1. New Mitochondria-Targeted Fisetin Derivative Compromises Mitophagy and Limits Survival of Drug-Induced Senescent Breast Cancer Cells.
- Author
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Rzeszutek I, Cybularczyk-Cecotka M, Deręgowska A, Stec P, Wnuk M, Kołodziej O, Kałafut J, Wawruszak A, Witkowski W, Litwinienko G, and Lewińska A
- Subjects
- Humans, Female, Animals, Cell Line, Tumor, Membrane Potential, Mitochondrial drug effects, Apoptosis drug effects, Cell Survival drug effects, Cell Proliferation drug effects, Mice, Oxidative Stress drug effects, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Breast Neoplasms metabolism, Flavonols pharmacology, Flavonols chemistry, Mitochondria drug effects, Mitochondria metabolism, Cellular Senescence drug effects, Mitophagy drug effects, Flavonoids pharmacology, Flavonoids chemistry, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents chemical synthesis
- Abstract
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.
- Published
- 2024
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