Rhodiola Rosea Extracts, Salidroside and Bladder Cancer Chemoprevention

红景天提取物、红景天苷和膀胱癌的化学预防

• 批准号: 8114959
• 负责人: Xiaolin Zi
• 金额: $ 19.97万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-08 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8114959
• 关键词: Adverse effects; Affect; Age; Aging; Aging-Related Process; Altitude; Animals; Apoptotic; Arctic Regions; Asia; Autophagocytosis; Binding; Biological Factors; Biological Models; Bladder; Body Weight; Cancer Patient; Cancer Relapse; Cancer cell line; Cell Culture System; Cells; Cessation of life; Chemoprevention; Chemopreventive Agent; Clinical Research; Crassulaceae; DNA Damage; Data; Diagnosis; Disease; Drosophila genus; Drug Interactions; Elderly; Epithelial Cells; Europe; Event; Exhibits; Experimental Models; Family; Fatigue; Folk Medicine; Frequencies; Genome; Goals; Grant; Growth; Health Benefit; Human; In Vitro; Incidence; Institutes; Insulin-Like Growth Factor I; Link; Longevity; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mediating; Memory; Molecular; Molecular Target; Moods; Morphology; Nature; Non-Malignant; Nutrient; Oral; Outcome; Oxidative Stress; Papillary Transitional Cell Carcinoma; Pathway interactions; Patients; Performance; Pharmacologic Substance; Phosphorylation; Phosphorylation Site; Phosphotransferases; Plant Roots; Plants; Population; Preventive; Proto-Oncogene Proteins c-akt; Psyche structure; Publishing; Regulatory Pathway; Reporting; Rhodiola; Risk Factors; Roseroot; Russia; STK11 gene; Safety; Signal Transduction; Staging; Stem cells; Stream; Stress; TSC2 gene; Testing; Toxic effect; Transgenic Mice; Translation Initiation; Treatment outcome; Tumor Burden; Tumor Suppressor Proteins; Ureter; Urothelium; Weight; age effect; age related; anti aging; base; bladder cancer prevention; cancer chemoprevention; cancer prevention; carcinogenesis; cell growth; clinically relevant; detection of nutrient; dietary supplements; drinking water; feeding; fighting; high risk; human old age (65+); improved; in vivo; indexing; mTOR protein; mouse model; mutant; novel; prevent; senescence; tumor

DESCRIPTION (provided by applicant): Age is one of major risk factors for human urinary bladder cancer. In addition, age appears to increase the risk of higher-stage bladder cancer and to adversely affect treatment outcomes. Therefore, there is an urgent need to prevent bladder cancer in the elderly. Cancer and age share certain common disruptions in molecular pathways and regulatory mechanisms [e.g. the nutrient-sensing mammalian Target of Rapamycin (mTOR) pathway]. Delay aging and extends life span in animals can reduce the incidence of age-related diseases, including cancers. Given their similarity in molecular targets and excellent safety profiles, certain natural product anti- aging agents could be ideal cancer chemopreventive agents. Thus, our long term goal is to examine the usefulness of these agents for prevention of bladder cancer in the elderly. Nevertheless, due to the complexity of aging, there are very few promising pharmaceutical agents with demonstrated anti-aging effects. Rhodiola rosea L, also known as "golden root" or "Arctic root" is a perennial herbaceous plant of the Crassulaceae family, widely distributed at high altitudes (up to 2280 m) in the arctic and mountainous regions throughout Europe and Asia. Radiola has been used as folk medicines to improve stamina, memory and mood, to fight fatigues and to reduce stress for centuries. Rhodiola rosea extracts (RRE) have been the subject of clinical studies with no reported side effects or drug interactions. Our published data have demonstrated that the RRE increased the mean and maximum life-span of the fruit fly up to 24% and 31%, respectively. Moreover, our preliminary data have shown that the RRE and salidroside, one of its major active compounds, preferably inhibit the growth of bladder cancer cell lines versus non-malignant bladder epithelial cells. In addition, we have observed that the growth inhibitory effect of the RRE requires, at least in part, the existence of TSC2, a major upstream regulator for mTOR, and that the RRE and salidroside activated AMPK-a and caused the dephophorylation of 4E-BP1 and the binding of 4E-BP1 to m7GTP CAP, leading to induction of autophagy. These results suggest a novel link between the mTOR pathway and mechanisms of the RRE and salidroside's actions. Therefore, we hypothesize that the RRE which contains salidroside is a novel chemopreventive dietary supplement agent, which targets the mTOR pathway, a converging pathway for both aging and carcinogenesis, leading to its anti-proliferative efficacy against bladder cancer. Our specific aims are two folds: First, we will determined the chemopreventive efficacy of the RRE and salidroside in UPII- mutant Ha-ras transgenic mice that produce superficial papillary transitional cell carcinoma; Second, we will investigate mechanisms of the RRE and salidroside's action on the mTOR pathway mediated translation initiation and cell growth both in vitro and in vivo. Since the RRE is conveniently ingested via oral and has multiple claims of health benefits and excellent safety profiles for long-term human use, successful completion of the proposed studies would suggest a novel, yet practical agent for bladder cancer chemoprevention. Therefore, the outcome of proposed studies will form a firm basis for a well-developed R01 grant to further evaluate the usefulness of an anti-aging agent, the RRE, via targeting the mTOR pathway for bladder cancer chemoprevention. PUBLIC HEALTH RELEVANCE: Given that anti-aging and cancer prevention share certain similar molecular targets (e.g. the nutrient-sensing mTOR pathway) and safety requirement for long-term use in human, we propose to examine the efficacy of a novel dietary supplement, Rhodiola Rosea Extracts with published anti-aging effects in experimental model systems, for chemoprevention of bladder carcinogenesis in a clinically relevant transgenic mouse model and for inhibition of the mTOR pathway in human urinary bladder cancer cell lines.

