Polyphenols Regulate Lipid inflammatory Processes in Pancreatic Cancer
Principle Investigator: Diane Harris, PhD
Co-Investigator: Guido Eibl, MD
Co-Investigator: Vay Liang W. Go, MD
Hypothesis: We hypothesize that polyphenolic compounds from green tea and Scutellaria baicalensis (SB):
(1) inhibit eicosanoid production in pancreatic cancer cells
(2) lower the risk of developing pancreatic cancer (preventive effect)
(3) reduce the growth and spread of established pancreatic cancer (therapeutic effect)
We will use metabolic tracer technology to evaluate the overall phenotypic effect of polyphenols on pancreatic cancer cells. The proposed studies will heavily utilize the Metabolomic, Phytonutrient, and Animal Model Cores of the Center.
Specific Aim 1: To determine if mixed extracts from green tea and SB inhibit cell proliferation in vitro and if this activity is mediated through the eicosanoid-generating pathways. It will be divided into three subaims.
a) To determine the effects of green tea, SB, and their isolated polyphenolic compounds (EGCG, EGC, ECG, and EC for green tea and baicalin, bacalein, and wogonin for SB) on pancreatic cancer cell proliferation, apoptosis, and cell cycle progression compared to vehicle control and two pharmaceutical controls (indomethacin and nordihydroguaiaretic acid (ADGA)). The primary objective is to determine if the extracts diminish cell proliferation in physiologically achievable doses. Secondary aims are to compare the response of the mixed extract to isolated polyphenolic compounds found in these extracts and pharmaceutical inhibitors and to see if the effect varies by cell phenotype in 6 different lines.
b) To evaluate the efficacy of green tea and SB polyphenols to inhibit eicosanoid production in cultured pancreatic cancer cells;
c) Determine the effects of green tea and SB extracts on the metabolic profile of pancreatic cancer cells using metabolic tracer technologies:
1. To characterize phenotypic changes using [1,2-13C2] glucose; and
2. To use isotopic labeled arachidonic acid and COX and LOX products as recovery standards to determine turnover of archidonic acid as well as quantitative analysis of eicosanoids.
Specific Aim 2: To evaluate the preventive effects of green tea and SB polyphenols on the development and progression of pancreatic cancer precursor lesions using a transgenic animal model. It will also include two secondary subaims to determine.
a) the relative level of COX and LOX expression and eicosanoid content (PGE2 and LTB4) in each microdissected PanIN relative to normal duct epithelium; and
b) the metabolic phenotype of each lesion in the progression from normal epithelium to high-grade PanIN and correlate to changes in eicosanoid production.
Specific Aim 3: To determine the therapeutic role of green tea and SB extracts on pancreatic cancer growth in vivo using xenograft animal models. Secondary subaims will be to determine relative levels of immunohistochemical markers of proliferation and apoptosis and COX and LOX expression plus PGE2 and LTB4 levels in tumor tissue