Effects of Danshen constituent Tanshinone IIA on tumor vasculature

产品描述（由申请人提供）：丹参（Radix Salvia miltiorrhiza）是中国传统医学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疾病、炎症和癌症。丹参酮IIA（tanshinone IIA，Tan IIA）是丹参中的一种二萜类化合物，是丹参的主要生物活性成分。除了抗氧化、抗炎和抗凝活性外，Tan IIA还显示出诱导肿瘤细胞死亡和抑制肿瘤生长。然而，其抗癌作用的机制仍然知之甚少。由于肿瘤血管系统在肿瘤生长和进展中起重要作用，并且丹参及其成分Tan IIA是众所周知的治疗血管疾病的药物，因此推测Tan IIA可能改变肿瘤血管功能以抑制肿瘤生长。本实验室和其他研究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释放诱导内皮细胞凋亡。目前还没有关于Tan IIA对肿瘤血管影响的报道。因此，本研究的一个目标是确定Tan IIA是否可以改变肿瘤血管结构和功能，导致肿瘤消退。由于丹参通常与其他中草药或常规化疗药物联合用于治疗癌症，因此本研究的另一个目的是确定Tan 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对抗癌药物的输送和效果的影响。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）连同静态离体成像（即光、荧光和电子显微镜成像）将互补地用于确定Tan IIA对肿瘤脉管系统的影响以及Tan IIA是否可以增强化疗剂阿霉素的递送和治疗效果。本研究的结果将有助于深入了解中药丹参的抗肿瘤作用机制，并为中药丹参作为肿瘤血管靶向药物的临床应用奠定基础。 公共卫生相关性：本研究旨在探讨中药丹参的主要活性成分丹参酮Ⅱ A是否具有靶向肿瘤血管的作用，并增强化疗药物的抗肿瘤作用。本研究的结果将有助于更好地了解丹参的抗癌机制。

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.