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The Dietary Flavonoid Fisetin Causes Cell Cycle Arrest, Caspase‐Dependent Apoptosis, and Enhanced Cytotoxicity of Chemotherapeutic Drugs in Triple‐Negative Breast Cancer Cells
Author(s) -
Smith Matthew L.,
Murphy Kaylee,
Doucette Carolyn D.,
Greenshields Anna L.,
Hoskin David W.
Publication year - 2016
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.25490
Subject(s) - fisetin , triple negative breast cancer , cancer research , apoptosis , cancer cell , cytotoxic t cell , programmed cell death , biology , cell cycle , pharmacology , chemistry , cancer , biochemistry , breast cancer , flavonoid , genetics , in vitro , antioxidant
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.