{"title":"New Mitochondria-Targeted Fisetin Derivative Compromises Mitophagy and Limits Survival of Drug-Induced Senescent Breast Cancer Cells.","authors":"Iwona Rzeszutek,Martyna Cybularczyk-Cecotka,Anna Deręgowska,Paulina Stec,Maciej Wnuk,Olga Kołodziej,Joanna Kałafut,Anna Wawruszak,Wojciech Witkowski,Grzegorz Litwinienko,Anna Lewińska","doi":"10.1021/acs.jmedchem.4c01664","DOIUrl":null,"url":null,"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.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8000,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acs.jmedchem.4c01664","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
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.
期刊介绍:
The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents.
The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.