Self-Assembling Imidazolium Nanoaggregates Trigger a Unique Dynamin-Dependent Cell Death via Cytoplasmic Vacuolization and Mitochondrial Dysfunction in Human Lung Adenocarcinoma

The identification of alternative cell death pathways
is key to
developing therapies for apoptosis-resistant cancers. We investigated
cell death induced by delocalized lipophilic cation (DLC) nanoaggregates
in A549 lung carcinoma cells. These DLCs trigger a dynamin-dependent,
nonapoptotic pathway involving cytoplasmic vesicle accumulation and
mitochondrial dysfunction. Leveraging the mitochondria-targeting ability
of lipophilic cations, we designed and synthesized fluorescent mitochondrion-toxic
molecules with potent cytotoxicity against A549, MDA-MB-231, and MCF-7
cells. Dynamic light scattering revealed the nanoaggregate formation
of the lead compound, L3, in the RPMI media. L3 inhibited metastasis
and clonal expansion, induced vacuole formation post endocytosis,
and impaired the mitochondrial function, disrupting ATP levels. This
led to mitochondrial permeability transition pore (MPTP) opening and
oxidative imbalance via glutathione perturbation. L3 demonstrated
strong antitumor activity in vitro and in
vivo, showing high potential for treating apoptosis-resistant
cancers.