"Description
FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT
This invention was made with Government support of Grant No. AT000151 awarded by the National Institutes of Health. The Government has certain rights in this invention.
INTRODUCTION
Ellagitannins (ETs) are polymeric polyphenols abundant in some fruits and nuts such as pomegranates, raspberries, strawberries, black raspberries, walnuts and almonds. Despite numerous reports of the biological properties and human health benefits of ETs, knowledge of their bioavailability, pharmacokinetics, disposition and metabolic fate in humans is limited.
Pomegranate (Punica granatum L.) fruits are widely consumed fresh and as beverages such as juice (PJ). In commercial juice processing methods, ETs which are abundant in the fruit peels, are extracted in large quantities into the juice. Punicalagin [2,3 hexahydroxydiphenoyl-4,6-gallagylglucose], which occurs as isomers (FIG. 1), is the predominant ET present in PJ as a result of this process. ETs belong to the chemical class of hydrolyzable tannins, which release ellagic acid (EA) on hydrolysis. In addition, PJ contains other polyphenols such as anthocyanins, which are present in the fruit arils, imparting its brilliant ruby-red color.
The potent antioxidant properties of PJ have been attributed to its high content of punicalagin isomers which can reach levels>2 g/L juice. ETs have also been identified as the active anti-atherogenic compounds in PJ. It has been suggested that pomegranate ETs and pomegranate fruit extracts inhibit the proliferation of human cancer cells and modulate inflammatory sub-cellular signaling pathways and apoptosis, see, for example, Seeram et al. (2005) J Nutr Biochem. 2005; 16:360-7; Adams et al. (2006) J Agric Food Chem. 2006, 54, 980-85; Afaq et al. (2005) Photochem Photobiol. 2005; 81:38-45; Afaq et al. (2005) Int J. Cancer. 2005; 113:423-33. Pomegranate fruit extract has also been suggested to reduce prostate tumor growth and prostate serum antigen (PSA) levels in athymic nude mice implanted with CWR22Rv1 prostate cells (Malik et al. (2005) Proc Natl Acad. Sci. 2005; 102: 14813-8.
Although the absorption, metabolism, distribution and excretion of pomegranate ETs in animals and in humans, have been reported, their pharmacokinetic parameters remain uninvestigated. It is becoming clear that considerable inter-individual variability occurs in polyphenol metabolism in humans. As such, there is a need to establish bioavailability, metabolism and pharmacokinetic parameters of pomegranate ETs in human volunteers and to link ETs and/or metabolites thereof to specific beneficial properties, e.g., antioxidant, cancer cell antiproliferative and pro-apoptotic effects, etc. This invention meets these and other needs.
SUMMARY OF THE INVENTION
The present invention is drawn to metabolites of pomegranate polyphenols (e.g., ellagitannins) or derivatives thereof, which polyphenols find use in methods of treating and/or preventing a hyperproliferative disease in a subject. The subject ellagitannin metabolites are shown herein to have an anti-proliferative and/or pro-apoptotic effect on cells, and as such, find use in the treatment and prevention of a number of disease states, e.g. to inhibit tumor growth, to decrease inflammation associated with a lymphoproliferative disorder, to inhibit graft rejection, or neurological damage due to tissue repair, etc.
In one embodiment of the invention, a pharmaceutical composition is provided, comprising an effective dose of an ellagitannin metabolite and a pharmaceutically acceptable excipient. The effective dose will usually be effective for inhibiting the proliferation of a cell, including tumor cells, e.g. solid tumor cells, such as carcinomas, e.g. pancreatic carcinomas, prostate carcinomas, and the like. In certain embodiments, the ellagitannin metabolites of interest are urolithins and/or derivatives thereof.
In another embodiment of the invention, methods are provided for inhibiting undesirable cell proliferation, the method comprising contacting the cells with an effective dose of an ellagitannin metabolite and a pharmaceutically acceptable excipient. Cells of interest include, without limitation, tumor cells, e.g. solid tumor cells, such as carcinomas, e.g. pancreatic carcinomas, prostate carcinomas, and the like. In certain embodiments, the ellagitannin metabolites of interest are urolithins and/or derivatives thereof.
In some embodiments of the invention, patients are classified as metabolite producers and metabolite non-producers, where treatment may be tailored to the status of the patient."
goes on much further below:
Patent US8648112 - Therapeutic uses of urolithins - Google Patents
Has a lot of prostate cancer fighting properties
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