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FELD, Catherine J, JOHNSON, Alice, XIAO, Zhiyin and SUNTHARALINGAM, Kogularamanan (2020). Breast Cancer Stem Cell Potency of Nickel(II)-Polypyridyl Complexes Containing Non-steroidal Anti-inflammatory Drugs. Chemistry, 26 (61), 14011-14017.
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Abstract
We report the breast cancer stem cell (CSC) potency of two nickel(II)-3,4,7,8-tetramethyl-1,10-phenanthroline complexes, 1 and 3, containing the non-steroidal anti-inflammatory drugs (NSAIDs), naproxen and indomethacin, respectively. The nickel(II) complexes, 1 and 3 kill breast CSCs and bulk breast cancer cells in the micromolar range. Notably, 1 and 3 display comparable or better potency towards breast CSCs than salinomycin, an established CSC-active agent. The complexes, 1 and 3 also display significantly lower toxicity towards non-cancerous epithelial breast cells than breast CSCs or bulk breast cancer cells (up to 4.6-fold). Mechanistic studies suggest that 1 and 3 downregulate cyclooxygenase-2 (COX-2) in breast CSCs and kill breast CSCs in a COX-2 dependent manner. Furthermore, the potency of 1 and 3 towards breast CSCs decreased upon co-treatment with necroptosis inhibitors (necrostatin-1 and dabrafenib), implying that 1 and 3 induce necroptosis, an ordered form of necrosis, in breast CSCs. As apoptosis resistance is a hallmark of CSCs, compounds like 1 and 3, which potentially provide access to alternative (non-apoptotic) cell death pathways could hold the key to overcoming hard-to-kill CSCs. To the best of our knowledge, 1 and 3 are the first compounds to be associated to COX-2 inhibition and necroptosis induction in CSCs.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | antitumor agents; bioinorganic chemistry; cyclooxygenase-2; necroptosis; nickel; Anti-Inflammatory Agents, Non-Steroidal; Breast Neoplasms; Coordination Complexes; Female; Humans; Neoplastic Stem Cells; Nickel; Humans; Breast Neoplasms; Nickel; Anti-Inflammatory Agents, Non-Steroidal; Female; Neoplastic Stem Cells; Coordination Complexes; 03 Chemical Sciences; General Chemistry |
| Identification Number: | https://doi.org/10.1002/chem.202001578 |
| Page Range: | 14011-14017 |
| SWORD Depositor: | Symplectic Elements |
| Depositing User: | Symplectic Elements |
| Date Deposited: | 11 May 2022 15:04 |
| Last Modified: | 11 May 2022 15:04 |
| URI: | https://shura.shu.ac.uk/id/eprint/29943 |
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