Abstract 618: Rhodiola rosea L. extract, SHR-5, and metformin exhibit potent activity against bladder carcinogenesis in the UPII-mutant Ha-ras transgenic model.

Abstract

Abstract The incidence of human urinary bladder cancer increases markedly with age, suggesting a mechanistic connection between aging and bladder carcinogenesis and a potential use of anti-aging agents in bladder cancer chemoprevention. Rhodiola rosea, growing in high altitude or cold regions of the world, has been reported to have anti-aging effects in Drosophila. Metformin, a popular anti-diabetics drug, has also shown anti-aging effect in mice. In addition, both agents have been shown to inhibit the mTOR pathway. Therefore, we examined the effect of SHR-5 and Metformin on bladder carcinogenesis in the UPII-mutant Ha-ras transgenic mouse bladder model. This model mimics human papillary transitional cell carcinoma and exhibits enhanced mTOR activity in the bladder tumors. The homozygous mutant Ha-ras transgenic mice were identified through genotyping using Southern blotting analysis. 0.625% SHR-5 or 0.1% Metformin in drinking water was given to the mice starting at 6 weeks of age and ending at 6 months of age. About 42% of homozygous mutant Ha-ras male transgenic mice which drank normal water died of urinary tract obstruction and hydronephrosis within 6 months of age, while more than 93% and 89% of mice which drank SHR-5 or Metformin containing water survived. The mean bladder weights in male mice drinking SHR-5 or Metformin decreased by 69% and 62%, respectively, compared to control group (Bladder weights for mice drinking normal water versus SHR-5 or Metformin are 0.3382± 0.061versus 0.1278± 0.02 or 0.1053±0.015 gram, P=0.0197 or 0.0082). The mean bladder weights in female mice which drank SHR-5 or Metformin containing water also decreased by about 40% or 39.8 %, respectively, compared to those which drank normal water (Bladder weights for normal water versus SHR-5 or Metformin: 0.07149 ±0.0036 versus 0.04301 ±0.0032 or 0.04295±0.0115 gram, P<0.0001 or =0.0007). Chemstrip tests showed that mice which drank SHR-5 or metformin water developed less hematurine than those which drank normal water. Histological analysis of H&E staining bladder sections from SHR-5 and Metformin treated mice demonstrated more differentiated tumors compared to those from the transgenic mice which drank normal water. Immunohistochemistry staining revealed that SHR-5 and Metformin treatments decreased cell proliferation in the urothelium. Taken together, our results suggest a potential new method for bladder cancer prevention by drinking SHR-5 or Metformin. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 618. doi:1538-7445.AM2012-618