Bladder cancer is one of the commonly diagnosed malignancies in both males and females. One approach to control bladder cancer is growth inhibition wherein the disease is prevented, slowed, or reversed significantly by the administration of naturally occurring non-toxic compounds. In this regard, dietary polyphenols are of high interest in recent year because of their promising efficacy with little or no toxicity in several pre-clinical cancer models. One such natural occurring fruit is cranberry. Cranberry fruits are rich in flavonoids and it is well known that cranberry juice is helpful in treating and preventing urinary tract infections (UTIs) of E. coli. Our preliminary data have demonstrated that a commercially available cranberry juice concentrate can prevent urinary bladder cancers dose-dependently in N-butyl-N-(4-hydroxybutyl)-nitrosamine (OH-BBN) induced bladder carcinogenesis in rats when compared to the control group. The decreased number and size of the bladder cancers suggest that cranberry juice has an antiproliferative activity. Furthermore, the effect was observed when the cranberry juice concentrate was administered during the promotion/progression stage of carcinogenesis. Our data also indicated that cranberry components once ingested, reach to the urinary bladder and concentrate in the urine either intact or metabolized forms, and prevent against the progression of carcinogenesis. Because urinary bladder cancers occur almost exclusively in the bladder epithelium, which is directly exposed to the urine stored in the bladder, we hypothesize that cranberry juice is an effective cancer chemopreventive agent for bladder cancer and its chemopreventive effect is due to the urinary metabolites of cranberry phytochemicals. The objectives of this project are to understand- what phytochemicals are available in cranberry juice;what metabolites of cranberry are bioavailable in the urine stored in the bladder and which metabolites are responsible against bladder carcinogenesis. To test our hypothesis and accomplish the overall objective of this application, we will (1) perform comprehensive metabolite profiling of starting material (cranberry juice concentrate) and urinary metabolites after cranberry administration in rats using Ultra Fast Liquid Chromatography Tandem Mass Spectrometry (UFLC-MS/MS);(2) in order to identify the active metabolites responsible for chemoprevention of bladder cancer, we will perform high content cell based assay with parallel mass spectrometry screening of HPLC fractionated urinary metabolites of cranberry juice concentrate and examine the effects of each fraction on growth inhibition and apoptosis induction in bladder cancer cell lines and (3) we will identify active metabolite(s) responsible for growth inhibition and apoptosis induction in bladder cancer cell lines. This work can be further extended to understand their mechanism of action. In particular, we will identify potential targets of cranberry phytochemicals and their metabolites that are linked to growth suppression in tumor bladder cells. If this project proves to be successful, it is intended to submit a R01 application to NIH.
The goal of this study is to understand- what phytochemicals are available in cranberry juice;what metabolites of cranberry are bioavailable in the urine stored in the bladder and which metabolites are responsible against bladder carcinogenesis. This study will profile all metabolites of cranberry and purify the active fractions to the level of pure single compound or a group of few compounds to identify the bioactive metabolite(s) using high content screening in parallel with mass spectrometry analysis of metabolite. The proposed studies will be the first to address systematically what are the chemopreventive cranberry metabolites against urinary bladder carcinogenesis.
|Prasain, Jeevan K; Rajbhandari, Rajani; Keeton, Adam B et al. (2016) Metabolism and growth inhibitory activity of cranberry derived flavonoids in bladder cancer cells. Food Funct 7:4012-4019|
|Rajbhandari, Rajani; Peng, Ning; Moore, Ray et al. (2011) Determination of cranberry phenolic metabolites in rats by liquid chromatography-tandem mass spectrometry. J Agric Food Chem 59:6682-8|