Oldenlandia diffusa for prostate cancer treatment

描述(由申请人提供)：根据PA-06-400，这项探索性建议旨在进行临床前研究，以证明中草药白花蛇舌草(OD)治疗前列腺癌的疗效。OD在民间中药中已被用作抗癌药物。然而，目前已有有限的临床前研究来研究其疗效并确定其有效的抗癌成分。OD在前列腺癌中的作用尚未得到充分的研究。我们的初步数据显示，OD抑制前列腺癌细胞的生长，部分是通过诱导细胞凋亡，并在体外抑制癌细胞的侵袭和血管生成。在这个开发方案中，我们将应用基于细胞功能的体外分析来确定前列腺癌治疗中OD组分的有效组合。我们假设OD含有生物活性成分，它们以协同或相加的方式相互作用，以靶向前列腺癌的生长、转移和血管生成。具体目的1是鉴定体外抑制前列腺癌细胞生长和侵袭以及抑制血管生成的OD活性成分。我们将应用基于细胞功能的分析来鉴定活性成分。正常的前列腺上皮细胞将用于评估可能的副作用。当确定副作用小的活性成分时，将进行系统评估，以制定既针对前列腺癌间隔(细胞生长和侵袭)又针对内皮间隔(内皮细胞生长、迁移和导管形成)的候选联合方案。具体目的2是在动物模型上验证所制定的联合方案治疗前列腺癌的有效性。两项动物研究，一项针对雄激素敏感型前列腺癌(LNCaP肿瘤)，另一项针对雄激素非依赖性前列腺癌(PC-3或DU 145)，将用于确定候选方案的疗效。我们将首先通过使用实验设计来确定有效的联合方案，该设计允许通过在癌细胞被原位植入后开始治疗方案来确定最大疗效(目标2a)。当为每种肿瘤表型确定一种有效的联合方案时，其有效性将在其相应的动物模型中通过使用“生长延迟”实验设计来证实(目标2b)。具体目标3是阐明联合用药可能以协同方式有效抑制前列腺癌进展的细胞机制。由于联合方案是基于明确的协同/相加细胞功能而制定的，因此我们将在动物研究中验证细胞标志物的调节。预期这一探索性建议的结果将成功地从OD成分中确定用于前列腺癌治疗的有效组合方案，并将提供足够的实验证据来支持RO1建议的发展，以调查OD作为前列腺癌治疗的潜在补充方法。这项拟议项目的目标是确定OD是否含有治疗前列腺癌的活性成分。在体外，基于细胞功能的生物测定将被应用于识别针对前列腺癌生长、侵袭和血管生成的活性成分。针对前列腺癌和血管生成隔室的OD活性成分的配方组合方案将在临床相关的原位前列腺癌动物模型中评估它们对雄激素依赖和雄激素非依赖性前列腺癌生长的效果。细胞标记物将在活体样本中确定。

DESCRIPTION (provided by applicant): 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.