Tetranuclear copper(ii) complexes containing multiple diclofenac and Schiff base moieties, 1-4, are shown to kill bulk cancer cells and cancer stem cells (CSCs) with low micromolar potency. The most effective complex, 1, elicits its cytotoxic effect by elevating the intracellular reactive oxygen species (ROS) levels and inhibiting cyclooxygenase-2 (COX-2) expression.
We report the cancer stem cell (CSC) potency of a novel series of copper(ii)-phenanthroline complexes bearing nonsteriodial anti-inflammatory drugs: naproxen, tolfenamic acid, and indomethacin (2a-3c). Two of the complexes, 2a and 3c, kill breast CSC-enriched HMLER-shEcad cells (grown in both monolayer and three-dimensional cell cultures) to a significantly better extent than salinomycin, a well-established CSC toxin. The most potent complex in the series, 3c induces its cytotoxic effect by generating intracellular reactive oxygen species (ROS) and inhibiting cyclooxgenase-2 (COX-2) activity. Encapsulation of 3c using biodegradable methoxy poly(ethylene glycol)-b-poly(d,l-lactic-co-glycolic) acid (PEG-PLGA) copolymers at the appropriate feed (5%, 3c NP) enhances breast CSC uptake and reduces overall toxicity. The nanoparticle formulation, 3c NP selectively kills breast CSCs over bulk breast cancer cells, and evokes a similar cellular response to the payload, 3c. To the best of our knowledge, this is the first study to demonstrate that polymeric nanoparticles can be used to effectively deliver CSC-potent metal complexes into CSCs.
The breast cancer stem cell (CSC) and bulk breast cancer cell potency of a series of metallopeptides containing dichloro(1,10-phenanthroline)copper(II) and various organelle-targeting peptide sequences is reported. The mitochondria-targeting metallopeptide 1 exploits the higher mitochondrial load in breast CSCs over the corresponding non-CSCs and the vulnerability of breast CSCs to mitochondrial damage to potently and selectively kill breast CSCs. Strikingly, 1 reduces the formation and size of mammospheres to a greater extent than salinomycin, an established CSC-potent agent. Mechanistic studies show that 1 enters CSC mitochondria, induces mitochondrial dysfunction, generates reactive oxygen species (ROS), activates JNK and p38 pathways, and prompts apoptosis. To the best of our knowledge, 1 is the first metallopeptide to selectivity kill breast CSCs in vitro.
The preparation of multinuclear metal complexes offers ar oute to novel anticancer agents and delivery systems. The potency of an ovel triangular multinuclear complex containing three platinum atoms, Pt-3,t owards breast cancer stem cells (CSCs) is reported. The trinuclear platinum(II) complex, Pt-3 exhibits selective toxicity towards breast CSCs over bulk breast cancer cells and non-tumorigenic breast cells. Remarkably, Pt-3 inhibits the formation, size, and viability of mammospheres to ab etter extent than salinomycin, an established CSC-potent agent, and cisplatin and carboplatin, clinically used platinum drugs.M echanism of action studies show that Pt-3 effectively enters breast CSCs,p enetrates the nucleus,induces genomic DNAdamage,and prompts caspasedependent apoptosis.T othe best of our knowledge, Pt-3 is the first multinuclear platinum complex to selectively kill breast CSCs over other breast cell types.
The cytotoxic properties of a series of nickel(II)-dithiocarbamate phenanthroline complexes is reported. The complexes 1-6 kill bulk cancer cells and cancer stem cells (CSCs) with micromolar potency. Two of the complexes, 2 and 6, kill twice as many breast cancer stem cell (CSC)-enriched HMLER-shEcad cells as compared to breast CSC-depleted HMLER cells. Complex 2 inhibits mammosphere formation to a similar extent as salinomycin (a CSC-specific toxin). Detailed mechanistic studies suggest that 2 induces CSC death by necroptosis, a programmed form of necrosis. Specifically, 2 triggers MLKL phosphorylation, oligomerization, and translocation to the cell membrane. Additionally, 2 induces necrosome-mediated propidium iodide (PI) uptake and mitochondrial membrane depolarisation, as well as morphological changes consistent with necroptotosis. Strikingly, 2 does not evoke necroptosis by intracellular reactive oxygen species (ROS) production or poly(ADP) ribose polymerase (PARP-1) activation.
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