Tanshinones for prevention of bladder cancer progression

丹参酮预防膀胱癌进展

• 批准号: 8296497
• 负责人: JIN-RONG ZHOU
• 金额: $ 8.7万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-05 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8296497
• 关键词: Adverse effects; Aftercare; Angiogenesis Inhibition; Animal Model; Apoptosis; Bile fluid; Biological Assay; Biological Markers; Bladder; Bladder Neoplasm; Bladder mucosa; Blood Circulation; Body Weight; Cancer Intervention; Cancer Patient; Chemoprevention; Chemopreventive Agent; Chinese Herbs; Clinical Research; Clinical Trials; Development; Diagnosis; Dose; Down-Regulation; Eating; Endothelial Cells; Epithelial Cells; Evaluation; Face; Future; Gene Expression; Gene Proteins; Goals; Grant; Growth; Human; In Vitro; Induction of Apoptosis; Inhibition of Apoptosis; Investigation; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Measures; Modeling; Molecular; Neoplasm Metastasis; Normal Cell; Prevention; Prevention Research; Primary Prevention; Public Health; Recurrence; Research; Salvia miltiorrhiza; Sampling; Small Interfering RNA; System; Testing; Therapeutic Agents; Toxic effect; Translations; Tube; United States; Urinary tract; angiogenesis; antiangiogenesis therapy; anticancer research; bladder cancer prevention; cancer cell; cancer prevention; carcinogenesis; cell growth; clinically relevant; design; effective intervention; gene function; human STK6 protein; in vivo; in vivo Model; insight; loss of function; matrigel; novel; overexpression; pre-clinical; prevent; programs; response; stable cell line; tumor; tumor progression; urinary

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：本探索性提案旨在评估新型生物活性成分丹参酮I （T1）预防膀胱癌进展的功效，并为了解T1作用机制提供必要的初步证据。膀胱癌是美国第五大最常见的恶性肿瘤。由于膀胱癌发生的病因不明，以及膀胱癌患者在治疗后既面临转移的威胁，又面临无法控制的局部复发，因此迫切需要确定有效的膀胱癌进展干预或化学预防策略。因此，寻找有效、安全的策略来预防或延缓膀胱癌的进展和转移仍然是膀胱癌研究的重中之重。为了鉴定其生物活性成分，我们发现丹参酮，特别是丹参酮I (T1)，在体外具有抑制膀胱癌细胞生长的活性，部分原因是通过诱导细胞凋亡并下调极光a的表达。在体外和体内，T1也显示出抑制血管生成的有效活性。此外，T1在体外和体内的毒性和副作用都小得多。基因功能分析显示，siRNA敲低Aurora A可显著降低癌细胞的生长并诱导细胞凋亡，而T1诱导细胞凋亡和抑制细胞生长的活性由于Aurora A功能的丧失而基本丧失。这些有希望的初步结果支持了T1可能通过诱导膀胱癌细胞凋亡和抑制血管生成作为一种有效和安全的化学预防剂来预防膀胱癌进展的假设，并且Aurora A可能是T1作用的功能靶点。由于一定水平的T1及其代谢物通过尿路排出，与膀胱粘膜直接接触，T1在体内系统的干预膀胱癌的活性可能比体外评估的更强，通过血液循环和尿暴露发挥其抗膀胱癌活性，原位膀胱肿瘤模型的应用是评估T1对膀胱癌进展的相关前提。为了验证这一假设，具体目的1是确定T1对原位膀胱肿瘤模型中高分化/低转移和低分化/高转移人类膀胱肿瘤进展的影响；具体目的2是确定与T1体内疗效相关的细胞和分子生物标志物；具体目的3是提出进一步确定下调Aurora A在诱导膀胱癌细胞凋亡和抑制血管生成中的T1活性是否在功能上起作用。本研究将确定一种高效、安全的预防膀胱癌进展的化学药物，该结果可能为未来的临床研究奠定基础，使T1成为膀胱癌的化学预防和/或治疗药物。本研究的结果也将为RO1的应用提供支持证据。