Polypyridyl Zinc(II)-Indomethacin Complexes with Potent Anti-Breast Cancer Stem Cell Activity

Abstract

Cancer stem cells (CSCs) are thought of as a clinically pertinent subpopulation of tumors, partly responsible for cancer relapse and metastasis. Research programs aimed at discovering anti-CSC agents have largely focused on biologics and purely organic molecules. Recently, we showed that a family of redox-active copper(II) complexes with phenanthroline-based ligands and nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin, are capable of potently and selectively killing breast CSCs. Herein we present analogous redox-inactive, zinc(II)-phenanthroline-indomethacin complexes with the ability to kill breast CSCs and bulk breast cancer cells with equal potency (in the submicro- or micromolar range). A single dose of the zinc(II) complexes could theoretically be administered to eliminate whole tumor populations. Excitingly, some of the zinc(II) complexes decrease the growth and viability of mammospheres to a comparable or higher degree than salinomycin, a compound known to effectively kill breast CSCs. As far as we are aware this is the first report to examine the anti-breast CSC activity of zinc(II)-containing compounds.

Integrated Design of a Membrane‐Lytic Peptide‐Based Intravenous Nanotherapeutic Suppresses Triple‐Negative Breast Cancer

“…[ 1 , 2 ] Peptides that permeabilize membranes are a ubiquitous part of the innate immune defense and have long been envisioned as therapeutic candidates against bacteria, fungi, and viruses. [ 3 , 4 , 5 , 6 ] Against cancer, membrane‐lytic peptides can lead to rapid necrotic cell death of their target cells, [ 7 ] and the growing enthusiasm toward these tailorable therapeutic candidates are accompanied by increasingly sophisticated efforts at expanding their synthetic flexibilities and chemical repertoire. [ 8 , 9 ] The action mechanism via physical damage by membrane‐perforating peptides may help address several common shortcomings among standard‐of‐care small molecule chemotherapeutics targeting biochemical pathways, including drug‐resistance development and ineffectiveness against quiescent cancer cells that are frequently associated with treatment failure and tumor relapse.…”

NSAIDs: Old Acquaintance in the Pipeline for Cancer Treatment and Prevention─Structural Modulation, Mechanisms of Action, and Bright Future

“…Numerous studies have demonstrated that metal-NSAID complexes, including zinc­(II)-NSAIDs, − iridium­(III)-aspirin, ruthenium­(II)-NSAIDs, − nickel­(II)-NSAIDs, silver­(I)-NSAIDs, − manganese­(II)-NSAIDs, , and organotin­(IV)-NSAIDs, also exhibit potent cytotoxic activity against several cancer cells. The most likely modes of action of these complexes are increase of COX-2 selectivity, , induction of ROS, interaction with serum albumins, and intercalation of DNA .…”

The in vitro apoptotic effect of new zinc complex possessing folic acid and phenanthroline on cervix cancer cells

“…[ 4 ] Also, Zn(II)‐based complexes have therapeutic potential in cancer therapy due to the low toxicity, redox inertness, and superior biocompatibility of Zinc ions. [ 5 ] On the other hand, it has been reported that zinc can both cause apoptosis in some cancerous tumors and prevent the induction of apoptosis in some tumors. [ 6 ] Furthermore, a decrease in cellular Zn levels and also overload can cause oxidative stress, raising the risk of prostate, breast, and ovarian cancer, as well as pancreatic adenocarcinoma and hepatocellular carcinoma.…”