Rhodiola Rosea Extracts, Salidroside and Bladder Cancer Chemoprevention

描述（由申请人提供）：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，预防老年人膀胱癌迫在眉睫。癌症和年龄在分子通路和调控机制上有一些共同的破坏[例如，营养感应哺乳动物雷帕霉素靶点（mTOR）通路]。延缓衰老和延长动物寿命可以减少与年龄有关的疾病，包括癌症的发病率。鉴于其分子靶点的相似性和良好的安全性，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效性。然而，由于衰老的复杂性，很少有具有抗衰老作用的有前景的药物。红景天（Rhodiola rosea L），又称“金根”或“北极根”，是天竺葵科多年生草本植物，广泛分布于欧亚各地北极和山区的高海拔地区（海拔可达2280米）。几个世纪以来，Radiola一直被用作民间药物，以提高耐力、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，没有报道的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长寿命分别增加了24%和31%。此外，我们的初步数据表明，RRE及其主要活性化合物之一红景天苷对膀胱癌细胞系的生长有较好的抑制作用，而非恶性膀胱上皮细胞。此外，我们观察到RRE的生长抑制作用至少部分需要TSC2的存在，TSC2是mTOR的主要上游调节因子，RRE和红皮苷激活AMPK-a，引起4E-BP1的去磷酸化，并使4E-BP1与m7GTP CAP结合，从而诱导自噬。这些结果表明mTOR途径与RRE机制和红柳苷的作用之间存在新的联系。因此，我们假设含有红柳苷的RRE是一种新型的化学预防膳食补充剂，其作用于mTOR通路，这是衰老和致癌的汇合途径，从而具有抗膀胱癌的增生性作用。我们的具体目标有两个方面：首先，我们将确定RRE和红柳苷对产生浅表乳头状移行细胞癌的UPII-突变Ha-ras转基因小鼠的化学预防作用；其次，我们将在体外和体内研究RRE和红景天苷对mTOR途径介导的翻译起始和细胞生长的作用机制。由于RRE通过口服摄入方便，并且具有多种健康益处和长期人体使用的良好安全性，因此成功完成拟议的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剂RRE通过靶向mTOR途径用于膀胱癌化学预防的有效性。

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.