A Copper(II) Phenanthroline Metallopeptide That Targets and Disrupts Mitochondrial Function in Breast Cancer Stem Cells

Abstract

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 Next Generation of Anticancer Metallopharmaceuticals: Cancer Stem Cell‐Active Inorganics

“…Therefore, mitochondrial targeting could offer a viable approach for the selective elimination of CSCs over bulk cancer cells. Metallopeptide 13 consisting of dichloro(1,10‐phenanthroline)copper(II) (a ROS‐generating CSC‐potent complex) and a mitochondrial‐penetrating peptide (MPP) (Scheme ) has been reported to exploit the higher mitochondrial load in breast CSCs (over non‐CSCs) and the vulnerability of breast CSCs to mitochondrial damage to kill breast CSCs potently (micromolar range) and selectively over bulk breast cancer cells . The metallopeptide was identified to enter CSC mitochondria, induce mitochondrial dysfunction and prompt apoptosis.…”

“…ChemBioChem 2018ChemBioChem , 19,2246ChemBioChem -2253 www.chembiochem.org bulk breast cancerc ells. [29] The metallopeptide wasi dentified to enter CSC mitochondria, induce mitochondrial dysfunction and prompt apoptosis. This is the first metallopeptide or metal-containing mitochondriotropic to kill breast CSCs selectivity in vitro.…”

CpRu Complexes Containing Water Soluble Phosphane PTA and Natural Purines Adenine, Guanine and Theophylline: Synthesis, Characterization, and Antiproliferative Properties

“…Although the use of cis platin and its analogues present important secondary effects, they are still some of most widely used chemotherapeutic agents up to date . To overcome the drawbacks associated to the platinum drugs, the research on metal complexes bearing different metals is a topic of primary interest . Among the non‐platinum cytotoxic complexes those containing ruthenium are the most promising , .…”

Highly Charged, Cytotoxic, Cyclometalated Iridium(III) Complexes as Cancer Stem Cell Mitochondriotropics

“…We recently reported am etallopeptide containing dichloro(1,10-phenanthroline) copper(II), aR OS-generating CSC-potent complex, affixed to an established mitochondrial-penetratingp eptides (MPPs), capable of selectively killing breast CSCs over bulk breast cancer cells through mitochondrial dysfunction. [7] Although this metallopeptide exhibited promisingi nv itro CSC potency,p otential in vivo application is limited by the high reactivity of the copper(II)-phenanthroline warhead, and akin to otherp eptidebased chemotherapeutics, challenges relatingt op harmacokineticsa nd clearance. [8] Ta rgeting CSC mitochondriau sing chemically inert smallm olecules could be am ore effective and translatable strategy.…”

“…The Log P valueso f1-4 are consistentw ith other mitochondriotropics (Log P > À1. 7), suggesting that the iridium(III) complexes should be readily taken up by cells and enter the mitochondrial matrix. [16,18] UV/Vis and high-resolution ESI mass spectroscopys tudies were carriedo ut to assesst he stabilityo f3 and 4,t aken as representative mem- (Figures S25 andS 26).…”