Pt(IV) derivatives of cisplatin and oxaliplatin with phenylbutyrate axial ligands are potent cytotoxic agents that act by several mechanisms of action

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68081707%3A_____%2F16%3A00471983" target="_blank" >RIV/68081707:_____/16:00471983 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/61989592:15310/16:33161172

Výsledek na webu

<a href="http://dx.doi.org/10.1039/c5sc04205d" target="_blank" >http://dx.doi.org/10.1039/c5sc04205d</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1039/c5sc04205d" target="_blank" >10.1039/c5sc04205d</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Pt(IV) derivatives of cisplatin and oxaliplatin with phenylbutyrate axial ligands are potent cytotoxic agents that act by several mechanisms of action

Popis výsledku v původním jazyce

Our study demonstrates that Pt(IV) derivative of cisplatin, with two axial PhB ligands, ctc-[Pt(NH3)(2)(PhB)(2)Cl-2], is a very potent cytotoxic agent against many different human cancer cell lines and is up to 100 fold more potent than cisplatin, and significantly more potent than the Pt(IV) derivatives of cisplatin with either two hydroxido, two acetato or two valproato ligands. The high potency of this compound (and some others) is due to several factors including enhanced internalization, probably driven by "synergistic accumulation" of both the Pt moiety and the phenylbutyrate, that correlates with enhanced DNA binding and cytotoxicity. ctc-[Pt(NH3)(2)(PhB)(2)Cl-2] inhibits 60-70% HDAC activity in cancer cells, at levels below the IC50 values of PhB, suggesting synergism between Pt and PhB. Mechanistically, ctc[Pt(NH3)(2)(PhB)(2)Cl-2] induces activation of caspases (3 and 9) triggering apoptotic signaling via the mitochondrial pathway. Data also suggest that the antiproliferative effect of ctc-[Pt(NH3)(2)(PhB)(2)Cl-2] may not depend of p53. Pt(IV) derivatives of cisplatin with either two axial PhB or valproate ligands are more potent than their oxaliplatin analogs. ctc-[Pt(NH3)(2)(PhB)(2)Cl-2] is significantly more potent than its valproate analog ctc-[Pt(NH3)(2)(VPA)(2)Cl-2]. These compounds combine multiple effects such as efficient uptake of both Pt and PhB with DNA binding, HDAC inhibition and activation of caspases to effectively kill cancer cells.

Název v anglickém jazyce

Pt(IV) derivatives of cisplatin and oxaliplatin with phenylbutyrate axial ligands are potent cytotoxic agents that act by several mechanisms of action

Popis výsledku anglicky

Our study demonstrates that Pt(IV) derivative of cisplatin, with two axial PhB ligands, ctc-[Pt(NH3)(2)(PhB)(2)Cl-2], is a very potent cytotoxic agent against many different human cancer cell lines and is up to 100 fold more potent than cisplatin, and significantly more potent than the Pt(IV) derivatives of cisplatin with either two hydroxido, two acetato or two valproato ligands. The high potency of this compound (and some others) is due to several factors including enhanced internalization, probably driven by "synergistic accumulation" of both the Pt moiety and the phenylbutyrate, that correlates with enhanced DNA binding and cytotoxicity. ctc-[Pt(NH3)(2)(PhB)(2)Cl-2] inhibits 60-70% HDAC activity in cancer cells, at levels below the IC50 values of PhB, suggesting synergism between Pt and PhB. Mechanistically, ctc[Pt(NH3)(2)(PhB)(2)Cl-2] induces activation of caspases (3 and 9) triggering apoptotic signaling via the mitochondrial pathway. Data also suggest that the antiproliferative effect of ctc-[Pt(NH3)(2)(PhB)(2)Cl-2] may not depend of p53. Pt(IV) derivatives of cisplatin with either two axial PhB or valproate ligands are more potent than their oxaliplatin analogs. ctc-[Pt(NH3)(2)(PhB)(2)Cl-2] is significantly more potent than its valproate analog ctc-[Pt(NH3)(2)(VPA)(2)Cl-2]. These compounds combine multiple effects such as efficient uptake of both Pt and PhB with DNA binding, HDAC inhibition and activation of caspases to effectively kill cancer cells.

Druh

J_x - Nezařazeno - Článek v odborném periodiku (Jimp, Jsc a Jost)

CEP obor

BO - Biofyzika

OECD FORD obor

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Projekt

<a href="/cs/project/GA14-21053S" target="_blank" >GA14-21053S: Mechanistické studie o duálním cílení DNA a deacetylázy histonů bifunkčními inhibitory</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2016

Kód důvěrnosti údajů

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

Název periodika

Chemical Science

ISSN

2041-6520

e-ISSN

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Svazek periodika

7

Číslo periodika v rámci svazku

3

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

11

Strana od-do

2381-2391

Kód UT WoS článku

000371021900096

EID výsledku v databázi Scopus

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