A Novel Dietary Flavonoid Fisetin Inhibits Androgen Receptor Signaling and Tumor Growth in Athymic Nude Mice

Abstract

Androgen receptor (AR)-mediated signaling plays an important role in the development and progression of prostate cancer (PCa). Hormonal therapies, mainly with combinations of antiandrogens and androgen deprivation, are the mainstay treatment for advanced disease. However, emergence of androgen resistance largely due to inefficient antihormone action limits their therapeutic usefulness. Here, we report that fisetin, a novel dietary flavonoid, acts as a novel AR ligand by competing with the high-affinity androgen to interact with the ligand binding domain of AR. We show that this physical interaction results in substantial decrease in AR stability and decrease in amino-terminal/carboxyl-terminal (N-C) interaction of AR. This results in blunting of AR-mediated transactivation of target genes including prostate-specific antigen (PSA). In addition, treatment of LNCaP cells with fisetin decreased AR protein levels, in part, by decreasing its promoter activity and by accelerating its degradation. Fisetin also synergized with Casodex in inducing apoptosis in LNCaP cells. Treatment with fisetin in athymic nude mice implanted with AR-positive CWR22RU1 human PCa cells resulted in inhibition of tumor growth and reduction in serum PSA levels. These data identify fisetin as an inhibitor of AR signaling axis and suggest that it could be a useful chemopreventive and chemotherapeutic agent to delay progression of PCa. [Cancer Res 2008;68(20):8555-63]

Inhibition of prostate cancer cell growth by 3′,4′,5′-trimethoxyflavonol (TMFol)

“…human prostate tumours grown in nude mice in vivo [2]. A mechanism by which fisetin is thought to interfere with prostate cancer cell survival is induction of apoptosis [2,3].…”

“…A mechanism by which fisetin is thought to interfere with prostate cancer cell survival is induction of apoptosis [2,3]. The fisetin analogue quercetin (3ʹ,4ʹ,5,7-tetrahydroxyflavonol), the biological properties of which have been widely studied [4], at concentrations of 10-100 μM has also exhibited growth-arresting properties in human-derived prostate cancer cells [5].…”

Therapeutic use of fisetin, curcumin, and mesoporous carbon nanoparticle loaded fisetin in bleomycin-induced idiopathic pulmonary fibrosis

“…In the past years, fisetin was a subject of research because of its antiproliferative (Haddad et al, 2006;Khan et al, 2008;Suh et al, 2009), apoptotic (Suh et al, 2009;Sung et al, 2007), and antioxidant (Hou et al, 2001) activities. Several studies indicate that fisetin is a promising novel antioxidant.…”

Flavones and Flavonols may have Clinical Potential as CK2 Inhibitors in Cancer Therapy

“…Here are citations for the xenograft studies: apigenin, 65-81 luteolin, 111-122 kaempferol, 123 fisetin, [124][125][126] quercetin, 127-145 myrcetin. 146 There are at least 53 published studies in which flavones or flavonols have decreased the growth of human xenografts in nude mice.…”