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.

The Natural Flavonoid Fisetin Inhibits Cellular Proliferation of Hepatic, Colorectal, and Pancreatic Cancer Cells through Modulation of Multiple Signaling Pathways

“…It also inhibits micro-ophthalmia associated transcription factor (MITF) in melanoma cells and inhibits invasion of melanoma cells via modulation of the MAPK and NF-κB pathways [20–22]. Recently, it was reported that fisetin causes cell cycle arrest, apoptosis (caspase-dependent), and potentiate the anti-tumor effect of Chemotherapeutics in triple-negative breast cancer cells [23]. …”

Flavonoids in Triple Negative Breast Cancer: Chemopreventive Phytonutrients

“…For example, Fisetin inhibited MDA-MB-468 and MDA-MB-231 cell's division and induced apoptosis involving mitochondrial membrane depolarization and activation of caspase-9 and caspase-8, as well as cleavage of PARP 1 [12]. Similarly, quercetin, another flavonoid compound also causees loss of membrane potential and activation of caspase cascade and PARP cleavage.…”

“…On the other hand, different studies determined G2/M phase arrest in MDA-MB-468 and MDA-MB-231 cells in response to fisetin and genistein treatments [12,19]. Results from another study suggesting that genistein-induced G2/M cell cycle arrest in MDA-MB-231 cells by modulating Ras/ MAPK/AP-1 cancer signaling pathway [20].…”

“…Since neither receptors nor HER2 overexpression is occurred in TNBC therefore the therapies are found to be ineffective [11]. Interestingly, several in-vitro experiments determined the risk reducing effect of flavonoids in TNBC and suggesting them as a promising therapy.For example, Fisetin inhibited MDA-MB-468 and MDA-MB-231 cell's division and induced apoptosis involving mitochondrial membrane depolarization and activation of caspase-9 and caspase-8, as well as cleavage of PARP 1 [12]. Similarly, quercetin, another flavonoid compound also causees loss of membrane potential and activation of caspase cascade and PARP cleavage.…”

Toxicity of four novel Polyhedral Oligomeric Silsesquioxane (POSS) particles used in anti-cancer drug delivery

“…Live cells remained adhered to the plate and dead cells were washed away (Smith et al, 2016, Chiba et al, 1998. Three replicate plates were performed for cell count using crystal violet assay, each plate included 6 technical replicate wells per treatment.…”