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作用，用于未来对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的重要生物学潜流。许多炎症性疾病状态会增加特定器官的癌症风险；胃癌的胃炎和结肠癌的结肠炎就是例子。习惯使用非类固醇抗炎药(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非类固醇类药物是一个复杂的问题，受到包括长时间出血、溃疡和中风风险在内的主要副作用的影响；其中一些事件甚至在选择性COX-2抑制剂出现的情况下也会发生。西非有丰富的本土医疗实践，包括知识和使用具有广泛抗炎作用的植物药物。需要检验的假设是，来自西非的本土药用植物传统上用于缓解疼痛、发烧和炎症，它们相互作用，抑制环氧合酶1和环氧合酶2，这与人类肿瘤所选择的受损细胞信号通路有关。我们推测，这些非洲植物药将具有非甾体类抗炎药的作用，并将抑制与结肠癌有关的COX途径，但将具有更广泛的安全边际的优势。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、塞内加尔红木、非洲罗勒和金基里西灌木)的化学指纹图谱，作为初步的质量控制措施，并为今后有效成分的分离和分离奠定基础。确定5种西非药用植物提取物(煎剂)是否对一系列COX表达水平不同的结肠癌细胞株具有潜在的细胞抑制或细胞毒作用；3)确定非洲药用植物提取物是否抑制结肠癌细胞株中COX-1和COX-2亚型；以及4)确定选定研究的非洲植物是否参与诱导结肠癌细胞株凋亡的COX依赖或独立途径。所使用的方法是COX-1和COX-2的RNA和蛋白质表达分析，使用人结肠癌细胞株的标准剂量反应细胞毒性分析，以及流式细胞术介导的细胞凋亡和凋亡蛋白的检测。该项目的长期目标是建立一个生物驱动的分级计划，以进一步表征在活性非洲药用植物中检测到的活性抑制物。我们预计，能够获得这种独特的生物活性天然产物来源，结合使用传统的和功能的体外生物测定，将导致发现新的化学预防药物，这些药物最终可以开发成临床有效的药物。我们有独特的途径获得西非真正的传统治疗师使用的具有抗炎活性的实际植物。

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.