Fisetin Inhibits the Activities of Cyclin-Dependent Kinases Leading to Cell Cycle Arrest in HT-29 Human Colon Cancer Cells

Abstract

Fisetin, a natural flavonol present in edible vegetables, fruits, and wine, was reported to exert anticarcinogenic effects. The objective of the current study was to examine the effect of fisetin on the cell cycle progression of the human colon cancer cell line HT-29. HT-29 cells were cultured in serum-free medium with 0, 20, 40, or 60 micromol/L fisetin. Fisetin dose dependently inhibited both cell growth and DNA synthesis (P < 0.05), with a 79 +/- 1% decrease in cell number observed 72 h after the addition of 60 micromol/L fisetin. Perturbed cell cycle progression from the G(1) to S phase was observed at 8 h with 60 micromol/L fisetin treatment, whereas a G(2)/M phase arrest was observed after 24 h (P < 0.05). The phosphorylation state of the retinoblastoma proteins shifted from hyperphosphorylated to hypophosphorylated in cells treated with 40 micromol/L fisetin. (P < 0.05). Fisetin decreased the activities of cyclin-dependent kinases (CDK)2 and CDK4; these effects were likely attributable to decreases in the levels of cyclin E and D1 and an increase in p21(CIP1/WAF1) levels (P < 0.05). However, fisetin also inhibited CDk4 activity in a cell-free system (P < 0.05), indicating that it may directly inhibit CDk4 activity. The protein levels of cell division cycles (CDC)2 and CDC25C and the activity of CDC2 were also decreased in fisetin-treated cells (P < 0.05). These results indicate that inhibition of cell cycle progression in HT-29 cells after treatment with fisetin can be explained, at least in part, by modification of CDK activities.

Fisetin, a dietary flavonoid induces apoptosis via modulating the MAPK and PI3K/Akt signalling pathways in human osteosarcoma (U-2 OS) cells

“…Recent research have reported anti-proliferative (Chen et al, 2002;Haddad et al, 2006) and anti-metastasic effects (Chou et al, 2013) of fisetin, a polyphenolic flavonoid present in many fruits such as strawberries and cucumbers (Kim et al, 2012). Mechanisms through which fisetin exerts its action is yet to be elucidated completely, although it has been demonstrated to increase expressions of p53, down-regulate cyclin D1 and cyclin E levels (Chen et al, 2002;Lee et al, 2002;Lu et al, 2005b;Haddad et al, 2006). Present study investigates whether fisetin induces apoptosis of human osteosarcoma cells and modulats the MAPK and PI3/Akt signalling pathways.…”

The pleiotropic effects of fisetin and hesperetin on human acute promyelocytic leukemia cells are mediated through apoptosis, cell cycle arrest, and alterations in signaling networks

“…Previous studies demonstrated that fisetin and hesperetin inhibited the proliferation of cancer cells by inducing G2/M or G0/G1 arrest. For instance, fisetin induced G2/M arrest in human epidermoid carcinoma A431 cells [25], HT-29 colon cancer cells [8], and PC3 prostate cancer cells [26]. Human cervical SiHa cells treated with hesperetin displayed G2/M arrest in a dose-dependent manner as well [23].…”

“…Despite that fisetin has been shown to induce apoptosis in a variety of cell lines, fisetin-mediated antiproliferative and apoptotic effects were specific for cancer cells based on differential modulation of cellular signaling pathways. The mechanisms behind fisetin's actions include induction of cell cycle arrest by altering cell cycle regulators [8], inhibition of signaling pathways such as NF-κB and PI3K/Akt pathways [9,10], prevention of cell invasion and metastasis [11], and modulation of apoptotic and anti-apoptotic molecules [12]. These effects of fisetin have been evaluated on various cancer types such as colon, prostate, pancreas, and lung cancers; however, there is no study investigating the underlying mechanism(s) of fisetin in APL.…”

Isolation of Fisetin from Elaeagnus indica Serv. Bull. (Elaeagnaceae) with antioxidant and antiproliferative activity

“…Agullo et al 29 stated that the antiproliferative effects of compounds on cancer cells are mainly due to their antioxidant potential which strengthens the findings of the present study. The extensive studies have been conducted to show that fisetin could inhibit several molecular targets, including cyclin-dependent kinases, [30][31][32] DNA topoisomerases I and II, 33,34 urokinase, 35 actin polymerization 36 and androgen receptor signaling. 37 Moreover, fisetin has been recently reported to possess interesting anticancer activity in mice lung carcinoma 38 and prostate tumours.…”