Turn-folded magainin lipopeptide analog induces cytoplasmic vacuoles in MDA-MB-231 cells through G2-phase arrest

Selective induced non-canonical programmed deaths in the lipid raft type 1-enriched MDA-MB-231 is a promising treatment approach. Cationic amphiphilic peptides conjugated to relatively long fatty acyl chains that tend to self-aggregate are prone to upregulate necroptotic and paraptotic signaling. We investigated the toxic effects of an N-terminally palmitoylated magainin derivate (P1MK5E) in the MDA-MB-231 cells in relation to its structure at molecular level. The modeling showed that the palmitoylation reinforces a turn-like structural motif in the lipopeptide which is likely required for its activity. P1MK5E triggered intracellular generation of reactive oxygen species (ROS), G2-phase arrest, mitochondrial membrane potential (ΔΨ_mt) disturbance and presumable flopping of phosphatidylserine (PtdSer) to the cancer cell membrane outer surface in a comparable manner to doxorubicin (DOX) that induces apoptotic signaling. Despite forming extensive congregates of different sizes at the cell surface, P1MK5E had little impacts on the MDA-MB-231 membrane integrity. The cell death upon exposure to the lipopeptide was, however, caspase 3 independent and characterized by cytoplasmic vacuolation and no distinct nuclear fragmentation that is to be privileged in the treatment of apoptotic resistance pathways in triple-negative breast cancers (TNBCs).