A molecular view of cisplatin's mode of action: interplay with DNA bases and acquired resistance
Main Author: | |
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Publication Date: | 2015 |
Other Authors: | , , , , , , |
Format: | Article |
Language: | eng |
Source: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Download full: | http://hdl.handle.net/10316/33721 https://doi.org/10.1039/c4cp05183a |
Summary: | The interaction of the widely used anticancer drug cisplatin with DNA bases was studied by EXAFS and vibrational spectroscopy (FTIR, Raman and INS), coupled with DFT/plane-wave calculations. Detailed information was obtained on the local atomic structure around the Pt(ii) centre, both in the cisplatin-purine (adenine and guanine) and cisplatin-glutathione adducts. Simultaneous neutron and Raman scattering experiments allowed us to obtain a reliable and definite picture of this cisplatin interplay with its main pharmacological target (DNA), at the molecular level. The vibrational experimental spectra were fully assigned in the light of the calculated pattern for the most favoured geometry of each drug-purine adduct, and cisplatin's preference for guanine (G) relative to adenine (A) within the DNA double helix was experimentally verified: a complete N by S substitution in the metal coordination sphere was only observed for [cDDP-A2], reflecting a somewhat weaker Pt-A binding relative to Pt-G. The role of glutathione on the drug's pharmacokinetics, as well as on the stability of platinated DNA adducts, was evaluated as this is the basis for glutathione-mediated intracellular drug scavenging and in vivo resistance to Pt-based anticancer drugs. Spectroscopic evidence of the metal's preference for glutathione's sulfur over purine's nitrogen binding sites was gathered, at least two sulfur atoms being detected in platinum's first coordination sphere. |
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A molecular view of cisplatin's mode of action: interplay with DNA bases and acquired resistanceAdenineAntineoplastic AgentsCisplatinDNA AdductsGlutathioneGuanineModels, MolecularNucleic Acid ConformationSpectroscopy, Fourier Transform InfraredSpectrum Analysis, RamanX-Ray Absorption SpectroscopyThe interaction of the widely used anticancer drug cisplatin with DNA bases was studied by EXAFS and vibrational spectroscopy (FTIR, Raman and INS), coupled with DFT/plane-wave calculations. Detailed information was obtained on the local atomic structure around the Pt(ii) centre, both in the cisplatin-purine (adenine and guanine) and cisplatin-glutathione adducts. Simultaneous neutron and Raman scattering experiments allowed us to obtain a reliable and definite picture of this cisplatin interplay with its main pharmacological target (DNA), at the molecular level. The vibrational experimental spectra were fully assigned in the light of the calculated pattern for the most favoured geometry of each drug-purine adduct, and cisplatin's preference for guanine (G) relative to adenine (A) within the DNA double helix was experimentally verified: a complete N by S substitution in the metal coordination sphere was only observed for [cDDP-A2], reflecting a somewhat weaker Pt-A binding relative to Pt-G. The role of glutathione on the drug's pharmacokinetics, as well as on the stability of platinated DNA adducts, was evaluated as this is the basis for glutathione-mediated intracellular drug scavenging and in vivo resistance to Pt-based anticancer drugs. Spectroscopic evidence of the metal's preference for glutathione's sulfur over purine's nitrogen binding sites was gathered, at least two sulfur atoms being detected in platinum's first coordination sphere.2015-02-21info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://hdl.handle.net/10316/33721http://hdl.handle.net/10316/33721https://doi.org/10.1039/c4cp05183aengMarques, M. P. M.Gianolio, DiegoCibin, GiannantonioTomkinson, JohnParker, Stewart F.Valero, RosendoPedro Lopes, RCarvalho, Luís A. E. Batista deinfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2021-10-08T07:58:49Zoai:estudogeral.uc.pt:10316/33721Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T20:55:25.514066Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
