title: The Dietary Flavonoid Fisetin Causes Cell Cycle Arrest, Caspase-Dependent Apoptosis, and Enhanced Cytotoxicity of Chemotherapeutic Drugs in Triple-Negative Breast Cancer Cells.
abstract: Fisetin (3,3',4',7-tetrahydroxyflavone), a flavonoid found in a number of fruits and vegetables, has diverse biological activities, including cytotoxic effects on cancer cells. In this study, we investigated the effect of fisetin on triple-negative breast cancer (TNBC) cells. TNBC has a poorer prognosis than other types of breast cancer and treatment options for this disease are limited. Fisetin inhibited the growth of MDA-MB-468 and MDA-MB-231 TNBC cells, as well as their ability to form colonies, without substantially affecting the growth of non-malignant cells. In addition, fisetin inhibited the growth of estrogen receptor-bearing MCF-7 breast cancer cells and human epidermal growth factor receptor 2-overexpressing SK-BR-3 breast cancer cells. Fisetin inhibited TNBC cell division and induced apoptosis, which was associated with mitochondrial membrane permeabilization and the activation of caspase-9 and caspase-8, as well as the cleavage of poly(ADP-ribose) polymerase-1. Induction of caspase-dependent apoptosis by fisetin was confirmed by reduced killing of TNBC cells in the presence of the pan-caspase inhibitors Z-VAD-FMK and BOC-D-FMK. Decreased phosphorylation of histone H3 at serine 10 in fisetin-treated TNBC cells at G2/M phase of the cell cycle suggested that fisetin-induced apoptosis was the result of Aurora B kinase inhibition. Interestingly, the cytotoxic effect of cisplatin, 5-fluorouracil, and 4-hydroxycyclophosphamide metabolite of cyclophosphamide on TNBC cells was increased in the presence of fisetin. These findings suggest that further investigation of fisetin is warranted for possible use in the management of TNBC. J. Cell. Biochem. 117: 1913-1925, 2016. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Surgery, Dalhousie University, Halifax, Nova Scotia, B3H 4R2, Canada.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Smith
authors.affiliation: Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, B3H 4R2, Canada.
authors.forename: Kaylee
authors.initials: K
authors.lastname: Murphy
authors.affiliation: Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, B3H 4R2, Canada.
authors.forename: Carolyn D
authors.initials: CD
authors.lastname: Doucette
authors.affiliation: Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, B3H 4R2, Canada.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Greenshields
authors.affiliation: Department of Surgery, Dalhousie University, Halifax, Nova Scotia, B3H 4R2, Canada.|Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, B3H 4R2, Canada.|Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, B3H 4R2, Canada.
authors.forename: David W
authors.initials: DW
authors.lastname: Hoskin
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D053181:Caspase 8 / Q000378:metabolism*; D053453:Caspase 9 / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D003603:Cytotoxins / Q000494:pharmacology*; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D044948:Flavonols; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D003603:Cytotoxins; D005419:Flavonoids; D044948:Flavonols; D009363:Neoplasm Proteins; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; C017875:fisetin
keywords: APOPTOSIS; BREAST CANCER; CELL CYCLE ARREST; CHEMOTHERAPY; FISETIN; FLAVONOID