Preclinical Studies of 3',4',5'-Trimethoxyflavonol, a Putative Agent for the Chemoprevention and the Management of Prostate Cancer
thesisposted on 2012-02-03, 11:04 authored by Shaban Eljali Ali Saad
Flavonoids have shown much promise for the chemoprevention of PCa but their poor bioavailability is thought to hinder their chemopreventive efficacy in vivo. However, methoxylation of the flavonoid scaffold could improve bioavailability and efficacy. 3’,4’,5’-trimethoxyflavonol (TMFol) was identified as the most potent growth-inhibitory agent against the PCa cell lines tested. TMFol was 5-15 times more growth inhibitory than fisetin and quercetin, two widely studied flavonols. TMFol caused a G2/M arrest in androgen-dependent cells (LNCaP and TRAMP C2) whereas S phase arrest in the androgen-independent cells (PC-3). TMFol induced more apoptosis in the androgen-dependent cells than the androgen-independent one TMFol inhibited the expression and activity of the AR and also repressed the mRNA levels of both AR and PSA. TMFol also modulated a number of key apoptotic proteins. In vitro data suggests that TMFol may modulate similar proteins to that of quercetin and fisetin, however, exerting its activity at much lower concentrations. Pharmacokinetic data revealed that TMFol levels achievable in the prostate tissue were higher than the concentrations required in vitro to exert pharmacological activity. Nude mice were administered either control diet or diet supplemented with 0.2% w/w TMFol one week prior to cell inoculation. TRAMP C2 cells were implanted into the right flanks of the mice and tumours, once established, were measured twice a week. TMFol significantly reduced the size and weight of the tumour versus control (p<0.05). Equimolar concentrations of quercetin and fisetin in the same model failed to exert efficacy. The expression of p27, bax and survivin which were significantly altered in vitro were also significantly changed following TMFol intervention. These results further our understanding of the in vitro and in vivo pharmacology and cancer preventative activity of TMFol and provide evidence that TMFol may be investigated in preference to quercetin or fisetin for the management of PCa.
Supervisor(s)Sale, Stewart; Brown, Karen
Date of award2011-12-01
Awarding institutionUniversity of Leicester