Breast Cancer Stem Cell Potency of Nickel(II)‐Polypyridyl Complexes Containing Non‐steroidal Anti‐inflammatory Drugs

Abstract

We report the breastc ancer stem cell (CSC) potency of two nickel(II)-3,4,7,8-tetramethyl-1,10-phenanthroline complexes, 1 and 3,containingthe non-steroidalanti-inflammatoryd rugs (NSAIDs), naproxen and indomethacin, respectively.T he 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,a ne stablished CSC-activea gent.T he complexes, 1 and 3 also display significantly lower toxicity towardsn on-cancerous epithelial breast cells than breast CSCs or bulk breast cancerc ells (up to 4.6-fold). Mechanistic studiess uggest that 1 and 3 downregulate cyclooxygenase-2(COX-2) in breast CSCs and kill breast CSCs in aC OX-2 dependentm anner.F urthermore, the potencyo f1 and 3 towardsb reast CSCs decreasedu pon co-treatment with necroptosisi nhibitors (necrostatin-1 and dabrafenib), implying that 1 and 3 inducen ecroptosis, an ordered form of necrosis, in breast CSCs. As apoptosis resistance is ah allmark of CSCs, compounds like 1 and 3,w hich potentially provide accesst oa lternative (non-apoptotic) cell death pathways could hold the key to overcoming hard-to-killC SCs. 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.

An Osteosarcoma Stem Cell Potent Nickel(II)-Polypyridyl Complex Containing Flufenamic Acid

“…This suggests a monodentate binding mode for the carboxylic acid moiety on flufenamic acid to the nickel(II) centre in 1 and a mixed monodentate-bidentate binding mode for 2 (as shown in Figure 1 ). The carboxylic acid group binding mode assignment for 1 and 2 is consistent with previous studies on structurally similar nickel(II)-polypyridyl complexes containing flufenamic acid and other NSAIDs [ 19 , 26 ]. The UV-vis spectra of 1 and 2 (50 µM) in PBS:DMSO (100:1) displayed intense signals between 277–288 nm associated to π–π* and metal-perturbed π–π* transitions originating from the flufenamic acid and 3,4,7,8-tetramethyl-1,10-phenanthroline or 4,7-diphenyl-1,10-phenanthroline units ( Figure S2 ).…”

“…The latter showed that [Ni( N , N -diethyldithiocarbamate) 2 (1,10-phenanthroline)] acted in a similar way to shikonin, a well-established necroptosis-inducer [ 17 ]. More recently we reported a series of nickel(II)-polypyridyl complexes bearing the non-steroidal anti-inflammatory drugs (NSAIDs) naproxen and indomethacin, with micromolar potency towards breast CSCs [ 19 ]. Mechanistic studies showed that the nickel(II) complexes triggered breast CSC death via a cyclooxygenase-2 (COX-2)-dependent pathway and in a manner that is blocked by necroptosis inhibitors [ 19 ].…”

“…More recently we reported a series of nickel(II)-polypyridyl complexes bearing the non-steroidal anti-inflammatory drugs (NSAIDs) naproxen and indomethacin, with micromolar potency towards breast CSCs [ 19 ]. Mechanistic studies showed that the nickel(II) complexes triggered breast CSC death via a cyclooxygenase-2 (COX-2)-dependent pathway and in a manner that is blocked by necroptosis inhibitors [ 19 ]. Here, we have sought to expand this promising class of necroptosis-inducing agents by incorporating flufenamic acid, an NSAID that has been successfully used as a chemopreventive in various cancer models [ 20 , 21 ].…”

Synthesis, structural determination, in vitro and in silico biological evaluation of divalent or trivalent cobalt complexes with indomethacin

“…In the literature, there is a plethora of cobalt-NSAID complexes, such as those with tolfenamic acid [ 23 ], diflunisal, niflumic acid, flufenamic acid, mefenamic acid [ [26] , [27] , [28] ], diclofenac [ 15 , 16 , 29 ] and naproxen [ 30 ]. There is also a great number of transition metal complexes with indomethacin ligands [ 21 ], including manganese(II) [ 31 ], nickel(II) [ 32 , 33 ], copper(II) [ 34 , 35 ], tin(IV) [ 36 ] and zinc(II) complexes [ 37 ]. Another reason for the study of metals and their complexes is also their potential use in diagnostics which was also already used for detection of coronavirus MERS-CoV [ 38 , 39 ].…”

The Novel Function of Unsymmetrical Chiral CCN Pincer Nickel Complexes as Chemotherapeutic Agents Targeting Prostate Cancer Cells

“…Nickel complexes could be applied as valuable alternatives to anticancer platinum agents. Indeed, nickel-incorporated complexes have shown anticancer properties in prostate, breast, lung, and colon cancer cells [ 18 , 19 , 20 ].…”