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Triplex metallohelices have enantiomer-dependent mechanisms of action in colon cancer cells
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SYSNO ASEP 0572385 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Triplex metallohelices have enantiomer-dependent mechanisms of action in colon cancer cells Tvůrce(i) Coverdale, J.P.C. (GB)
Kostrhunová, Hana (BFU-R) RID, ORCID
Marková, Lenka (BFU-R) ORCID
Song, H. (GB)
Postings, M. (GB)
Bridgewater, H. (GB)
Brabec, Viktor (BFU-R) RID, ORCID
Rogers, N.J. (GB)
Scott, P. (GB)Celkový počet autorů 9 Zdroj.dok. Dalton Transactions. - : Royal Society of Chemistry - ISSN 1477-9226
Roč. 52, č. 20 (2023), s. 6656-6667Poč.str. 12 s. Forma vydání Tištěná - P Jazyk dok. eng - angličtina Země vyd. GB - Velká Británie Klíč. slova METALLOSUPRAMOLECULAR CYLINDERS ; BINDING ; TARGET Vědní obor RIV CA - Anorganická chemie Obor OECD Inorganic and nuclear chemistry CEP GA21-27514S GA ČR - Grantová agentura ČR Způsob publikování Open access Institucionální podpora BFU-R - RVO:68081707 UT WOS 000975765100001 EID SCOPUS 85158816033 DOI 10.1039/d3dt00948c Anotace 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. Pracoviště Biofyzikální ústav Kontakt Jana Poláková, polakova@ibp.cz, Tel.: 541 517 244 Rok sběru 2024 Elektronická adresa https://pubs.rsc.org/en/content/articlelanding/2023/dt/d3dt00948c
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