A molecular view of cisplatin's mode of action: interplay with DNA bases and acquired resistance |
title |
A molecular view of cisplatin's mode of action: interplay with DNA bases and acquired resistance |
spellingShingle |
A molecular view of cisplatin's mode of action: interplay with DNA bases and acquired resistance Marques, M. P. M. Adenine Antineoplastic Agents Cisplatin DNA Adducts Glutathione Guanine Models, Molecular Nucleic Acid Conformation Spectroscopy, Fourier Transform Infrared Spectrum Analysis, Raman X-Ray Absorption Spectroscopy |
title_short |
A molecular view of cisplatin's mode of action: interplay with DNA bases and acquired resistance |
title_full |
A molecular view of cisplatin's mode of action: interplay with DNA bases and acquired resistance |
title_fullStr |
A molecular view of cisplatin's mode of action: interplay with DNA bases and acquired resistance |
title_full_unstemmed |
A molecular view of cisplatin's mode of action: interplay with DNA bases and acquired resistance |
title_sort |
A molecular view of cisplatin's mode of action: interplay with DNA bases and acquired resistance |
author |
Marques, M. P. M. |
author_facet |
Marques, M. P. M. Gianolio, Diego Cibin, Giannantonio Tomkinson, John Parker, Stewart F. Valero, Rosendo Pedro Lopes, R Carvalho, Luís A. E. Batista de |
author_role |
author |
author2 |
Gianolio, Diego Cibin, Giannantonio Tomkinson, John Parker, Stewart F. Valero, Rosendo Pedro Lopes, R Carvalho, Luís A. E. Batista de |
author2_role |
author author author author author author author |
dc.contributor.author.fl_str_mv |
Marques, M. P. M. Gianolio, Diego Cibin, Giannantonio Tomkinson, John Parker, Stewart F. Valero, Rosendo Pedro Lopes, R Carvalho, Luís A. E. Batista de |
dc.subject.por.fl_str_mv |
Adenine Antineoplastic Agents Cisplatin DNA Adducts Glutathione Guanine Models, Molecular Nucleic Acid Conformation Spectroscopy, Fourier Transform Infrared Spectrum Analysis, Raman X-Ray Absorption Spectroscopy |
topic |
Adenine Antineoplastic Agents Cisplatin DNA Adducts Glutathione Guanine Models, Molecular Nucleic Acid Conformation Spectroscopy, Fourier Transform Infrared Spectrum Analysis, Raman X-Ray Absorption Spectroscopy |
description |
The interaction of the widely used anticancer drug cisplatin with DNA bases was studied by EXAFS and vibrational spectroscopy (FTIR, Raman and INS), coupled with DFT/plane-wave calculations. Detailed information was obtained on the local atomic structure around the Pt(ii) centre, both in the cisplatin-purine (adenine and guanine) and cisplatin-glutathione adducts. Simultaneous neutron and Raman scattering experiments allowed us to obtain a reliable and definite picture of this cisplatin interplay with its main pharmacological target (DNA), at the molecular level. The vibrational experimental spectra were fully assigned in the light of the calculated pattern for the most favoured geometry of each drug-purine adduct, and cisplatin's preference for guanine (G) relative to adenine (A) within the DNA double helix was experimentally verified: a complete N by S substitution in the metal coordination sphere was only observed for [cDDP-A2], reflecting a somewhat weaker Pt-A binding relative to Pt-G. The role of glutathione on the drug's pharmacokinetics, as well as on the stability of platinated DNA adducts, was evaluated as this is the basis for glutathione-mediated intracellular drug scavenging and in vivo resistance to Pt-based anticancer drugs. Spectroscopic evidence of the metal's preference for glutathione's sulfur over purine's nitrogen binding sites was gathered, at least two sulfur atoms being detected in platinum's first coordination sphere. |
publishDate |
2015 |
dc.date.none.fl_str_mv |
2015-02-21 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10316/33721 http://hdl.handle.net/10316/33721 https://doi.org/10.1039/c4cp05183a |
url |
http://hdl.handle.net/10316/33721 https://doi.org/10.1039/c4cp05183a |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.source.none.fl_str_mv |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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1799133841623875584 |