Epigenetic and antitumor effects of platinum(IV)-octanoato conjugates

Abstract We present the anticancer properties of cis, cis, trans-[Pt(IV)(NH3)2Cl2(OA)2] [Pt(IV)diOA] (OA = octanoato), Pt(IV) derivative of cisplatin containing two OA units appended to the axial positions of a six-coordinate Pt(IV) center. Our results demonstrate that Pt(IV)diOA is a potent cytotox...

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Autores principales:	Vojtech Novohradsky, Ilaria Zanellato, Cristina Marzano, Jitka Pracharova, Jana Kasparkova, Dan Gibson, Valentina Gandin, Domenico Osella, Viktor Brabec
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8c8d7ac8a35249ac83c6856771eb6c7d
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spelling	oai:doaj.org-article:8c8d7ac8a35249ac83c6856771eb6c7d2021-12-02T15:05:35ZEpigenetic and antitumor effects of platinum(IV)-octanoato conjugates10.1038/s41598-017-03864-w2045-2322https://doaj.org/article/8c8d7ac8a35249ac83c6856771eb6c7d2017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03864-whttps://doaj.org/toc/2045-2322Abstract We present the anticancer properties of cis, cis, trans-[Pt(IV)(NH3)2Cl2(OA)2] [Pt(IV)diOA] (OA = octanoato), Pt(IV) derivative of cisplatin containing two OA units appended to the axial positions of a six-coordinate Pt(IV) center. Our results demonstrate that Pt(IV)diOA is a potent cytotoxic agent against many cancer cell lines (the IC50 values are approximately two orders of magnitude lower than those of clinically used cisplatin or Pt(IV) derivatives with biologically inactive axial ligands). Importantly, Pt(IV)diOA overcomes resistance to cisplatin, is significantly more potent than its branched Pt(IV) valproato isomer and exhibits promising in vivo antitumor activity. The potency of Pt(IV)diOA is a consequence of several factors including enhanced cellular accumulation correlating with enhanced DNA platination and cytotoxicity. Pt(IV)diOA induces DNA hypermethylation and reduces mitochondrial membrane potential in cancer cells at levels markedly lower than the IC50 value of free OA suggesting the synergistic action of platinum and OA moieties. Collectively, the remarkable antitumor effects of Pt(IV)diOA are a consequence of the enhanced cellular uptake which makes it possible to simultaneously accumulate high levels of both cisplatin and OA in cells. The simultaneous dual action of cisplatin and OA by different mechanisms in tumor cells may result in a markedly enhanced and unique antitumor effects of Pt(IV) prodrugs.Vojtech NovohradskyIlaria ZanellatoCristina MarzanoJitka PracharovaJana KasparkovaDan GibsonValentina GandinDomenico OsellaViktor BrabecNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Vojtech Novohradsky Ilaria Zanellato Cristina Marzano Jitka Pracharova Jana Kasparkova Dan Gibson Valentina Gandin Domenico Osella Viktor Brabec Epigenetic and antitumor effects of platinum(IV)-octanoato conjugates
description	Abstract We present the anticancer properties of cis, cis, trans-[Pt(IV)(NH3)2Cl2(OA)2] [Pt(IV)diOA] (OA = octanoato), Pt(IV) derivative of cisplatin containing two OA units appended to the axial positions of a six-coordinate Pt(IV) center. Our results demonstrate that Pt(IV)diOA is a potent cytotoxic agent against many cancer cell lines (the IC50 values are approximately two orders of magnitude lower than those of clinically used cisplatin or Pt(IV) derivatives with biologically inactive axial ligands). Importantly, Pt(IV)diOA overcomes resistance to cisplatin, is significantly more potent than its branched Pt(IV) valproato isomer and exhibits promising in vivo antitumor activity. The potency of Pt(IV)diOA is a consequence of several factors including enhanced cellular accumulation correlating with enhanced DNA platination and cytotoxicity. Pt(IV)diOA induces DNA hypermethylation and reduces mitochondrial membrane potential in cancer cells at levels markedly lower than the IC50 value of free OA suggesting the synergistic action of platinum and OA moieties. Collectively, the remarkable antitumor effects of Pt(IV)diOA are a consequence of the enhanced cellular uptake which makes it possible to simultaneously accumulate high levels of both cisplatin and OA in cells. The simultaneous dual action of cisplatin and OA by different mechanisms in tumor cells may result in a markedly enhanced and unique antitumor effects of Pt(IV) prodrugs.
format	article
author	Vojtech Novohradsky Ilaria Zanellato Cristina Marzano Jitka Pracharova Jana Kasparkova Dan Gibson Valentina Gandin Domenico Osella Viktor Brabec
author_facet	Vojtech Novohradsky Ilaria Zanellato Cristina Marzano Jitka Pracharova Jana Kasparkova Dan Gibson Valentina Gandin Domenico Osella Viktor Brabec
author_sort	Vojtech Novohradsky
title	Epigenetic and antitumor effects of platinum(IV)-octanoato conjugates
title_short	Epigenetic and antitumor effects of platinum(IV)-octanoato conjugates
title_full	Epigenetic and antitumor effects of platinum(IV)-octanoato conjugates
title_fullStr	Epigenetic and antitumor effects of platinum(IV)-octanoato conjugates
title_full_unstemmed	Epigenetic and antitumor effects of platinum(IV)-octanoato conjugates
title_sort	epigenetic and antitumor effects of platinum(iv)-octanoato conjugates
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/8c8d7ac8a35249ac83c6856771eb6c7d
work_keys_str_mv	AT vojtechnovohradsky epigeneticandantitumoreffectsofplatinumivoctanoatoconjugates AT ilariazanellato epigeneticandantitumoreffectsofplatinumivoctanoatoconjugates AT cristinamarzano epigeneticandantitumoreffectsofplatinumivoctanoatoconjugates AT jitkapracharova epigeneticandantitumoreffectsofplatinumivoctanoatoconjugates AT janakasparkova epigeneticandantitumoreffectsofplatinumivoctanoatoconjugates AT dangibson epigeneticandantitumoreffectsofplatinumivoctanoatoconjugates AT valentinagandin epigeneticandantitumoreffectsofplatinumivoctanoatoconjugates AT domenicoosella epigeneticandantitumoreffectsofplatinumivoctanoatoconjugates AT viktorbrabec epigeneticandantitumoreffectsofplatinumivoctanoatoconjugates
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Epigenetic and antitumor effects of platinum(IV)-octanoato conjugates

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