title: Short-term resveratrol exposure causes in vitro and in vivo growth inhibition and apoptosis of bladder cancer cells.
abstract: Conventional adjuvant chemotherapies for bladder transitional cell carcinomas (TCCs) may cause strong systemic toxicity and local irritation. Non-toxic resveratrol inhibits TCC cell growth but its feasibility in clinical management of TCCs remains obscure. This study aimed to evaluate the safety and anti-TCC efficacy of resveratrol, using the experimental models closer to the clinical treatment condition. Human TCC EJ cells were exposed to 100 µM, 150 µM and 200 µM resveratrol respectively for 1 hour and 2 hours to mimic intravesical drug instillation and the cell responses were analyzed by multiple experimental approaches. An orthotopic TCC nude mouse model was established by injecting EJ cells into the sub-urothelial layer and used for short-term intravesical resveratrol instillation. The safety of resveratrol instillation was evaluated and compared with that of MCC. The results revealed that 2 h 150 µM or 200 µM resveratrol treatment leaded to remarkable S phase arrest and apoptosis at 72 h time-point, accompanied with attenuated phosphorylation, nuclear translocation and transcription of STAT3, down-regulation of STAT3 downstream genes (survivin, cyclinD1, c-Myc and VEGF) and nuclear translocations of Sirt1 and p53. The importance of STAT3 signaling in cell growth was confirmed by treating EJ cells with JAK2 inhibitor tyrphostin AG490. The efficacy and safety of resveratrol instillation were proved by the findings from nude mouse orthotopic xenograft models, because this treatment caused growth suppression, distinctive apoptosis and STAT3 inactivation of the transplanted tumors without affecting normal urothelium. Our results thus suggest for the first time the practical values of resveratrol as a safe and effective agent in the post-operative treatment of TCCs.
authors.affiliation: Liaoning Laboratory of Cancer Genetics and Epigenomics and Department of Cell Biology, College of Basic Medical Sciences, Dalian Medical University, Dalian, China.
authors.forename: Mo-Li
authors.initials: ML
authors.lastname: Wu
authors.affiliation: Liaoning Laboratory of Cancer Genetics and Epigenomics and Department of Cell Biology, College of Basic Medical Sciences, Dalian Medical University, Dalian, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Liaoning Laboratory of Cancer Genetics and Epigenomics and Department of Cell Biology, College of Basic Medical Sciences, Dalian Medical University, Dalian, China.
authors.forename: Li-Jun
authors.initials: LJ
authors.lastname: Yu
authors.affiliation: Liaoning Laboratory of Cancer Genetics and Epigenomics and Department of Cell Biology, College of Basic Medical Sciences, Dalian Medical University, Dalian, China.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Chen
authors.affiliation: Liaoning Laboratory of Cancer Genetics and Epigenomics and Department of Cell Biology, College of Basic Medical Sciences, Dalian Medical University, Dalian, China.
authors.forename: Qing-You
authors.initials: QY
authors.lastname: Kong
authors.affiliation: Liaoning Laboratory of Cancer Genetics and Epigenomics and Department of Cell Biology, College of Basic Medical Sciences, Dalian Medical University, Dalian, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Song
authors.affiliation: Liaoning Laboratory of Cancer Genetics and Epigenomics and Department of Cell Biology, College of Basic Medical Sciences, Dalian Medical University, Dalian, China.
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Shu
authors.affiliation: Liaoning Laboratory of Cancer Genetics and Epigenomics and Department of Cell Biology, College of Basic Medical Sciences, Dalian Medical University, Dalian, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D017931:DNA Primers / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D000077185:Resveratrol; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology* / Q000627:therapeutic use; D020032:Tyrphostins; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*
chemical_list: D017931:DNA Primers; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D013267:Stilbenes; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D000077185:Resveratrol