Cationic block amphiphiles show anti-mitochondrial activity in multi-drug resistant breast cancer cells.

Currently, there are limited treatment options for multi-drug resistant breast cancer. Lipid-modified cationic peptides have the potential to reach the mitochondria, which are attractive targets for the treatment of multi-drug resistant (MDR) breast cancer; yet, little is known about their mitochondrial targeting and anti-cancer activity. Interestingly, lipid-modified cationic peptides, typically used as gene transfection agents, exhibit similar structural features to mitochondrial targeted peptides. Using octahistidine-octaarginine (H8R8) as a model cationic peptide for cell penetration and endosomal escape, we explored the anti-cancer potential of lipid-modified cationic peptides as a function of amphiphilicity, biodegradability and lipid structure. We found that cationic peptides modified with a lipid that is at least 12 carbons in length exhibit potent anti-cancer activity in the low micromolar range in both EMT6/P and EMT6/AR-1 breast cancer cells. Comparing degradable and non-degradable linkers, as well as L- and D-amino acid sequences, we found that the anti-cancer activity is mostly independent of the biodegradation of the lipid-modified cationic peptides. Two candidates, stearyl-H8R8 (Str-H8R8) and vitamin E succinate-H8R8 (VES-H8R8) were cytotoxic to cancer cells by mitochondria depolarization. We observed increased reactive oxygen species (ROS) production, reduced cell bioenergetics and drug efflux, triggering apoptosis and G1 cell cycle arrest. Compared to Str-H8R8, VES-H8R8 showed enhanced cancer cell selectivity and drug efflux inhibition, thereby serving as a potential novel therapeutic agent. This study deepens our understanding of lipid-modified cationic peptides and uncovers their potential in multi-drug resistant breast cancer.