The metabolites of polyphenols from pomegranate fruit and green tea produced by the intestinal microbiome - effect on prostate tumors and the action of drugs used in their conventional therapy in an in vitro model.

The aim of the project is to determine whether and to what extent the metabolites of ellagotanoids and flavan-3-ol-urolithin and 5- (3 ', 4', 5'-trihydroxyphenyl) -g-valerolactone produced by the intestinal microbiome can contribute to the beneficial effects of rich preparations in polyphenols, such as pomegranate preparations and green tea, in prostate cancer. During the project implementation, the effect of the above-mentioned metabolites and their mixtures with drugs used in the conventional treatment of prostate cancer, the anti-androgen bicalutamide and the chemotherapeutic agent docetaxel, on the proliferation and survival of prostate cancer cells will be investigated. Two prostate cancer cell lines differing in their sensitivity to bicalutamide and docetaxel, LNCaP and DU-145, will serve as in vitro models of neoplastic cells, while the PZ-HPV-7 immortalized cell line will be a model of normal prostate cells. The first stage of the work will investigate the proliferation and apoptosis of cells after incubation with the test compounds and their mixtures. The results of proliferation studies will be used to determine whether there are pharmacodynamic interactions between polyphenol metabolites and drugs and, if appropriate, to determine their nature (synergism, additivity, antagonism). The second stage of the project will focus on determining the influence of the test compounds and their mixtures on the previously selected signal transduction pathways and molecular targets that play an important role and often malfunction in the course of prostate cancer: androgen receptor, signal transducer and activator 3 (STAT3), Akt kinase and NF-kB transcription factor and expression of proteins controlling cell survival (Bcl-2, Bax, survivin). Prostate neoplasms are among the most common and among the leading causes of cancer death in men in the world. About 30% of prostate cancer patients use supplements, often containing plant-based ingredients, to improve disease control. Moreover, it was found that patients with more advanced disease were significantly more likely to use complementary and alternative medicine (CAM). Preparations containing polyphenols from pomegranate fruit and green tea are commonly used by patients with prostate cancer. While the use of phytotherapeutic drugs is generally safe for the general population, it may not be safe for pharmacotherapy of cancer. Many compounds of plant origin interact with drugs used in cancer therapy, limiting their effectiveness or increasing toxicity. Despite the encouraging results of studies on the effect of processed pomegranates and green tea on animal models of prostate cancer in vivo, it is difficult to explain the observed results by the direct action of the polyphenols present in them. The polyphenols present in green tea and pomegranate have poor bioavailability after oral administration. On the other hand, the products of their biotransformation by the intestinal microbiome are easily absorbed in the intestines and reach concentrations at least several times higher in body fluids than their parent compounds. Determining the role of polyphenol metabolites produced by the intestinal microbiome in the systemic action of polyphenols after oral administration will provide useful information on the combined effects of the intestinal microbiome and phytotherapeutic agents, and will contribute to a better understanding of the mechanisms of beneficial outflow of the use of a diet or preparations rich in polyphenols.