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Triplex metallohelices have enantiomer-dependent mechanisms of action in colon cancer cells
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Coverdale, James P. C., Kostrhunova, H., Markova, L., Song, Hualong, Postings, Miles, Bridgewater, Hannah E., Brabec, V. (Viktor), Rogers, Nicola J. and Scott, Peter (2023) Triplex metallohelices have enantiomer-dependent mechanisms of action in colon cancer cells. Dalton Transactions, 52 (20). pp. 6656-6667. doi:10.1039/d3dt00948c ISSN 1477-9234.
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Official URL: https://doi.org/10.1039/d3dt00948c
Abstract
Self-assembled enantiomers of an asymmetric di-iron metallohelix differ in their antiproliferative activities against HCT116 colon cancer cells such that the compound with Λ-helicity at the metals becomes more potent than the Δ compound with increasing exposure time. From concentration- and temperature-dependent 57Fe isotopic labelling studies of cellular accumulation we postulate that while the more potent Λ enantiomer undergoes carrier-mediated efflux, for Δ 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 Δ enantiomer induces mild arrest in the G1 phase, while Λ causes a very large dose-dependent increase in the G2/M population at a concentration significantly below the relevant IC50. Correspondingly, G2-M checkpoint failure as a result of Λ-metallohelix binding to DNA is shown to be feasible by linear dichroism studies, which indicate, in contrast to the Δ 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 G2/M arrest, is established as a feasible mechanism for the Λ helix via drug combination (synergy) studies and the discovery of tubulin and actin inhibition. Here, while the Λ compound stabilizes F-actin and induces a distinct change in tubulin architecture of HCT116 cells, Δ promotes depolymerization and more subtle changes in microtubule and actin networks.
Item Type: | Journal Article | ||||||||
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Subjects: | Q Science > QD Chemistry R Medicine > RC Internal medicine |
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | ||||||||
SWORD Depositor: | Library Publications Router | ||||||||
Library of Congress Subject Headings (LCSH): | Colon (Anatomy) -- Cancer -- Treatment, Organometallic compounds -- Synthesis, Enantiomers | ||||||||
Journal or Publication Title: | Dalton Transactions | ||||||||
Publisher: | The Royal Society of Chemistry | ||||||||
ISSN: | 1477-9234 | ||||||||
Official Date: | 28 May 2023 | ||||||||
Dates: |
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Volume: | 52 | ||||||||
Number: | 20 | ||||||||
Page Range: | pp. 6656-6667 | ||||||||
DOI: | 10.1039/d3dt00948c | ||||||||
Status: | Peer Reviewed | ||||||||
Publication Status: | Published | ||||||||
Access rights to Published version: | Open Access (Creative Commons) | ||||||||
Copyright Holders: | This journal is © The Royal Society of Chemistry 2023 | ||||||||
Date of first compliant deposit: | 2 May 2023 | ||||||||
Date of first compliant Open Access: | 2 May 2023 | ||||||||
RIOXX Funder/Project Grant: |
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