Triplex metallohelices have enantiomer-dependent mechanisms of action in colon cancer cells

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68081707%3A_____%2F23%3A00572385" target="_blank" >RIV/68081707:_____/23:00572385 - isvavai.cz</a>

Výsledek na webu

<a href="https://pubs.rsc.org/en/content/articlelanding/2023/dt/d3dt00948c" target="_blank" >https://pubs.rsc.org/en/content/articlelanding/2023/dt/d3dt00948c</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1039/d3dt00948c" target="_blank" >10.1039/d3dt00948c</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Triplex metallohelices have enantiomer-dependent mechanisms of action in colon cancer cells

Popis výsledku v původním jazyce

Self-assembled enantiomers of an asymmetric di-iron metallohelix differ in their antiproliferative activities against HCT116 colon cancer cells such that the compound with ?-helicity at the metals becomes more potent than the Delta compound with increasing exposure time. From concentration- and temperature-dependent Fe-57 isotopic labelling studies of cellular accumulation we postulate that while the more potent ? enantiomer undergoes carrier-mediated efflux, for Delta the process is principally equilibrative. Cell fractionation studies demonstrate that both enantiomers localise in a similar fashion, compound is observed mostly within the cytoskeleton and/or genomic DNA, with significant amounts also found in the nucleus and membrane, but with negligible concentration in the cytosol. Cell cycle analyses using flow cytometry reveal that the Delta enantiomer induces mild arrest in the G(1) phase, while ? causes a very large dose-dependent increase in the G(2)/M population at a concentration significantly below the relevant IC50. Correspondingly, G(2)-M checkpoint failure as a result of ?-metallohelix binding to DNA is shown to be feasible by linear dichroism studies, which indicate, in contrast to the Delta compound, a quite specific mode of binding, probably in the major groove. Further, spindle assembly checkpoint (SAC) failure, which could also be responsible for the observed G(2)/M arrest, is established as a feasible mechanism for the ? helix via drug combination (synergy) studies and the discovery of tubulin and actin inhibition. Here, while the ? compound stabilizes F-actin and induces a distinct change in tubulin architecture of HCT116 cells, Delta promotes depolymerization and more subtle changes in microtubule and actin networks.

Název v anglickém jazyce

Triplex metallohelices have enantiomer-dependent mechanisms of action in colon cancer cells

Popis výsledku anglicky

Self-assembled enantiomers of an asymmetric di-iron metallohelix differ in their antiproliferative activities against HCT116 colon cancer cells such that the compound with ?-helicity at the metals becomes more potent than the Delta compound with increasing exposure time. From concentration- and temperature-dependent Fe-57 isotopic labelling studies of cellular accumulation we postulate that while the more potent ? enantiomer undergoes carrier-mediated efflux, for Delta the process is principally equilibrative. Cell fractionation studies demonstrate that both enantiomers localise in a similar fashion, compound is observed mostly within the cytoskeleton and/or genomic DNA, with significant amounts also found in the nucleus and membrane, but with negligible concentration in the cytosol. Cell cycle analyses using flow cytometry reveal that the Delta enantiomer induces mild arrest in the G(1) phase, while ? causes a very large dose-dependent increase in the G(2)/M population at a concentration significantly below the relevant IC50. Correspondingly, G(2)-M checkpoint failure as a result of ?-metallohelix binding to DNA is shown to be feasible by linear dichroism studies, which indicate, in contrast to the Delta compound, a quite specific mode of binding, probably in the major groove. Further, spindle assembly checkpoint (SAC) failure, which could also be responsible for the observed G(2)/M arrest, is established as a feasible mechanism for the ? helix via drug combination (synergy) studies and the discovery of tubulin and actin inhibition. Here, while the ? compound stabilizes F-actin and induces a distinct change in tubulin architecture of HCT116 cells, Delta promotes depolymerization and more subtle changes in microtubule and actin networks.

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/GA21-27514S" target="_blank" >GA21-27514S: Sloučeniny kovů pro zvýšenou imunoterapii rakoviny</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2023

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

1477-9234

Svazek periodika

52

Číslo periodika v rámci svazku

20

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

12

Strana od-do

6656-6667

Kód UT WoS článku

000975765100001

EID výsledku v databázi Scopus

2-s2.0-85158816033