Anticancer Effects of Honokiol via Mitochondrial Dysfunction Are Strongly Enhanced by the Mitochondria-Targeting Carrier Berberine

Mitochondrion
is a favorable therapeutic target in cancer, given
its regulation of bioenergetics and cell death. Honokiol exhibits
antiproliferative effects through mitochondria-mediated death signaling.
To enhance its anticancer potential and selectivity, we conjugated
honokiol to berberine, a mitochondria-targeting carrier. All designed
derivatives displayed 1 order of magnitude increased cytotoxicity
compared with the parent compounds, especially with massive cytoplasmic
vacuoles. Biological evaluation demonstrated the representative compound 6b localized within the mitochondria, and mitochondrial dilation
resulted in vacuolization. 6b induced vacuolation-associated
cell death and apoptosis with obvious mitochondrial dysfunction, as
demonstrated by booming reactive oxygen species generation, opening
mitochondrial permeability transition pore, and reducing mitochondrial
membrane potential. The targeting property also conferred 6b with selectivity for tumor cells compared to normal cells. 6b inhibited cancer cell proliferation in the zebrafish xenograft
model. These results demonstrate that berberine-linked honokiol derivatives
open up a direction for novel mitochondrial-targeting antitumor agents.