The Potent Inhibitory Effect of a Naproxen-Appended Cobalt(III)-Cyclam Complex on Cancer Stem Cells

Paul B Cressey; Arvin Eskandari; Peter M Bruno; Chunxin Lu; Michael T Hemann; Kogularamanan Suntharalingam

doi:10.1002/cbic.201600368

The Potent Inhibitory Effect of a Naproxen-Appended Cobalt(III)-Cyclam Complex on Cancer Stem Cells

Chembiochem. 2016 Sep 15;17(18):1713-8. doi: 10.1002/cbic.201600368. Epub 2016 Aug 11.

Authors

Paul B Cressey¹, Arvin Eskandari¹, Peter M Bruno², Chunxin Lu¹, Michael T Hemann², Kogularamanan Suntharalingam³

Affiliations

¹ Department of Chemistry, King's College London, Britannia House, 7 Trinity Street, London, SE1 1DB, UK.
² The Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Building 76, 500 Main Street, Cambridge, MA, 02139, USA.
³ Department of Chemistry, King's College London, Britannia House, 7 Trinity Street, London, SE1 1DB, UK. kogularamanan.suntharalingam@kcl.ac.uk.

PMID: 27377813
DOI: 10.1002/cbic.201600368

Abstract

We report the potency against cancer stem cells (CSCs) of a new cobalt(III)-cyclam complex (1) that bears the nonsteroidal anti-inflammatory drug, naproxen. The complex displays selective potency for breast CSC-enriched HMLER-shEcad cells over breast CSC-depleted HMLER cells. Additionally, it inhibited the formation of three-dimensional tumour-like mammospheres, and reduced their viability to a greater extent than clinically used breast cancer drugs (vinorelbine, cisplatin and paclitaxel). The anti-mammosphere potency of 1 was enhanced under hypoxia-mimicking conditions. Detailed mechanistic studies revealed that DNA damage and cyclooxygenase-2 (COX-2) inhibition contribute to the cytotoxic mechanism of 1. To the best of our knowledge, 1 is the first cobalt-containing compound to show selective potency for CSCs over bulk cancer cells.

Keywords: antitumour agents; bioinorganic chemistry; cancer; cobalt; cox inhibition.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cobalt / chemistry
Cobalt / pharmacology*
Cyclooxygenase 2 / metabolism
Cyclooxygenase 2 Inhibitors / chemical synthesis
Cyclooxygenase 2 Inhibitors / chemistry
Cyclooxygenase 2 Inhibitors / pharmacology*
DNA Damage / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Molecular Conformation
Naproxen / chemistry
Naproxen / pharmacology*
Neoplastic Stem Cells / drug effects*
Neoplastic Stem Cells / pathology*
Organometallic Compounds / chemical synthesis
Organometallic Compounds / chemistry
Organometallic Compounds / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Cyclooxygenase 2 Inhibitors
Organometallic Compounds
Cobalt
Naproxen
Cyclooxygenase 2