A Triangular Platinum(II) Multinuclear Complex with Cytotoxicity Towards Breast Cancer Stem Cells

Abstract

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.

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

“…Notably, the mammosphere potency of 1 and 3 was much lower than salinomycin, cisplatin, and the corresponding copper(II) complex with naproxen, Cu‐1 under identical conditions (Table 1). [8b, 16, 18] Previous reports and control experiments conducted in this study showed that NiCl 2 ⋅6 H 2 O, naproxen, and indomethacin were all non‐toxic towards mammospheres (IC 50 >133 μ m , Figure S18 and Table 1). [8a] Therefore the mammosphere potency observed for 1 and 3 is likely to be due to the intact mammosphere uptake of the nickel(II) complexes, which facilitates the concerted co‐delivery of all the complex components.…”

“…The corresponding copper(II) complex with indomethacin, Cu‐3 (see Figure S13 for chemical structure) preferentially killed HMLER cells over HMLER‐shEcad cells [8b] . Strikingly, the indomethacin‐containing nickel(II) complex, 3 displayed 2.3‐fold ( p <0.05, n =12) and 3.1‐fold ( p <0.05, n =12) greater potency for CSC‐enriched HMLER‐shEcad cells than salinomycin and cisplatin (a platinum‐based anticancer agent), respectively [8a, 16] . The NSAIDs components, naproxen and indomethacin were previously shown to be non‐toxic towards both HMLER and HMLER‐shEcad cells (IC 50 values >100 μ m ) under identical conditions [8a, b] .…”

“…[b] Determined after 5 days incubation (mean of three independent experiments ±SD). [c] Reported in references [8a, b, 16, 18]; n.d.=not determined.…”

Immunogenic Cell Death of Breast Cancer Stem Cells Induced by an Endoplasmic Reticulum‐Targeting Copper(II) Complex

“…Strikingly, the IC 50 value for 4 (0.54 � 0.01 μM) was 34 and 25 times lower than that reported for salinomycin and cisplatin, respectively, under identical conditions. [17,21] [Cu(L 1 )Cl] displayed significantly (p < 0.05) lower potency for HMLER-shEcad spheroids than 1-4, ( Figure S17, Table 1) indicating that the intact copper(II) complexes containing both the Schiff base, L 1 and the corresponding polypyridyl ligand are responsible for the observed activities with HMLER-shEcad spheroids. The addition of the most potent copper(II) complex, 4 (IC value for 5 days) to single cell suspensions of nontumorigenic breast epithelial MCF10 A cells did not significantly (p = 0.20) change the number or size of MCF10 A spheroids formed ( Figure 3A and C).…”

“…The most potent complex within the series, 4 displayed 13‐fold and 18‐fold greater potency ( p <0.05, n=18) for CSC‐enriched HMLER‐shEcad cells than salinomycin and cisplatin, respectively (Table 1). [16a,21] Control studies showed that [Cu( L 1 )Cl] was nontoxic towards HMLER and HMLER‐shEcad cells (IC 50 >100 μM), indicating that the cytotoxicity of 1 – 4 towards bulk breast cancer cells and breast CSCs is likely to result from the intact copper(II) complexes, containing both the Schiff base, L 1 and the corresponding polypyridyl ligand (Figure S13, Table 1).…”