Effects of Danshen constituent Tanshinone IIA on tumor vasculature

丹参成分丹参酮IIA对肿瘤血管的影响

基本信息

批准号：
8037157
负责人：
BIN CHEN
金额：
$ 18.04万
依托单位：
UNIVERSITY OF THE SCIENCES PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8037157
关键词：
Animals Anti-Inflammatory Agents Anti-inflammatory Anticoagulants Antineoplastic Agents Antioxidants Apoptosis Asians Biological Blood Blood Vessels Blood flow Cardiovascular system Cell Death Cell Line Cell Survival Cell physiology Chemicals China Chinese Herbs Chinese Traditional Medicine Clinical Country Disease Diterpenes Doxorubicin Electrons Endothelial Cells Fluorescence Goals Herb Herbal Medicine Human Image Inflammatory Lead Life Light Malignant Neoplasms Microscopic Modeling Morphology Pharmaceutical Preparations Play Prostatic Neoplasms Reporting Role Salvia miltiorrhiza Structure Swelling Testing Therapeutic Therapeutic Effect Time Tissues Translations Tube Ultrasonography Vascular Diseases Vascular System cancer therapy chemotherapeutic agent cytochrome c cytotoxicity fluorescence imaging imaging modality migration neoplastic cell public health relevance theories tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): Danshen (Radix Salvia miltiorrhiza), one of the most important herbal drugs in traditional Chinese medicine, is widely used for the treatment of cardiovascular, inflammatory and cancer diseases in China and some other Asian countries. Being a major biologically active constituent isolated from Danshen, tanshinone IIA (Tan IIA), a diterpenoid, is found to be responsible for many of the actions of Danshen. In addition to antioxidant, anti-inflammatory and anticoagulant activities, Tan IIA has been shown to induce tumor cell death and inhibit tumor growth. However, the mechanism responsible for its anticancer effect is still poorly understood. Since tumor vasculature plays an important role in tumor growth and progression, and Danshen as well as its constituent Tan IIA are well-known to treat vascular diseases, it is hypothesize that Tan IIA may modify tumor vascular function to inhibit tumor growth. This hypothesis is further supported by recent studies from our lab and other groups indicating that Tan IIA is able to induce endothelial cell apoptosis through triggering cytochrome c release. So far there is no report studying the effect of Tan IIA on tumor vasculature. Thus, one goal of this proposed study is to determine whether Tan IIA can modify tumor vascular structure and function, leading to tumor regression. Since Danshen is usually used in combination with other Chinese herbs or conventional chemotherapeutic agents in the treatment of cancer, the other goal of this study is to determine whether Tan IIA is able to enhance the delivery and effects of other anticancer agents through modifying tumor vascular function. The specific aims of this proposal are to: (1) determine the effects of Tan IIA on endothelial cell viability, morphology and function, (2) determine the effects of Tan IIA on tumor vascular structure and function, (3) determine the effects of Tan IIA on the delivery and effect of anticancer drug. Multi-modality imaging including live animal imaging (i.e. intravital fluorescence imaging, whole body fluorescence imaging and ultrasound imaging) together with static ex vivo imaging (i.e. light, fluorescence and electron microscopic imaging) will be used complementarily to determine the effects of Tan IIA on tumor vasculature and whether Tan IIA can enhance the delivery and therapeutic effect of chemotherapeutic agent doxorubicin. Results from this study will help understand the anticancer mechanism of Chinese herb Danshen and contribute to the clinical translation of this herbal molecule as a tumor vascular-targeting agent. PUBLIC HEALTH RELEVANCE: This study will determine whether tanshinone IIA, a major active constituent of Chinese herbal medicine Danshen, is able to target tumor vasculature and enhance the antitumor effect of chemotherapeutic agent. Results from this study will lead to a better understanding of anticancer mechanisms of Danshen.

描述（申请人提供）：丹参（Radix Salvia miltiorriza）是传统中药中最重要的草药之一，在中国和其他一些亚洲国家广泛用于治疗心血管、炎症和癌症疾病。丹参酮 IIA (Tan IIA) 是一种二萜类化合物，是从丹参中分离出来的主要生物活性成分，被发现与丹参的许多作用有关。除了抗氧化、抗炎和抗凝血活性外，Tan IIA 还被证明可以诱导肿瘤细胞死亡并抑制肿瘤生长。然而，其抗癌作用的机制仍知之甚少。由于肿瘤血管系统在肿瘤生长和进展中发挥着重要作用，而丹参及其成分 Tan IIA 众所周知可以治疗血管疾病，因此推测 Tan IIA 可能会改变肿瘤血管功能以抑制肿瘤生长。我们实验室和其他小组最近的研究进一步支持了这一假设，表明 Tan IIA 能够通过触发细胞色素 c 释放来诱导内皮细胞凋亡。目前尚未见Tan IIA对肿瘤血管影响的研究报道。因此，这项研究的目标之一是确定 Tan IIA 是否可以改变肿瘤血管结构和功能，从而导致肿瘤消退。由于丹参通常与其他中药或常规化疗药物联合使用来治疗癌症，因此本研究的另一个目标是确定丹参IIA是否能够通过改变肿瘤血管功能来增强其他抗癌药物的递送和效果。本提案的具体目的是：（1）确定 Tan IIA 对内皮细胞活力、形态和功能的影响，（2）确定 Tan IIA 对肿瘤血管结构和功能的影响，（3）确定Tan IIA 抗癌药物的递送和效果。多模态成像，包括活体动物成像（即活体荧光成像、全身荧光成像和超声成像）以及静态离体成像（即光、荧光和电子显微镜成像）将被补充使用，以确定 Tan IIA 对肿瘤血管系统以及 Tan IIA 是否可以增强化疗药物阿霉素的递送和治疗效果。这项研究的结果将有助于了解中草药丹参的抗癌机制，并有助于该草药分子作为肿瘤血管靶向剂的临床转化。公共健康相关性：本研究将确定中草药丹参的主要活性成分丹参酮 IIA 是否能够靶向肿瘤脉管系统并增强化疗药物的抗肿瘤效果。这项研究的结果将有助于更好地了解丹参的抗癌机制。