Wnuk, MaciejRzeszutek, IwonaCybularczyk-Cecotka, MartynaDeręgowska, AnnaStec, PaulinaWnuk, MaciejKołodziej, OlgaKałafut, JoannaWawruszak, AnnaWitkowski, WojciechLitwinienko, GrzegorzLewińska, Anna2024-11-102024-11-102024-09-25Rzeszutek I, Cybularczyk-Cecotka M, Deręgowska A, Stec P, Wnuk M, Kołodziej O, Kałafut J, Wawruszak A, Witkowski W, Litwinienko G, Lewińska A. New Mitochondria-Targeted Fisetin Derivative Compromises Mitophagy and Limits Survival of Drug-Induced Senescent Breast Cancer Cells. J Med Chem. 2024 Oct 10;67(19):17676-17689.10.1021/acs.jmedchem.4c01664https://rdb.ur.edu.pl/handle/item/50The data presented in this study are available in the Supporting Information in https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c01664. ( 1) General Information on materials and methods; synthesis of mF3 and mF7 compounds: mF3–synthetic pathway and mF7–synthetic pathway; overall synthetic pathway for mF3; synthesis of FCPh2; derivative of fisetin with 4-chlorobutoxy residue at position 3; acetylation at position 7; exchange of terminal halogen atom in chlorobutyloxy residue; exchange of terminal iodine atom into triphenylphosphonium iodide; overall synthetic pathway for mF7; acetylation of hydroxy groups in position 3 and 7 of fisetin; derivative of fisetin with 4-chlorobutoxy residue at position 7; exchange of terminal halogen atom in chlorobutyl residue; exchange of terminal iodine atom into triphenylphosphonium iodide; 1H and 13C NMR spectra of compounds; normal phase isocratic HPLC profiles for mF3 and mF7; changes in the metabolic activity of ER-positive breast cancer cells upon stimulation with tamoxifen; fisetin derivative-mediated changes in mitochondrial parameters in proliferating noncancerous MCF10F cells and HCC1428 breast cancer cells; mF3-mediated apoptosis in BJ human fibroblasts; effect of mF3 on the levels of key markers of necroptotic cell death in HCC1428 breast cancer cells; and Western blot-based analysis of the levels of Bcl-2, Bcl-rambo, AKT, and phospho-AKT in mF3-treated proliferating normal MCF10F cells and HCC1428 breast cancer cells (PDF) (2)Molecular formula strings for mF3 and mF7 (CSV) Dataset 1: Additional original data used to generate the presentation of results in supplementary information file with NMR spectra of compounds. Dataset 2: Original data used to generate the presentation of results in figure 1-5 and SI20 and SI24.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.enAttribution 4.0 Internationalmitochondriotropic fisetin derivativemitophagyoxidative stressbreast cancerapoptosisraw dataset