This exploratory proposal, in response to the PA-06-400, is developed to conduct preclinical studies to demonstrate efficacy of the Chinese herb Oldenlandia diffusa (OD) for prostate cancer treatment. OD has been used in folk Chinese medicine as anti-cancer agent. However, there have been limited preclinical studies to investigate its efficacy and to identify its active anti-cancer components. The effect of OD on prostate cancer has not been adequately studied. Our preliminary data showed that OD inhibited the growth of prostate cancer cells in part via induction of apoptosis and inhibited cancer cell invasion and angiogenesis in vitro. In this developmental proposal, we will apply cellular function-based in vitro assays to identify the effective combinations of the OD components for prostate cancer treatment. We hypothesize that OD contains bioactive components that interact, in a synergistic or an additive manner, to target prostate cancer growth and metastasis and angiogenesis.
Specific aim 1 is to identify the active OD components for inhibition of growth and invasion of prostate cancer cells and for inhibition of angiogenesis in vitro. We will apply cellular function- based assays to identify the active components. Normal prostatic epithelial cells will be used for evaluation of possible side effect. When the active components with few side effects are identified, a systematic evaluation will be conducted to formulate the candidate combination regimens that target both prostate cancer compartment (cell growth and invasion) and endothelial compartment (endothelial cell growth, migration and tube formation).
Specific aim 2 is to verify efficacy of the formulated combination regimens on prostate cancer treatment in animal models. Two animal studies, one for androgen-sensitive prostate tumor (LNCaP tumor) and the other for androgen-independent prostate tumor (PC-3 or DU 145), will be used for determination of efficacy of the candidate regimens. We will first identify the potent combination regimens by using the experimental design that allows determination of maximal efficacy by starting treatment regimens after cancer cells are orthotopically implanted (Aim 2a). When a potent combination regimen is identified for each tumor phenotype, its efficacy will be confirmed in its corresponding animal model by using the """"""""growth delay"""""""" experimental design (Aim 2b).
Specific aim 3 is to elucidate cellular mechanisms whereby the combination regimens may effectively inhibit prostate cancer progression in a synergistic manner. Because the combination regimens are formulated based on defined synergistic/additive cellular functions, we will verify the modulation of cellular markers in animal studies. It is expected that results derived from this exploratory proposal will successfully identify the potent combination regimens from OD components for prostate cancer treatment, and will provide sufficient experimental evidence to support development of a RO1 proposal to investigate OD as a potential complementary approach for prostate cancer treatment. The goals of the proposed project are to determine if OD contains active components for treatment of prostate cancer. In vitro cellular function-based bioassays will be applied to identify the active components that target prostate cancer growth and invasion and angiogenesis. The formulated combination regimens of OD active components that target both prostate cancer and angiogenesis compartments will be evaluated for their efficacy on the growth of androgen-dependent and androgen-independent prostate tumors in clinically relevant orthotopic prostate tumor animal models. The cellular markers will be determined in the in vivo samples. ? ? ?
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