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

基本信息

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
项目类别：
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

项目摘要

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（申请人提供）：年龄是人类膀胱癌的主要危险因素之一。此外，年龄似乎会增加患晚期膀胱癌的风险并对治疗结果产生不利影响。因此，预防老年人膀胱癌刻不容缓。癌症和年龄在分子途径和调节机制方面存在某些共同的破坏[例如，营养感应哺乳动物雷帕霉素靶标 (mTOR) 途径]。延缓动物衰老并延长寿命可以减少与年龄相关的疾病（包括癌症）的发病率。鉴于其分子靶标的相似性和出色的安全性，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，我们的长期目标是检查这些药物在预防老年人膀胱癌方面的有效性。然而，由于衰老的复杂性，很少有有前景的具有抗衰老作用的药物。红景天，又称“金根”或“北极根”，是景天科多年生草本植物，广泛分布于整个欧洲和亚洲的北极和山区高海拔地区（最高可达2280 m）。几个世纪以来，Radiola 一直被用作民间药物来改善耐力、记忆力和情绪，对抗疲劳和减轻压力。红景天提取物 (RRE) 已成为临床研究的主题，尚未报告副作用或药物相互作用。我们发表的数据表明，RRE 使果蝇的平均寿命和最大寿命分别增加了 24% 和 31%。此外，我们的初步数据表明，与非恶性膀胱上皮细胞相比，RRE 和红景天苷（其主要活性化合物之一）可更好地抑制膀胱癌细胞系的生长。此外，我们观察到RRE的生长抑制作用至少部分需要TSC2（mTOR的主要上游调节因子）的存在，并且RRE和红景天苷激活AMPK-a并引起4E-去磷酸化。 BP1 以及 4E-BP1 与 m7GTP CAP 的结合，导致自噬的诱导。这些结果表明 mTOR 通路与 RRE 和红景天苷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是一种新型化学预防膳食补充剂，其靶向mTOR通路（衰老和致癌的聚合通路），从而具有抗膀胱癌增殖的功效。我们的具体目标有两个：首先，我们将确定 RRE 和红景天苷对产生浅表乳头状移行细胞癌的 UPII 突变型 Ha-ras 转基因小鼠的化学预防功效；其次，我们将在体外和体内研究 RRE 和红景天苷对 mTOR 通路介导的翻译起始和细胞生长的作用机制。由于 RRE 可以方便地通过口服摄入，并且具有多种健康益处和可供人类长期使用的良好安全性，因此成功完成拟议研究将为膀胱癌化学预防提供一种新颖而实用的药物。因此，拟议研究的结果将为完善的 R01 拨款奠定坚实的基础，以进一步评估抗衰老药物 RRE 通过靶向 mTOR 通路进行膀胱癌化学预防的有效性。公共健康相关性：鉴于抗衰老和癌症预防具有某些相似的分子靶点（例如营养感应 mTOR 通路）以及人类长期使用的安全性要求，我们建议研究一种新型膳食补充剂红景天的功效Rosea 提取物在实验模型系统中具有已发表的抗衰老作用，可用于临床相关转基因小鼠模型中膀胱癌的化学预防，以及抑制人膀胱癌细胞系中的 mTOR 通路。