An Anticancer Pt-IV Prodrug That Acts by Mechanisms Involving DNA Damage and Different Epigenetic Effects

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68081707%3A_____%2F19%3A00510854" target="_blank" >RIV/68081707:_____/19:00510854 - isvavai.cz</a>

Výsledek na webu

<a href="https://onlinelibrary.wiley.com/doi/abs/10.1002/chem.201805626" target="_blank" >https://onlinelibrary.wiley.com/doi/abs/10.1002/chem.201805626</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1002/chem.201805626" target="_blank" >10.1002/chem.201805626</a>

Jazyk výsledku

angličtina

Název v původním jazyce

An Anticancer Pt-IV Prodrug That Acts by Mechanisms Involving DNA Damage and Different Epigenetic Effects

Popis výsledku v původním jazyce

Dual- or multi-action Pt-IV prodrugs represent a new generation of platinum anticancer drugs. The important property of these Pt-IV prodrugs is that their antitumor action combines several different mechanisms owing to the presence of biologically active axial ligands. This work describes the synthesis and some biological properties of a triple-action prodrug that releases in cancer cells cisplatin and two different epigenetically acting moieties, octanoate and phenylbutyrate. It is demonstrated, with the aid of modern methods of molecular and cellular biology and pharmacology, that the presence of three different functionalities in a single molecule of the Pt-IV prodrug results in a selective and high potency in tumor cells including those resistant to cisplatin [the IC50 values in the screened malignant cell lines ranged from as low as 9nm (HCT-116) to 74nm (MDA-MB-231)]. It is also demonstrated that cellular activation of the Pt-IV prodrug results in covalent modification of DNA through the release of the platinum moiety accompanied by inhibition of the activity of histone deacetylases caused by phenylbutyrate and by global hypermethylation of DNA by octanoate. Thus, the Pt-IV prodrug introduced in this study acts as a true multi-action prodrug, which is over two orders of magnitude more active than clinically used cisplatin, in both 2D monolayer culture and 3D spheroid cancer cells.

Název v anglickém jazyce

An Anticancer Pt-IV Prodrug That Acts by Mechanisms Involving DNA Damage and Different Epigenetic Effects

Popis výsledku anglicky

Dual- or multi-action Pt-IV prodrugs represent a new generation of platinum anticancer drugs. The important property of these Pt-IV prodrugs is that their antitumor action combines several different mechanisms owing to the presence of biologically active axial ligands. This work describes the synthesis and some biological properties of a triple-action prodrug that releases in cancer cells cisplatin and two different epigenetically acting moieties, octanoate and phenylbutyrate. It is demonstrated, with the aid of modern methods of molecular and cellular biology and pharmacology, that the presence of three different functionalities in a single molecule of the Pt-IV prodrug results in a selective and high potency in tumor cells including those resistant to cisplatin [the IC50 values in the screened malignant cell lines ranged from as low as 9nm (HCT-116) to 74nm (MDA-MB-231)]. It is also demonstrated that cellular activation of the Pt-IV prodrug results in covalent modification of DNA through the release of the platinum moiety accompanied by inhibition of the activity of histone deacetylases caused by phenylbutyrate and by global hypermethylation of DNA by octanoate. Thus, the Pt-IV prodrug introduced in this study acts as a true multi-action prodrug, which is over two orders of magnitude more active than clinically used cisplatin, in both 2D monolayer culture and 3D spheroid cancer cells.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10406 - Analytical chemistry

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2019

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Chemistry - A European Journal

ISSN

0947-6539

e-ISSN

—

Svazek periodika

25

Číslo periodika v rámci svazku

20

Stát vydavatele periodika

DE - Spolková republika Německo

Počet stran výsledku

11

Strana od-do

5235-5245

Kód UT WoS článku

000468855200017

EID výsledku v databázi Scopus

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