Treatment of Cervical Cancer with Artemisinin

青蒿素治疗宫颈癌

• 批准号: 6823604
• 负责人: Richard Schlegel
• 金额: $ 23.28万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-15 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6823604
• 关键词: BCL2 gene /protein; alternative medicine; antimalarial agents; antineoplastics; apoptosis; athymic mouse; cervix neoplasms; ferritin; free radical oxygen; high performance liquid chromatography; human tissue; medicinal plants; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; plant extracts; therapy design /development; transferrin; transferrin receptor

DESCRIPTION (provided by applicant) Worldwide, cervical cancer kills more than 250,000 women each year and in the United States nearly 60,000 women are diagnosed with early stages of this malignancy. There are no effective pharmacologic treatments available for either cervical dysplasia or early cervical cancer and the clinical management of these lesions relies upon ablative surgical techniques. The development of a non-toxic, effective drug therapy would greatly simplify the treatment of this disease. In this proposal, we will explore the use of artemisinin for selectively killing cervical cancer cells. Artemisinin, derived from the Chinese herb, Artemisia annua, has been used for more than 2,000 years as a therapy for malaria and recent studies indicate that its anti-malarial activity depends upon an endoperoxide bond that is reduced by ferrous iron, resulting in the generation of reactive oxygen species. Interestingly, some cancer cell lines have been shown to be killed by artemisinin (and derivatives such as DHA), apparently based upon their increased iron content. The preliminary studies in this grant demonstrate that tumorigenic cervical cells express higher levels of transferrin receptor than normal cervical cells and are preferentially killed by artemisinin via the induction of apoptosis. This cell death is iron-dependent and our immediate goals are to define the precise apoptotic pathways which are activated. We will also determine whether this compound can be used to kill cervical cancer cells in a mouse model, using both topical and systemic administration. In addition, we will explore potential cooperativity between artemisinin and radiation, which is another treatment modality used for cervical cancer. If our apoptosis studies indicate that mitochondrial pathways are involved in artemisinin-induced cell death, we will also determine whether anti bcl-2 therapy can be used to selectively augment artemisinin activity. The ultimate goal of this pilot proposal is deepen our understanding of artemisinin's activities, to extend its use from in vitro to in vivo studies, and to generate supportive data for initiating human trials. Since artemisinin is already approved clinically for use as an antimalarial, the transition to human Phase trials should be greatly accelerated

描述（由申请人提供） 在世界范围内，宫颈癌每年夺去超过 250,000 名女性的生命，在美国，近 60,000 名女性被诊断出患有这种恶性肿瘤的早期阶段。对于宫颈发育不良或早期宫颈癌没有有效的药物治疗，这些病变的临床治疗依赖于消融手术技术。开发一种无毒、有效的药物疗法将大大简化这种疾病的治疗。在本提案中，我们将探索利用青蒿素选择性杀死宫颈癌细胞。青蒿素源自中草药黄花蒿，作为治疗疟疾的药物已有 2000 多年的历史，最近的研究表明，其抗疟疾活性取决于内过氧化物键，该键被亚铁还原，从而产生活性氧。有趣的是，一些癌细胞系已被证明可以被青蒿素（以及 DHA 等衍生物）杀死，这显然是因为它们的铁含量增加了。该资助的初步研究表明，致瘤宫颈细胞比正常宫颈细胞表达更高水平的转铁蛋白受体，并通过诱导细胞凋亡优先被青蒿素杀死。这种细胞死亡是铁依赖性的，我们的直接目标是确定被激活的精确细胞凋亡途径。我们还将确定该化合物是否可以通过局部和全身给药来杀死小鼠模型中的宫颈癌细胞。此外，我们将探索青蒿素和放射疗法之间的潜在协同作用，放射疗法是另一种用于宫颈癌的治疗方式。如果我们的细胞凋亡研究表明线粒体途径参与青蒿素诱导的细胞死亡，我们还将确定抗 bcl-2 疗法是否可用于选择性增强青蒿素活性。该试点提案的最终目标是加深我们对青蒿素活性的了解，将其用途从体外研究扩展到体内研究，并为启动人体试验提供支持数据。由于青蒿素已经在临床上被批准用作抗疟药，因此向人体试验的过渡应该大大加快