The novel amino-artemisinin derivative WHN-11 disrupts mitochondria and protein homeostasis, and induces autophagy and apoptosis in cancer cells.

Semi-synthetic derivatives of artemisinin exhibit anti-cancer activity in vitro and in vivo in addition to anti-malarial activity. Here, we report the anti-cancer and anti-cancer stem cell potential of novel C-10 substituted amino-artemisinin derivatives. Of these, the 4'-trifluoromethylarylurea piperazinyl derivative WHN-11 demonstrated cytotoxic activity at high nanomolar concentrations across a range of cancer cell lines. WHN-11 reduced short- and long-term survival of triple-negative breast cancer (TNBC) cells, a highly aggressive breast cancer subtype that currently lacks standardized targeted treatments. Mechanistically, WHN-11 induced a stress response and increased proteasome-mediated turnover of ubiquitinated proteins. WHN-11 promoted mitochondrial depolarization and fission, suppressing the expression of anti-apoptotic B-cell lymphoma extra-large (Bcl-xL) protein and ATP synthesis, thereby decreasing cellular energy production, and inducing apoptosis. WHN-11 treatment also increased autophagosomes, acidic vesicular organelles and lipid droplets. Activation or inhibition of autophagy synergized with the activity of WHN-11 in promoting cellular toxicity, as did increasing cellular dependence on oxidative phosphorylation. Unexpectedly, the effects of WHN-11 appear independent of substantial reactive oxygen species (ROS) production. Taken together, these data suggest that amino-artemisinins related to WHN-11 are promising candidates for anti-TNBC therapies targeting the mitochondria alone or in combination with autophagy modulators.