Cancer Prevention by West African Medicinal Plants

描述（由申请人提供）： 该项目的总体目标是从原产于西非的药用植物中发现新的抗炎化合物。广泛的长期目标是为这种未开发的天然产品来源建立一个角色，用于未来结肠癌和其他癌症的化学预防应用。炎症过程似乎是几种常见人类癌症中重要的生物学暗流。许多炎症性疾病状态会增加特定器官患癌症的风险;例如胃癌的胃炎和结肠癌的结肠炎。习惯使用非甾体抗炎药（NSAIDS）似乎可以降低几种人类癌症的风险，最明显的是结肠癌。然而，在癌症化学预防中长期使用NSAIDS是一个复杂的问题，其主要副作用包括长期出血、溃疡和中风风险;甚至在选择性考克斯-2抑制剂出现时，这些事件中的一些也会发生。西非有丰富的本土医学实践，包括知识和使用具有广泛抗炎作用的植物药。要测试的假设是，传统上用于缓解疼痛，发烧和炎症的西非原生药用植物相互作用，抑制环氧化酶1和2，涉及人类肿瘤所选择的受损细胞信号通路。我们假设这些非洲植物药具有NSAID样作用，并抑制结肠癌相关的考克斯通路，但具有更广泛的安全范围的优势。该项目的具体目标是：1）开发五种西非植物提取物（印楝树、猴面包树、塞内加尔桃花心木、非洲罗勒和金克里西灌木）的化学指纹图谱，作为初步质量控制措施和未来有效成分分级和分离的起始面板2）。以确定是否提取5种西非药用植物的提取物对一系列考克斯表达水平不同的结肠癌细胞系具有潜在的细胞抑制或细胞毒性作用; 3）确定非洲药用植物的提取物是否抑制结肠癌细胞系中的考克斯-1和考克斯- 2同种型;和4）确定选择用于研究的非洲植物是否参与结肠癌细胞系中COX-依赖性或非依赖性途径的细胞凋亡诱导。所用的方法是考克斯-1和考克斯-2的RNA和蛋白质表达测定、使用人结肠癌细胞系的标准剂量反应细胞毒性测定以及细胞凋亡和细胞凋亡蛋白的流式细胞术介导的检测。该项目的长期目标是建立一个生物驱动的分级程序，以进一步表征在活性非洲药用植物中检测到的活性抑制剂。我们期望，获得这种独特的生物活性天然产物来源，结合使用常规和功能性体外生物测定将导致发现新的化学预防剂，其最终可以发展成临床有效的药物。我们有独特的机会获得真正的植物与所谓的抗炎活性所使用的实际传统治疗师在西非。

DESCRIPTION (provided by applicant): The overall goal of this project is to discover novel, anti-inflammatory compounds from medicinal plants native to West Africa. The broad long-term objective is to establish a role for this unexploited source of natural products for future chemoprevention applications for colon and other cancers. The inflammatory process appears to be an important biological undercurrent in several common human cancers. Many inflammatory disease states increase the risk for cancer in a particular organ; gastritis for stomach cancer, and colitis for colon cancer are examples. Habitual use of non-steroidal anti-inflammatory drugs (NSAIDS) appears to reduce the risk for several types of human cancer, most notably, colon cancer. Yet, long-term use of NSAIDS in cancer chemoprevention is a complex issue, marred by major side effects including prolonged bleeding, ulceration, and risk of stroke; some of these events occur in even with the advent of selective COX-2 inhibitors. West Africa is rich in indigenous medicinal practices including knowledge and use of botanicals with wide anti-inflammatory effects. The hypothesis to be tested is that native medicinal plants from West Africa used traditionally for relief of pain, fever, and inflammation interacts to inhibit cyclooxgenases 1 and 2, implicated in corrupted cell signaling pathways co-opted by human tumors. We postulate that these African botanicals will have NSAID-like effects and will inhibit COX pathways involved in colon cancer, but will have the advantage of a wider margin of safety. The specific aims of this project are: 1) To develop chemical fingerprints of five West African plant extracts (neem tree, baobab tree, Senegal mahogany, African basil, and kinkirissi bush) as initial quality control measures and a starting panel for future fractionation and isolation of active principles 2). to determine if extracts (decoctions) of 5 West African medicinal plants have potential cytostatic or cytotoxic effects on a range of colon cancer cell lines differing in COX expression levels; 3) to determine whether extracts of African medicinal plants inhibit COX-1 and COX- 2 isoforms in colon cancer cell lines; and, 4) to determine if COX-dependent or independent pathways are involved in induction of apoptosis in colon cancer cell lines by the African botanicals selected for study. The methodologies used are RNA and protein expression assays for COX-1 and COX-2, standard dose response cytotoxicity assays using human colon cancer cell lines, and flow cytometry mediated detection of apoptosis and apoptotic proteins. The long-term goal of this project is to establish a biologically-driven fractionization program to further characterize active inhibitors detected in active African medicinal plants. We expect that having access to this unique source of bioactive natural products, combined with the use of both conventional and functional in vitro bioassays will lead to discovery of new chemopreventive agents which can be ultimately developed into clinically effective agents. We have unique access to actual plants with purported anti-inflammatory activity used by actual traditional healers in West Africa.