Nexrutine Phellodendron amurense bark extract: Potential use in Pancreatic Cancer

Nexrutine 黄柏树皮提取物：在胰腺癌中的潜在用途

• 批准号: 7990108
• 负责人: ADDANKI PRATAP KUMAR
• 金额: $ 22.28万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7990108
• 关键词: Address; Apoptosis; Biochemical; Biological; Biological Assay; Biological Availability; CREB1 gene; Cancer Patient; Cancer cell line; Cell Proliferation; Cell Survival; Data; Development; Diet; Disease; Drug resistance; Evaluation; Exocrine pancreas; Fluorine; Goals; Growth; Health; High Pressure Liquid Chromatography; Human; Immunoblotting; Immunohistochemistry; In Vitro; Incidence; Induction of Apoptosis; K-ras Oncogene; Knock-in Mouse; Knock-out; Laboratories; Lesion; Malignant neoplasm of pancreas; Mediating; Modeling; Molecular Abnormality; Molecular Genetics; Monitor; Mus; Mutation; Nature; Outcome; Pancreas; Pathogenesis; Pathway interactions; Phellodendron; Phosphotransferases; Poison; Pre-Clinical Model; Prevention; Preventive; Review Literature; Role; Serum; Signal Pathway; Signal Transduction; Signaling Molecule; Staging; Stream; Testing; Time; Tissues; Transgenic Mice; Transgenic Model; Tumor Tissue; Western Blotting; base; cancer cell; cancer prevention; chemotherapy; cost; design; dietary supplements; fluorodeoxyglucose positron emission tomography; human FRAP1 protein; in vivo; innovation; insight; intraepithelial; mortality; neoplastic; pancreatic neoplasm; pre-clinical; prevent; public health relevance; research study; response; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Despite significant progress in understanding the nature and development of pancreatic cancer (PanCA), it still remains a disease of near uniform lethality. Innovative strategies to prevent the development and progression of PanCA are urgently needed for its management. The goal of this exploratory application submitted in response to PA-08-185 is to test whether Nexrutine, an herbal extract from the bark of Phellodendron amurense can inhibit pancreatic cancer development in vivo and determine whether Nexrutine-mediated inhibition of Akt signaling is sufficient to inhibit pancreatic cancer growth. This goal is based on supporting data from our laboratory showing (i) inhibition of proliferation; (ii) induction of apoptosis and (iii) reduction in the levels of pAkt following treatment of multiple pancreatic cancer cell lines that differ in the status of K-Ras with Nexrutine. A review of the literature reveals that no known studies have been undertaken to assess the effect of Nexrutine in pancreatic cancer in vitro or in vivo. We have proposed two specific aims. Aim 1: Establish the preventive efficacy and bioavailability of Nexrutine in the pre clinical LSL K-ras G12D/Pdx-1Cre transgenic model. 4-5 week old LSL K-ras G12D/Pdx-1Cre transgenic mice will be administered 0, 150, 300, 600 and 900 mg/kg Nexrutine through diet for 6 months. Prevention of tumor development will be monitored by (i) non-invasive fluorine-18 fluorodeoxyglucose positron-emission tomography (FDG-PET) sequentially during progression at 8-weeks, 16-weeks and at the time of termination of the study and (ii) histological evaluation of the mPanIN lesions at the termination of the experiment. Levels of Nexrutine and expression of Akt signaling molecules will be analyzed in the pancreas using HPLC and immunohistochemistry respectively. Aim 2: Demonstrate the role of Akt and its upstream and downstream signaling pathways in Nexrutine-induced inhibition of proliferation. A variety of biochemical (cell proliferation, apoptosis), molecular and genetic approaches (knock-in and knock-out) will be used to explore the role of PI3K/Akt signaling in mediating the antiproliferative activity of Nexrutine in pancreatic cancer cells. Successful completion of this exploratory project with high translational potential will (i) identify a non-toxic compound for use in PanCA prevention; and (ii) identify Akt and down-stream signaling components as markers of Nexrutine action. Furthermore these studies will provide enough preliminary data to determine whether the efficacy of Nexrutine is specific to any particular stage of PanCA, to reverse chemotherapy induced drug resistance in preclinical models and to delineate the precise mechanism of action of Nexrutine. The LSL K-ras G12D/Pdx-1Cre transgenic model is highly appropriate murine model in which the development and progression of pancreatic cancer (PanCA) recapitulates human PanCA development and progression. Moreover since Nexrutine is already in human use the results obtained from this study may be extended to explore its use as a prevention agent for human pancreatic cancer. PUBLIC HEALTH RELEVANCE: Pancreatic cancer (PanCA) is a major health problem with incidence and mortality rates being equal. The goal of this application is to test a cost-effective and non toxic dietary supplement as an anti-PanCA agent using a preclinical model that recapitulates human pancreatic cancer. This is therefore very timely and highly significant.

