Effects of Danshen constituent Tanshinone IIA on tumor vasculature

描述（由申请人提供）：丹参是中国最重要的中草药之一，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）是一种从丹参中分离出来的主要生物活性成分，是一种二萜类化合物，与丹参的许多作用有关。除了抗氧化、抗炎和抗凝血外，Tan IIA还具有诱导肿瘤细胞死亡和抑制肿瘤生长的作用。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的生长和进展中起着重要作用，而丹参及其成分Tan IIA治疗血管疾病的作用众所周知，因此我们假设Tan IIA可能通过改变肿瘤血管功能来抑制肿瘤生长。我们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的释放来诱导内皮细胞凋亡。目前尚未见坦IIA对肿瘤血管系统影响的报道。因此，本研究的目的之一是确定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使用治疗癌症，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传递和作用。本课题的具体目的是：(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对抗癌药物传递和作用的影响。结合活体成像（活体荧光成像、全身荧光成像、超声成像）和静态离体成像（光、荧光、电镜成像）等多模态成像互补，确定Tan IIA对肿瘤血管的影响，以及Tan IIA是否能增强化疗药物阿霉素的输送和治疗效果。本研究结果将有助于了解丹参的抗癌机制，并有助于丹参分子作为肿瘤血管靶向药物的临床应用。

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.