This exploratory proposal is to evaluate the efficacy of a novel bioactive component tanshinone I (T1) on preventing bladder cancer progression and to generate essential preliminary evidence to understand the mechanisms of T1 actions. Bladder cancer is the fifth most commonly diagnosed malignancy in the United States. With the unknown etiological factors for bladder carcinogenesis and the fact that bladder cancer patients are facing both threat of metastases and uncontrolled local recurrence after treatment, additional efforts to define effective intervention or chemoprevention strategies against bladder cancer progression are urgently needed. Therefore, the searching for efficacious and safe strategies to prevent or delay the progression and metastasis of bladder cancer remains the top priority in bladder cancer research. In an effort to identify the bioactive components, we found that tanshinones from a Chinese herb Danshen, especially tanshinone I (T1), had potent activities in inhibiting the growth of bladder cancer cells in part via induction of apoptosis in vitro associated with downregulation of Aurora A expression. T1 also showed potent activities in inhibiting angiogenesis in both in vitro and in vivo. Furthermore, T1 showed much less toxicity and side effect in vitro and in vivo. Gene function assays showed that knockdown of Aurora A by siRNA significantly reduced the growth and induced apoptosis of cancer cells, and the T1 activities in inducing apoptosis and inhibiting cell growth were largely eliminated by the loss of Aurora A function. These promising preliminary results support the hypotheses that T1 may serve as an efficacious and safe chemopreventive agent against bladder cancer progression by both inducing bladder cancer cell apoptosis and inhibiting angiogenesis, and that Aurora A may be a functional target for T1 action. Since certain levels of T1 and its metabolites are excreted through the urinary tract and are in direct contact with mucosa of the bladder, T1 may have more potent activity in bladder cancer intervention in the in vivo system than that evaluated in vitro by exerting its anti-bladder cancer activities via both blood circulation and urinary exposure, and application of orthotopic bladder tumor model is a prerequisite for relevant evaluation of T1 on bladder cancer progression. To test the hypothesis, specific aim 1 is to determine the effect of T1 on progression of both well-differentiated/low metastatic and poorly differentiated/highly metastatic human bladder tumors in orthotopic bladder tumor models;
Specific aim 2 is determine the cellular and molecular biomarkers that are associated with the efficacy of T1 in vivo;
Specific aim 3 is to proposed to further determine if downregulation of Aurora A is functionally responsible for the T1 activities in inducing apoptosis of bladder cancer cells and inhibiting angiogenesis. This proposal will define a highly efficacious and safe chemopreventive agent against bladder cancer progression, and the results may result in future clinical investigations to develop T1 as a chemopreventive and/or therapeutic agent for bladder cancer. The results derived from this research will also provide supporting evidence for the RO1 application.
The goals of this proposed project are to gain experimental evidence to demonstrate the potent efficacy of a novel agent, tanshinones I (T1) in inhibiting the growth and progression of bladder cancer in orthotopic bladder tumor animal models, and to determine if one of the mechanisms by which T1 induces apoptosis and inhibits angiogenesis is by downregulation of Aurora A. The results derived from the proposed studies will provide essential preclinical evidence and mechanistic insights to support the future clinical investigation using this novel chemopreventive agent for effective prevention of bladder cancer progression, thus the proposed research will have significant impacts on public health.