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.