stevioside and Urinary-Bladder-Neoplasms

Bladder cancer (BC) is a global health issue that lacks effective treatment strategies. Growing evidence suggests that various natural products possess anti-tumour effects. This study aims to identify a novel agent that can be used in the treatment of BC.. High-throughput screening was conducted to search for potential anti-BC natural agents. Cell viabilities were measured by the CCK-8 assay. Cell death, cellular reactive oxygen species (ROS), and mitochondrial outer membrane potential (MOMP) were measured by flow cytometry. RNA sequencing was conducted to identify the affected signalling pathways. Western blots were used to measure the change of proteins. Xenografts models were used to assess the anti-tumour effects in vivo.. Through high-throughput screening, we identified stevioside, a diterpenoid glycoside isolated from Stevia rebaudiana, which selectively inhibited the viability of BC cells and induced their intrinsic apoptosis sparing normal cells. Stevioside also induced mitochondrial stress in BC cells, and activated Bax by downregulating Mcl-1 and upregulating Noxa. RNA sequencing revealed that stevioside treatment caused activation of GSK-3β and endoplasmic reticulum (ER) stress signalling pathways. Activation of GSK-3β induced upregulation of FBXW7, which effectuated the downregulation of Mcl-1. In addition, activation of GSK-3β triggered ER stress, leading to the upregulation of Noxa. Further investigations revealed that the accumulation of ROS was responsible for the activation of the GSK-3β signalling pathway in BC cells. Moreover, we also found that stevioside inhibited the growth of BC cells in vivo.. Collectively, our data suggest that stevioside can be a potential agent for the treatment of BC.

Topics: Apoptosis; Diterpenes, Kaurane; Early Detection of Cancer; Glucosides; Glycogen Synthase Kinase 3 beta; High-Throughput Screening Assays; Humans; Myeloid Cell Leukemia Sequence 1 Protein; Reactive Oxygen Species; Urinary Bladder Neoplasms

The effects of three sweeteners, sodium saccharin, aspartame and stevioside, on urinary bladder carcinogenesis in rats initiated by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) were evaluated. Male F344 rats were given 0.01% BBN in their drinking water for 4 weeks and then the test sweeteners in their diet for 32 weeks. All surviving rats were sacrificed after 36 weeks, and examined histologically. Treatment with sodium saccharin significantly increased the incidence and extent of preneoplastic lesions, papillary or nodular (PN) hyperplasia, in rats treated with BBN for 4 weeks. Administration of 5% aspartame or 5% stevioside in the diet did not, however, affect the incidence or extent of PN hyperplasia in BBN-treated rats. No preneoplastic or neoplastic lesions of the urinary bladder were observed in rats treated with the test sweeteners only. The results with sodium saccharin were consistent with those in our previous experiments. The data also suggest that aspartame and stevioside do not promote bladder carcinogenesis.

Topics: Animals; Aspartame; Butylhydroxybutylnitrosamine; Diterpenes; Diterpenes, Kaurane; Glucosides; Hyperplasia; Male; Rats; Rats, Inbred F344; Saccharin; Sweetening Agents; Terpenes; Urinary Bladder; Urinary Bladder Neoplasms