New Mitochondria-Targeted Fisetin Derivative Compromises Mitophagy and Limits Survival of Drug-Induced Senescent Breast Cancer Cells

Mitochondria are considered as promising targets for
cancer treatment.
In the present study, triphenyl phosphonium cationic group-conjugated
fisetin (mito-fisetin) was synthesized, and its anticancer activity
was investigated in several cellular models of estrogen receptor (ER)-positive
breast cancer in vitro and in vivo in proliferating and tamoxifen-promoted
senescent states. Mito-fisetin, when used at low micromolar concentrations,
stimulated the dissipation of mitochondrial membrane potential and
oxidative stress, and affected mitochondrial function, resulting in
apoptosis induction in senescent breast cancer cells. Mito-fisetin-mediated
cytotoxicity was due to increased levels of phosphorylated AMPK, decreased
levels of AKT and HSP90, and impaired mitophagic response, as judged
by the analysis of the markers of mitophagosome formation. Senescent
breast cancer cells were found to be more sensitive to mito-fisetin
treatment than proliferating ones. We postulate that mitochondrial
targeting in the case of fisetin may be considered as a promising
anticancer and senotherapeutic strategy to eliminate drug-resistant
senescent breast cancer cells.