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

J. P. C. Coverdale, H. Kostrhunova, L. Markova, H. Song, M. Postings, H. E. Bridgewater, V. Brabec, N. J. Rogers, P. Scott

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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 G 1 phase, while Λ causes a very large dose-dependent increase in the G 2/M population at a concentration significantly below the relevant IC 50. Correspondingly, G 2-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 G 2/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.

Original languageEnglish
Pages (from-to)6656-6667
Number of pages12
JournalDalton Transactions
Volume52
Issue number20
Early online date18 Apr 2023
DOIs
Publication statusE-pub ahead of print - 18 Apr 2023

Bibliographical note

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.
CC BY 3.0

Keywords

  • Inorganic Chemistry

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