Effects of Danshen constituent Tanshinone IIA on tumor vasculature

说明(申请人提供)：丹参(丹参)是中医药中最重要的中草药之一，在中国等亚洲国家广泛用于治疗心血管疾病、炎症和癌症。丹参酮IIA(Tan IIA)是从丹参中分离得到的一种主要生物活性成分，是一种二萜类化合物，与丹参的许多作用有关。除了抗氧化、抗炎和抗凝活性外，Tan IIA还被证明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。由于肿瘤血管在肿瘤的生长和发展中起着重要的作用，丹参及其成分丹参IIA治疗血管疾病是众所周知的，因此推测丹参IIA可能通过改变肿瘤的血管功能来抑制肿瘤的生长。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说，这些研究表明，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。到目前为止，还没有关于Tan IIA对肿瘤血管影响的研究报道。因此，这项拟议研究的目标之一是确定Tan IIA是否可以改变肿瘤的血管结构和功能，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用治疗癌症，本研究的另一个目的是确定丹参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转运和疗效。本研究的具体目的是：(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对抗癌药物转运和作用的影响。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)在内的多模式成像与静态体外成像(即光、荧光和电子显微镜成像)将互补用于确定Tan IIA对肿瘤血管的影响以及Tan IIA是否可以增强化疗药物阿霉素的转运和治疗效果。本研究的结果将有助于理解中药丹参的抗癌机制，并为丹参作为肿瘤血管靶向性药物的临床翻译提供帮助。 公共卫生相关性：本研究将确定丹参酮IIA是中草药丹参的主要活性成分，是否能够靶向肿瘤血管，增强化疗药物的抗肿瘤效果。本研究结果将有助于更好地了解丹参的抗癌作用机制。

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.