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. 2018 Sep 4;23(9):2253.
doi: 10.3390/molecules23092253.

Polypyridyl Zinc(II)-Indomethacin Complexes with Potent Anti-Breast Cancer Stem Cell Activity

Tiffany K Rundstadler  1 , Arvin Eskandari  2 , Sarah M Norman  3 , Kogularamanan Suntharalingam  4
Affiliations

Polypyridyl Zinc(II)-Indomethacin Complexes with Potent Anti-Breast Cancer Stem Cell Activity

Tiffany K Rundstadler et al. Molecules. .

Abstract

Cancer stem cells (CSCs) are thought of as a clinically pertinent subpopulation of tumors, partly responsible for cancer relapse and metastasis. Research programs aimed at discovering anti-CSC agents have largely focused on biologics and purely organic molecules. Recently, we showed that a family of redox-active copper(II) complexes with phenanthroline-based ligands and nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin, are capable of potently and selectively killing breast CSCs. Herein we present analogous redox-inactive, zinc(II)-phenanthroline-indomethacin complexes with the ability to kill breast CSCs and bulk breast cancer cells with equal potency (in the submicro- or micromolar range). A single dose of the zinc(II) complexes could theoretically be administered to eliminate whole tumor populations. Excitingly, some of the zinc(II) complexes decrease the growth and viability of mammospheres to a comparable or higher degree than salinomycin, a compound known to effectively kill breast CSCs. As far as we are aware this is the first report to examine the anti-breast CSC activity of zinc(II)-containing compounds.

Keywords: bioinorganic chemistry; metallopharmaceuticals; nonsteroidal anti-inflammatory drug; zinc.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
Representation of the synthetic route used to prepare the zinc(II)-phenanthroline complexes with two indomethacin units, 2–5, from diaquabis(η2-O,O′-indomethacin)zinc(II), 1 in acetonitrile.
Figure 1
Figure 1
Compound concentration versus percentage cell viability plots for 2–5 against (A) bulk breast cancer cells (HMLER) and (B) breast CSC-like cells (HMLER-shEcad cells) (72 h incubation). The difference in potency of 2–5 towards HMLER-shEcad cells and HMLER cells is not significant (Student t-test, p > 0.05).
Figure 2
Figure 2
(A) Representation of the number of mammospheres formed from HMLER-shEcad cell suspensions treated with 2–5 or salinomycin for 5 days at their respective IC20 values. Standard deviation was used to calculate the associated errors. (B) Bright-field images (taken using an inverted microscope) representative of untreated HMLER-shEcad mammospheres and those treated with 2–5 or salinomycin for 5 days at their respective IC20 values (×20 magnification). (C) Compound concentration versus percentage mammosphere viability plots for 2–5 against HMLER-shEcad mammospheres (5 days incubation).
Figure 2
Figure 2
(A) Representation of the number of mammospheres formed from HMLER-shEcad cell suspensions treated with 2–5 or salinomycin for 5 days at their respective IC20 values. Standard deviation was used to calculate the associated errors. (B) Bright-field images (taken using an inverted microscope) representative of untreated HMLER-shEcad mammospheres and those treated with 2–5 or salinomycin for 5 days at their respective IC20 values (×20 magnification). (C) Compound concentration versus percentage mammosphere viability plots for 2–5 against HMLER-shEcad mammospheres (5 days incubation).
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