描述（由申请人提供）：年龄是人类膀胱癌的主要风险因素之一。此外，年龄似乎会增加更高阶段膀胱癌的风险，并对治疗结果产生不利影响。因此，迫切需要预防老年人膀胱癌。癌症和年龄在分子途径和调节机制中共享某些共同的破坏[例如，营养感应哺乳动物雷帕霉素靶（mTOR）途径]。延缓衰老并延长动物寿命可以减少与年龄相关的疾病（包括癌症）的发病率。鉴于它们在分子靶点上的相似性和优异的安全性，某些天然产物抗衰老剂可能是理想的癌症化学预防剂。因此，我们的长期目标是研究这些药物对预防老年人膀胱癌的有用性。然而，由于衰老的复杂性，很少有有前景的药物具有抗衰老作用。红景天（Rhodiola rosea L），也被称为“金根”或“北极根”，是景天科（Crassulaceae）的多年生草本植物，广泛分布于北极的高海拔地区（高达2280米）以及整个欧洲和亚洲的山区。几个世纪以来，Radiola一直被用作民间药物，以改善耐力，记忆力和情绪，对抗疲劳和减轻压力。红景天提取物（RRE）一直是临床研究的主题，没有报道副作用或药物相互作用。我们发表的数据表明，RRE增加果蝇的平均寿命和最大寿命分别高达24%和31%。此外，我们的初步数据表明，RRE和红景天苷，其主要活性化合物之一，优选抑制膀胱癌细胞系相对于非恶性膀胱上皮细胞的生长。此外，我们已经观察到RRE的生长抑制作用至少部分地需要TSC 2（mTOR的主要上游调节剂）的存在，并且RRE和红景天苷激活AMPK-α并引起4 E-BP 1的脱磷酸化和4 E-BP 1与m7 GTP CAP的结合，导致诱导自噬。这些结果表明mTOR通路与RRE和红景天苷的作用机制之间存在新的联系。因此，我们假设含有红景天苷的RRE是一种新型的化学预防性膳食补充剂，其靶向mTOR途径，这是衰老和致癌的会聚途径，导致其对膀胱癌的抗增殖功效。我们的具体目标有两个方面：第一，我们将确定RRE和红景天苷在产生浅表乳头状移行细胞癌的UPII突变Ha-ras转基因小鼠中的化学预防功效;第二，我们将研究RRE和红景天苷在体外和体内对mTOR通路介导的翻译起始和细胞生长的作用机制。由于RRE通过口服方便地摄入，并且具有多种健康益处和良好的人类长期使用安全性，因此成功完成拟议的研究将提出一种新型但实用的膀胱癌化学预防剂。因此，拟议研究的结果将为完善的R 01拨款奠定坚实的基础，以进一步评估抗衰老剂RRE通过靶向mTOR通路用于膀胱癌化学预防的有效性。 公共卫生相关性：鉴于抗衰老和预防癌症有着某些相似的分子靶点，（例如，营养感应mTOR通路）和人类长期使用的安全性要求，我们建议在实验模型系统中检查具有已公布的抗衰老作用的新型膳食补充剂红景天提取物的功效，用于临床相关转基因小鼠模型中膀胱癌发生的化学预防和用于人膀胱癌细胞系中mTOR途径的抑制。