors.affiliation: School of Medicine, Università di Milano-Bicocca, Monza, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Cristofalo
authors.affiliation: School of Medicine, Università di Milano-Bicocca, Monza, Italy.
authors.forename: Natalia
authors.initials: N
authors.lastname: Missana
authors.affiliation: School of Medicine, Università di Milano-Bicocca, Monza, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Nardo
authors.affiliation: School of Medicine, Università di Milano-Bicocca, Monza, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Cassina
authors.affiliation: School of Medicine, Università di Milano-Bicocca, Monza, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Tempestini
authors.affiliation: Dipartimento di Scienze Chirurgiche, Università di Milano-Bicocca, Monza, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Giovannoni
authors.affiliation: Dipartimento di Scienze Chirurgiche, Università di Milano-Bicocca, Monza, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Cerrito
authors.affiliation: Dipartimento di Oncologia Sperimentale e Medicina Molecolare, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Zaffaroni
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina Translazionale, Università degli Studi di Milano, Segrate, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Bellini
authors.affiliation: School of Medicine, Università di Milano-Bicocca, Monza, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Mantegazza
mesh_terms: D000465:Algorithms; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D005615:Freezing; D015394:Molecular Structure; D009691:Nucleic Acid Denaturation / Q000187:drug effects; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D010957:Plasmids / Q000235:genetics; D013057:Spectrum Analysis
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C059267:dichlorotetraamine(1,6-hexamethylenediamine)diplatinum(II); D004247:DNA; C114062:BBR 3464; D002945:Cisplatin