描述（由申请人提供）：尽管在了解胰腺癌（PanCA）的性质和发展方面取得了重大进展，但它仍然是一种几乎一致致死率的疾病。其管理迫切需要创新策略来阻止 PanCA 的发展和进展。针对 PA-08-185 提交的探索性申请的目的是测试 Nexrutine（一种来自黄柏树皮的草药提取物）是否可以抑制体内胰腺癌的发展，并确定 Nexrutine 介导的 Akt 信号传导抑制是否足以抑制胰腺癌的生长。这一目标基于我们实验室的支持数据，显示（i）抑制增殖；用 Nexrutine 处理 K-Ras 状态不同的多种胰腺癌细胞系后，(ii) 诱导细胞凋亡和 (iii) 降低 pAkt 水平。文献综述表明，尚未进行任何已知的研究来评估 Nexrutine 在体外或体内对胰腺癌的作用。我们提出了两个具体目标。目标 1：在临床前 LSL K-ras G12D/Pdx-1Cre 转基因模型中建立 Nexrutine 的预防功效和生物利用度。 4-5周龄LSL K-ras G12D/Pdx-1Cre转基因小鼠将通过饮食施用0、150、300、600和900mg/kg Nexrutine，为期6个月。肿瘤发展的预防将通过(i)在8周、16周和研究终止时的进展过程中依次进行非侵入性氟18氟脱氧葡萄糖正电子发射断层扫描(FDG-PET)和(ii)在实验终止时对mPanIN病变进行组织学评估来监测。将分别使用 HPLC 和免疫组织化学分析胰腺中 Nexrutine 的水平和 Akt 信号分子的表达。目标 2：证明 Akt 及其上游和下游信号通路在 Nexrutine 诱导的增殖抑制中的作用。将使用各种生化（细胞增殖、凋亡）、分子和遗传学方法（敲入和敲除）来探索 PI3K/Akt 信号传导在介导 Nexrutine 的胰腺癌细胞抗增殖活性中的作用。成功完成这一具有高转化潜力的探索性项目将 (i) 确定一种用于预防 PanCA 的无毒化合物； (ii) 确定 Akt 和下游信号成分作为 Nexrutine 作用的标记。此外，这些研究将提供足够的初步数据，以确定 Nexrutine 的功效是否特定于 PanCA 的任何特定阶段，以逆转临床前模型中化疗诱导的耐药性，并描述 Nexrutine 的精确作用机制。 LSL K-ras G12D/Pdx-1Cre 转基因模型是非常合适的小鼠模型，其中胰腺癌 (PanCA) 的发生和进展概括了人类 PanCA 的发生和进展。此外，由于 Nexrutine 已经在人类中使用，因此从这项研究中获得的结果可以扩展以探索其作为人类胰腺癌预防剂的用途。 公众健康相关性：胰腺癌 (PanCA) 是一个主要的健康问题，其发病率和死亡率相当。本申请的目标是使用模拟人类胰腺癌的临床前模型来测试一种具有成本效益且无毒的膳食补充剂作为抗 PanCA 药物。因此，这是非常及时和非常重要的。