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

4 Citations (Scopus)

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

Fingerprint

Platinum
Drug Interactions
DNA
Platinum Compounds
Pharmaceutical Preparations
Cisplatin
Nucleic Acid Denaturation
Poisons
Drug Design
DNA Damage
Hot Temperature
Apoptosis

ASJC Scopus subject areas

  • Biophysics

Cite this

Salerno, D., Beretta, G. L., Zanchetta, G., Brioschi, S., Cristofalo, M., Missana, N., ... 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

Platinum-Based Drugs and DNA Interactions Studied by Single-Molecule and Bulk Measurements. / Salerno, Domenico; Beretta, Giovanni L.; Zanchetta, Giuliano; Brioschi, Simone; Cristofalo, Matteo; Missana, Natalia; Nardo, Luca; Cassina, Valeria; Tempestini, Alessia; Giovannoni, Roberto; Cerrito, Maria Grazia; Zaffaroni, Nadia; Bellini, Tommaso; Mantegazza, Francesco.

In: Biophysical Journal, Vol. 110, No. 10, 24.05.2016, p. 2151-2161.

Research output: Contribution to journalArticle

Salerno, D, Beretta, GL, Zanchetta, G, Brioschi, S, Cristofalo, M, Missana, N, Nardo, L, Cassina, V, Tempestini, A, Giovannoni, R, Cerrito, MG, Zaffaroni, N, Bellini, T & Mantegazza, F 2016, 'Platinum-Based Drugs and DNA Interactions Studied by Single-Molecule and Bulk Measurements', Biophysical Journal, vol. 110, no. 10, pp. 2151-2161. https://doi.org/10.1016/j.bpj.2016.02.030
Salerno D, Beretta GL, Zanchetta G, Brioschi S, Cristofalo M, Missana N et al. Platinum-Based Drugs and DNA Interactions Studied by Single-Molecule and Bulk Measurements. Biophysical Journal. 2016 May 24;110(10):2151-2161. https://doi.org/10.1016/j.bpj.2016.02.030
Salerno, Domenico ; Beretta, Giovanni L. ; Zanchetta, Giuliano ; Brioschi, Simone ; Cristofalo, Matteo ; Missana, Natalia ; Nardo, Luca ; Cassina, Valeria ; Tempestini, Alessia ; Giovannoni, Roberto ; Cerrito, Maria Grazia ; Zaffaroni, Nadia ; Bellini, Tommaso ; Mantegazza, Francesco. / Platinum-Based Drugs and DNA Interactions Studied by Single-Molecule and Bulk Measurements. In: Biophysical Journal. 2016 ; Vol. 110, No. 10. pp. 2151-2161.
@article{a56c9fda3567412387325687c70fe4b0,
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.",
author = "Domenico Salerno and Beretta, {Giovanni L.} and Giuliano Zanchetta and Simone Brioschi and Matteo Cristofalo and Natalia Missana and Luca Nardo and Valeria Cassina and Alessia Tempestini and Roberto Giovannoni and Cerrito, {Maria Grazia} and Nadia Zaffaroni and Tommaso Bellini and Francesco Mantegazza",
year = "2016",
month = "5",
day = "24",
doi = "10.1016/j.bpj.2016.02.030",
language = "English",
volume = "110",
pages = "2151--2161",
journal = "Biophysical Journal",
issn = "0006-3495",
publisher = "Biophysical Society",
number = "10",

}

TY - JOUR

T1 - Platinum-Based Drugs and DNA Interactions Studied by Single-Molecule and Bulk Measurements

AU - Salerno, Domenico

AU - Beretta, Giovanni L.

AU - Zanchetta, Giuliano

AU - Brioschi, Simone

AU - Cristofalo, Matteo

AU - Missana, Natalia

AU - Nardo, Luca

AU - Cassina, Valeria

AU - Tempestini, Alessia

AU - Giovannoni, Roberto

AU - Cerrito, Maria Grazia

AU - Zaffaroni, Nadia

AU - Bellini, Tommaso

AU - Mantegazza, Francesco

PY - 2016/5/24

Y1 - 2016/5/24

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84969760105&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84969760105&partnerID=8YFLogxK

U2 - 10.1016/j.bpj.2016.02.030

DO - 10.1016/j.bpj.2016.02.030

M3 - Article

AN - SCOPUS:84969760105

VL - 110

SP - 2151

EP - 2161

JO - Biophysical Journal

JF - Biophysical Journal

SN - 0006-3495

IS - 10

ER -