Antitumoral effects of mitochondria-targeting neutral and cationic cis-[bis(1,3-dibenzylimidazol-2-ylidene)Cl(L)]Pt(II) complexes

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68081707%3A_____%2F20%3A00535789" target="_blank" >RIV/68081707:_____/20:00535789 - isvavai.cz</a>

Výsledek na webu

<a href="https://pubs.rsc.org/en/content/articlelanding/2020/DT/D0DT01664K#!divAbstract" target="_blank" >https://pubs.rsc.org/en/content/articlelanding/2020/DT/D0DT01664K#!divAbstract</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1039/d0dt01664k" target="_blank" >10.1039/d0dt01664k</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Antitumoral effects of mitochondria-targeting neutral and cationic cis-[bis(1,3-dibenzylimidazol-2-ylidene)Cl(L)]Pt(II) complexes

Popis výsledku v původním jazyce

Recently, we opened a synthetic access to antitumoral platinum complexes of the typecis-[(NHC)(1)(NHC)(PtCl)-Pt-2-Cl-II(L)] which interact with DNA in a way correlated to the complex charge and to the sterical accessibility of the leaving chlorido ligand. We now identified mitochondria rather than nuclei as the cellular target of the neutral dichlorido complex1(L = Cl) and the delocalized lipophilic cationic phosphine complex2(L = PPh3), both carrying the samecis-bis(1,3-dibenzylimidazol-2-ylidene) ligands. Their uptake into 518A2 melanoma cells was concentration-dependent and distinctly greater for complex2which was also more cytotoxic against sensitive cancer cell lines with submicromolar IC(50)values. Both complexes interfered strongly with various forms of DNAin vitro, but only complex2caused a melanoma cell cycle arrest in G1-phase, setting both apart from the S-phase arresting drug cisplatin. Studies of the intracellular localisation of1and2were carried out with their alkyne-tagged analogues6and7, which showed identical patterns of cancer cell cytotoxicity, cell cycle interference and effects on mitochondria. Click reactions with 7-hydroxycoumarin azide, colocalisation with Mitotracker (TM) and confocal microscopy, proved complexes6and7to accumulate mainly in the mitochondria rather than the nuclei of melanoma cells. Complex1and even more so complex2reduced the mitochondrial membrane potential and also increased the cellular ROS levels. As a consequence, both complexes caused stress fibre formation in the F-actin cytoskeleton of melanoma cells, most distinctly so complex2which also activated the apoptotic cascade mediated by capases-3 and7.

Název v anglickém jazyce

Antitumoral effects of mitochondria-targeting neutral and cationic cis-[bis(1,3-dibenzylimidazol-2-ylidene)Cl(L)]Pt(II) complexes

Popis výsledku anglicky

Recently, we opened a synthetic access to antitumoral platinum complexes of the typecis-[(NHC)(1)(NHC)(PtCl)-Pt-2-Cl-II(L)] which interact with DNA in a way correlated to the complex charge and to the sterical accessibility of the leaving chlorido ligand. We now identified mitochondria rather than nuclei as the cellular target of the neutral dichlorido complex1(L = Cl) and the delocalized lipophilic cationic phosphine complex2(L = PPh3), both carrying the samecis-bis(1,3-dibenzylimidazol-2-ylidene) ligands. Their uptake into 518A2 melanoma cells was concentration-dependent and distinctly greater for complex2which was also more cytotoxic against sensitive cancer cell lines with submicromolar IC(50)values. Both complexes interfered strongly with various forms of DNAin vitro, but only complex2caused a melanoma cell cycle arrest in G1-phase, setting both apart from the S-phase arresting drug cisplatin. Studies of the intracellular localisation of1and2were carried out with their alkyne-tagged analogues6and7, which showed identical patterns of cancer cell cytotoxicity, cell cycle interference and effects on mitochondria. Click reactions with 7-hydroxycoumarin azide, colocalisation with Mitotracker (TM) and confocal microscopy, proved complexes6and7to accumulate mainly in the mitochondria rather than the nuclei of melanoma cells. Complex1and even more so complex2reduced the mitochondrial membrane potential and also increased the cellular ROS levels. As a consequence, both complexes caused stress fibre formation in the F-actin cytoskeleton of melanoma cells, most distinctly so complex2which also activated the apoptotic cascade mediated by capases-3 and7.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10402 - Inorganic and nuclear chemistry

Projekt

<a href="/cs/project/GA18-09502S" target="_blank" >GA18-09502S: Ovlivnění rezistence nádorových buněk k chemoterapii s cílem obnovit jejich citlivost k novým, existujícím a dosud neúspěšným metalofarmakům</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2020

Kód důvěrnosti údajů

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

Název periodika

Dalton Transactions

ISSN

1477-9226

e-ISSN

—

Svazek periodika

49

Číslo periodika v rámci svazku

26

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

10

Strana od-do

8901-8910

Kód UT WoS článku

000552458700009

EID výsledku v databázi Scopus

2-s2.0-85087768365