University of Leicester
Browse

Modulating the Chemical and Biological Properties of Cancer Stem Cell-Potent Copper(II)-Nonsteroidal Anti-Inflammatory Drug Complexes.

Download (699.57 kB)
journal contribution
posted on 2019-06-05, 09:23 authored by Jimin Shin, Arvin Eskandari, Kogularamanan Suntharalingam
Copper(II) complexes bearing nonsteroidal anti-inflammatory drugs (NSAIDs) are known to potently kill cancer stem cells (CSCs), a subpopulation of tumour cells with high metastatic and relapse fidelity. One of the major disadvantages associated to these copper(II) complexes is their instability in the presence of strong cellular reductants (such as ascorbic acid). Here we present a biologically stable copper(II)-NSAID complex containing a bathocuproinedisulfonic acid disodium ligand and two indomethacin moieties, Cu(bathocuproinedisulfonic acid disodium)(indomethacin)2, 2. The copper(II) complex, 2 kills bulk breast cancer cells and breast CSC equally (in the sub-micromolar range) and displays very low toxicity against non-tumorigenic breast and kidney cells (IC50 value > 100 µM). Three-dimensional cell culture studies show that 2 can significantly reduce the number and size of breast CSC mammospheres formed (from single suspensions) to a similar level as salinomycin (an established anti-breast CSC agent). The copper(II) complex, 2 is taken up reasonably by breast CSCs and localises largely in the cytoplasm (>90%). Cytotoxicity studies in the presence of specific inhibitors suggest that 2 induces CSC death via a reactive oxygen species (ROS) and cyclooxygenase isoenzyme-2 (COX-2) dependent apoptosis pathway.

Funding

A.E. is supported by a King’s College London (KCL) PhD scholarship. We are grateful to Robert Weinberg for providing the HMLER and HMLER-shEcad cell lines used in this study.

History

Citation

Molecules, 2019, 24 (9), 1677

Author affiliation

/Organisation/COLLEGE OF SCIENCE AND ENGINEERING/Department of Chemistry

Version

  • VoR (Version of Record)

Published in

Molecules

Publisher

MDPI

eissn

1420-3049

Acceptance date

2019-04-27

Copyright date

2019

Available date

2019-06-05

Publisher version

https://www.mdpi.com/1420-3049/24/9/1677

Notes

The following are available online, Experimental Details (including Figures S1–S11).

Language

en

Usage metrics

    University of Leicester Publications

    Categories

    No categories selected

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC