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Triple action Pt(iv) derivatives of cisplatin: a new class of potent anticancer agents that overcome resistance

A series of triple action Pt(iv) prodrugs was designed to test the hypothesis that multi-action compounds, where each bioactive moiety intervenes in several cellular processes, might be more effective than a single agent at killing cancer cells. In particular, “triple action” Pt(iv) derivatives of c...

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Autores principales: Petruzzella, Emanuele, Sirota, Roman, Solazzo, Irene, Gandin, Valentina, Gibson, Dan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Royal Society of Chemistry 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5944384/
https://www.ncbi.nlm.nih.gov/pubmed/29780561
http://dx.doi.org/10.1039/c8sc00428e
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author Petruzzella, Emanuele
Sirota, Roman
Solazzo, Irene
Gandin, Valentina
Gibson, Dan
author_facet Petruzzella, Emanuele
Sirota, Roman
Solazzo, Irene
Gandin, Valentina
Gibson, Dan
author_sort Petruzzella, Emanuele
collection PubMed
description A series of triple action Pt(iv) prodrugs was designed to test the hypothesis that multi-action compounds, where each bioactive moiety intervenes in several cellular processes, might be more effective than a single agent at killing cancer cells. In particular, “triple action” Pt(iv) derivatives of cisplatin, where the axial ligands are inhibitors of cyclooxygenase (COXi), histone deacetylase (HDACi) or pyruvate dehydrogenase kinase (PDKi) were developed. All compounds, ctc-[Pt(NH(3))(2)(COXi)(PDKi)Cl(2)], ctc-[Pt(NH(3))(2)(COXi)(HDACi)Cl(2)] and ctc-[Pt(NH(3))(2)(HDACi)(PDKi)Cl(2)], where COXi = aspirin or ibuprofen, PDKi = dichloroacetate and HDACi = valproate or phenylbutyrate, were significantly more cytotoxic than cisplatin against all cell lines of an in-house panel of human cancer cells. They were particularly effective against thyroid and pancreatic cancer cells in monolayer cytotoxicity tests. Remarkably, in 3D spheroid cancer cell cultures, some triple action compounds showed an antitumor potency up to 50-fold higher than cisplatin against a KRAS mutated pancreatic cancer cell line (PSN-1 cells). Standard biochemical assays classically employed to explore structure activity relationships of platinum drugs, such as cellular uptake and binding to potential biological targets (DNA, HDAC, mitochondria, and COX), do not provide linear correlations with the overall cytotoxicity data. We observed a preferential induction of ROS production and of an anti-mitochondrial effect in cancer cells compared to rapidly dividing non-cancerous cells. Thus, we propose that these new triple action Pt(iv) derivatives of cisplatin are a novel and interesting class of potent and selective cytotoxic agents.
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spelling pubmed-59443842018-05-18 Triple action Pt(iv) derivatives of cisplatin: a new class of potent anticancer agents that overcome resistance Petruzzella, Emanuele Sirota, Roman Solazzo, Irene Gandin, Valentina Gibson, Dan Chem Sci Chemistry A series of triple action Pt(iv) prodrugs was designed to test the hypothesis that multi-action compounds, where each bioactive moiety intervenes in several cellular processes, might be more effective than a single agent at killing cancer cells. In particular, “triple action” Pt(iv) derivatives of cisplatin, where the axial ligands are inhibitors of cyclooxygenase (COXi), histone deacetylase (HDACi) or pyruvate dehydrogenase kinase (PDKi) were developed. All compounds, ctc-[Pt(NH(3))(2)(COXi)(PDKi)Cl(2)], ctc-[Pt(NH(3))(2)(COXi)(HDACi)Cl(2)] and ctc-[Pt(NH(3))(2)(HDACi)(PDKi)Cl(2)], where COXi = aspirin or ibuprofen, PDKi = dichloroacetate and HDACi = valproate or phenylbutyrate, were significantly more cytotoxic than cisplatin against all cell lines of an in-house panel of human cancer cells. They were particularly effective against thyroid and pancreatic cancer cells in monolayer cytotoxicity tests. Remarkably, in 3D spheroid cancer cell cultures, some triple action compounds showed an antitumor potency up to 50-fold higher than cisplatin against a KRAS mutated pancreatic cancer cell line (PSN-1 cells). Standard biochemical assays classically employed to explore structure activity relationships of platinum drugs, such as cellular uptake and binding to potential biological targets (DNA, HDAC, mitochondria, and COX), do not provide linear correlations with the overall cytotoxicity data. We observed a preferential induction of ROS production and of an anti-mitochondrial effect in cancer cells compared to rapidly dividing non-cancerous cells. Thus, we propose that these new triple action Pt(iv) derivatives of cisplatin are a novel and interesting class of potent and selective cytotoxic agents. Royal Society of Chemistry 2018-04-24 /pmc/articles/PMC5944384/ /pubmed/29780561 http://dx.doi.org/10.1039/c8sc00428e Text en This journal is © The Royal Society of Chemistry 2018 http://creativecommons.org/licenses/by-nc/3.0/ This article is freely available. This article is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported Licence (CC BY-NC 3.0)
spellingShingle Chemistry
Petruzzella, Emanuele
Sirota, Roman
Solazzo, Irene
Gandin, Valentina
Gibson, Dan
Triple action Pt(iv) derivatives of cisplatin: a new class of potent anticancer agents that overcome resistance
title Triple action Pt(iv) derivatives of cisplatin: a new class of potent anticancer agents that overcome resistance
title_full Triple action Pt(iv) derivatives of cisplatin: a new class of potent anticancer agents that overcome resistance
title_fullStr Triple action Pt(iv) derivatives of cisplatin: a new class of potent anticancer agents that overcome resistance
title_full_unstemmed Triple action Pt(iv) derivatives of cisplatin: a new class of potent anticancer agents that overcome resistance
title_short Triple action Pt(iv) derivatives of cisplatin: a new class of potent anticancer agents that overcome resistance
title_sort triple action pt(iv) derivatives of cisplatin: a new class of potent anticancer agents that overcome resistance
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5944384/
https://www.ncbi.nlm.nih.gov/pubmed/29780561
http://dx.doi.org/10.1039/c8sc00428e
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