Potentiation of mitochondrial dysfunction in tumor cells by conjugates of metabolic modulator dichloroacetate with a Pt(IV) derivative of oxaliplatin

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68081707%3A_____%2F16%3A00506413" target="_blank" >RIV/68081707:_____/16:00506413 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/61989592:15310/16:33161184

Výsledek na webu

<a href="https://www.sciencedirect.com/science/article/pii/S0162013415301331?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0162013415301331?via%3Dihub</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.jinorgbio.2015.12.003" target="_blank" >10.1016/j.jinorgbio.2015.12.003</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Potentiation of mitochondrial dysfunction in tumor cells by conjugates of metabolic modulator dichloroacetate with a Pt(IV) derivative of oxaliplatin

Popis výsledku v původním jazyce

The molecular and cellular mechanisms of enhanced toxic effects in tumor cells of the Pt(IV) derivatives of antitumor oxaliplatin containing axial dichloroacetate (DCA) ligands were investigated. DCA ligands were chosen because DCA has shown great potential as an apoptosis sensitizer and anticancer agent reverting the Wartburg effect. In addition, DCA reverses mitochondrial changes in a wide range of cancers, promoting tumor cell apoptosis in a mitochondrial-dependent pathway. We demonstrate that (i) the transformation of oxaliplatin to its Pt(IV) derivatives containing axial DCA ligands markedly enhances toxicity in cancer cells and helps overcome inherent and acquired resistance to cisplatin and oxaliplatin, (ii) a significant fraction of the intact molecules of DCA conjugates with Pt(IV) derivative of oxaliplatin accumulates in cancer cells where it releases free DCA, (iii) mechanism of biological action of the Pt(IV) derivatives of oxaliplatin containing DCA ligands is connected with the effects of DCA released in cancer cells from the Pt(IV) prodrugs on mitochondria and metabolism of glucose, (iv) treatments with the Pt(IV) derivatives of oxaliplatin containing DCA ligands activate an autophagic response in human colorectal cancer cells, (v) the toxic effects in cancer cells of the Pt(IV) derivatives of oxaliplatin containing DCA ligands can be potentiated if cells are treated with these prodrugs in combination with 5-fluorouracil. These properties of the Pt(IV) derivatives of oxaliplatin containing DCA ligands provide opportunities for further development of new platinum-based agents with the capability of killing cancer cells resistant to conventional antitumor platinum drugs used in the clinic. (C) 2015 Elsevier Inc. All rights reserved.

Název v anglickém jazyce

Potentiation of mitochondrial dysfunction in tumor cells by conjugates of metabolic modulator dichloroacetate with a Pt(IV) derivative of oxaliplatin

Popis výsledku anglicky

The molecular and cellular mechanisms of enhanced toxic effects in tumor cells of the Pt(IV) derivatives of antitumor oxaliplatin containing axial dichloroacetate (DCA) ligands were investigated. DCA ligands were chosen because DCA has shown great potential as an apoptosis sensitizer and anticancer agent reverting the Wartburg effect. In addition, DCA reverses mitochondrial changes in a wide range of cancers, promoting tumor cell apoptosis in a mitochondrial-dependent pathway. We demonstrate that (i) the transformation of oxaliplatin to its Pt(IV) derivatives containing axial DCA ligands markedly enhances toxicity in cancer cells and helps overcome inherent and acquired resistance to cisplatin and oxaliplatin, (ii) a significant fraction of the intact molecules of DCA conjugates with Pt(IV) derivative of oxaliplatin accumulates in cancer cells where it releases free DCA, (iii) mechanism of biological action of the Pt(IV) derivatives of oxaliplatin containing DCA ligands is connected with the effects of DCA released in cancer cells from the Pt(IV) prodrugs on mitochondria and metabolism of glucose, (iv) treatments with the Pt(IV) derivatives of oxaliplatin containing DCA ligands activate an autophagic response in human colorectal cancer cells, (v) the toxic effects in cancer cells of the Pt(IV) derivatives of oxaliplatin containing DCA ligands can be potentiated if cells are treated with these prodrugs in combination with 5-fluorouracil. These properties of the Pt(IV) derivatives of oxaliplatin containing DCA ligands provide opportunities for further development of new platinum-based agents with the capability of killing cancer cells resistant to conventional antitumor platinum drugs used in the clinic. (C) 2015 Elsevier Inc. All rights reserved.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

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

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

Rok uplatnění

2016

Kód důvěrnosti údajů

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

Název periodika

Journal of Inorganic Biochemistry

ISSN

0162-0134

e-ISSN

—

Svazek periodika

156

Číslo periodika v rámci svazku

MAR 2016

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

9

Strana od-do

89-97

Kód UT WoS článku

000370769400010

EID výsledku v databázi Scopus

—