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.
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.
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