Aglycone Polyether Nanchangmycin and Its Homologues Exhibit Apoptotic and Antiproliferative Activities against Cancer Stem Cells

The potential of
the polyether salinomycin as an inhibitory agent
against cancer stem cells has attracted interest in this family of
compounds. In this study, we found that the aglycone polyether nanchangmycin
and its homologues show promising activities against breast cancer
stem cells as well as 38 other different types of cancer cells by in vitro assays. We found that aglycone polyethers caused
elevations in calcium levels, an accumulation of reactive oxygen species
and mitochondrial inner membrane permeability to H+ and
K+, resulting in the release of cytochrome c and apoptosis-inducing factor and the triggering of caspase-dependent
apoptosis. Our analyses also indicate that aglycone polyethers are
potent Wnt/β-catenin signaling inhibitors, blocking the Wnt
pathway and resulting in reduced cell survival. Notably, the key autophagy-related
proteins LC3A/B were also activated by aglycone polyether treatment.
Furthermore, nanchangmycin showed inhibitory effects toward somatic
tumors developed from MCF-7 paclitaxel-resistant breast cancer cells
injected into BALB/c mice. Our study not only provides promising candidates
for therapy against cancer stem cells but also provides the groundwork
for identifying stronger therapeutic agents among the natural polyether
compounds.