Targeting plasma membrane and mitochondrial instability in breast cancer cells and breast epithelial to mesenchymal transition-model cells by adamantyl diaza-crown ether ZG613

Abstract

The adamantane derived diaza-crown ether ZG613 was assessed as a potential breast cancer cells and breast epithelial to mesenchymal transition (EMT)-model cells targeting agent. We postulated that ZG613 activity relies on its plasma/mitochondria membrane disruption ability based on adamantane hydrophobicity and/or crown ether related ionophoric properties. We performed molecular dynamics (MD) simulations and next generation sequencing, followed by in vitro study of cell death, membrane perturbations and ionophoric ability, as well as in vivo study of effects on the tumour growth. MD simulation and RNA sequencing pointed toward physical disruption of plasma membrane by ZG613, corroborated by measured increase in membrane permeability leading to cell death. Measurements of ion fluxes confirmed ZG613 inability to transport Na+ and K+, as predicted by MD simulation. EMT-model cells exhibit changes in mitochondrial morphology and ATP levels, successfully targeted by ZG613. ZG613 caused mild retardation of tumour growth in vivo. In conclusion, ZG613 kills breast cancer cells and breast EMT-model cells by physical disruption of plasma membrane and impairments of mitochondrial functions. Breast EMT cells represent good potential targets within the breast tumour, due to their plasma membrane and mitochondrial instability.