The Potent Anti-Tumor Effects of Rhodiola Drinking Are Associated with the Inhibition of the mTOR Pathway and Modification of Tumor Metabolism in the UPII-Mutant Ha-Ras Model

Simple Summary Bladder cancer occurs mainly in older people and is expensive to manage. Swedish Herbal Rhodiola-5 (SHR-5), a standardized Rhodiola Rosea extract from the Swedish Herbal Institute (the SHI, Gothenburg, Sweden), has been in clinical studies for managing mild to moderate depression and physical and mental fatigue. Previous studies have shown that SHR-5 extended the life span of the fruit fly through a mechanism that was not associated with dietary restriction. In this study, we examined whether drinking SHR-5 can delay tumor development in a superficial bladder cancer mouse model. Drinking SHR-5 daily markedly improved the survival rate of the bladder tumor-bearing mice, by an absolute 61.7%, and reduced urinary tract obstruction and tumor burden. SHR-5 drinking reshaped the tumor metabolism via the inhibition of the mTOR leading to a decreased tumor cell proliferation. Background: SHR-5 has been used as an adaptogen for enhancing physical and mental performance and for fighting stress in the healthy population. The purpose of this study is to determine the chemopreventive efficacy of SHR-5 for superficial bladder cancer and to investigate the underlying mechanisms of action. Methods: UPII-mutant Ha-ras bladder-cancer-transgenic mice, that developed low-grade and noninvasive papillary transitional urothelial cell carcinoma, were fed with 1.25 and 6.25 mg/mL SHR-5 in drinking water for 6 months. The survival of the mice, obstructive uropathy, tumor burden and morphology, and proliferation were evaluated by pathological, molecular, metabolic, and statistical analyses. Results: Approximately 95% or more of the male UPII-mutant Ha-ras mice that drank SHR-5 daily survived over 6 months of age, while only 33.3% of those mice that drank normal water survived over 6 months of age (p < 0.0001); SHR-5 drinking exposure also reduced tumor-bearing bladder weight and urinary tract obstruction and inhibited mTOR signaling in neoplastic tissues. Global metabolic analysis revealed that SHR-5 resulted in increased phenolic metabolites and decreased CoA, a critical metabolic cofactor for lipid metabolism. Conclusions: Our findings highlight the potential of SHR-5 as an anti-aging agent for bladder cancer prevention through reshaping tumor metabolism via the inhibition of the mTOR signaling. Global metabolomics profiling provides a unique and efficient tool for studying the mechanisms of complex herb extracts' action.

Automated summary

Swedish Herbal Rhodiola-5 (SHR-5) is a standardized Rhodiola Rosea extract that has shown potential in managing depression and fatigue. This study found that daily consumption of SHR-5 significantly improved survival rates and reduced tumor burden in bladder tumor-bearing mice. The mechanism of action is believed to be through the inhibition of mTOR and reshaping of tumor metabolism. These findings suggest that SHR-5 could be a potential anti-aging agent for bladder cancer prevention.