title: High Sensitivity of an Ha-RAS Transgenic Model of Superficial Bladder Cancer to Metformin Is Associated with ∼240-Fold Higher Drug Concentration in Urine than Serum.
abstract: While pharmacoepidemiologic and laboratory studies have supported the hypothesis that the antidiabetic drug metformin may be useful in treating or preventing cancer, there is limited evidence to suggest which specific cancer sites may be particularly sensitive. Sensitivity likely is determined both by features of tumor pathophysiology and by pharmacokinetic factors. We used UPII-mutant Ha-ras transgenic mice that develop hyperplasia and low-grade, papillary urothelial cell carcinoma to determine whether metformin has activity in a model of superficial bladder cancer. Metformin significantly improved survival, reduced urinary tract obstruction, reduced bladder weight (a surrogate for tumor volume), and led to clear activation of AMP α kinase and inhibition of mTOR signaling in neoplastic tissue. We investigated the basis of the unusual sensitivity of this model to metformin, and observed that following oral dosing, urothelium is exposed to drug concentrations via the urine that are approximately 240-fold higher than those in the circulation. In addition, we observed that bladder cancer cell lines (RT4, UMUC-3, and J82) with homozygous deletion of either TSC1 or PTEN are more sensitive to metformin than those (TEU2, TCCSUP, and HT1376) with wild-type TSC1 and PTEN genes. Our findings provide a strong rationale for clinical trials of oral metformin in treatment of superficial bladder cancer.
authors.affiliation: Department of Urology, University of California, Irvine, Orange, California.
authors.forename: Zhongbo
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Urology, University of California, Irvine, Orange, California.
authors.forename: Noriko N
authors.initials: NN
authors.lastname: Yokoyama
authors.affiliation: Department of Urology, University of California, Irvine, Orange, California.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Blair
authors.affiliation: Department of Urology, University of California, Irvine, Orange, California.
authors.forename: Xuesen
authors.initials: X
authors.lastname: Li
authors.affiliation: Metabolomics Core Facility, Goodman Cancer Research Center, McGill University, Montreal, Quebec, Canada.
authors.forename: Daina
authors.initials: D
authors.lastname: Avizonis
authors.affiliation: Departments of Urology and Pathology, New York University School of Medicine and Veterans Affairs New York Harbor Healthcare System, Manhattan Campus, New York, New York.
authors.forename: Xue-Ru
authors.initials: XR
authors.lastname: Wu
authors.affiliation: Department of Urology, University of California, Irvine, Orange, California.
authors.forename: Edward
authors.initials: E
authors.lastname: Uchio
authors.affiliation: Department of Urology, University of California, Irvine, Orange, California.
authors.forename: Ramy
authors.initials: R
authors.lastname: Youssef
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Irvine, Orange, California.
authors.forename: Michael
authors.initials: M
authors.lastname: McClelland
authors.affiliation: Department of Oncology and Segal Cancer Center, McGill University, Montreal, Quebec, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Pollak
authors.affiliation: Department of Urology, University of California, Irvine, Orange, California. Department of Pharmacology, University of California, Irvine, Orange, California. Chao Family Comprehensive Cancer Center, University of California, Irvine, Orange, California. xzi@uci.edu.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Zi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D015415:Biomarkers; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D011905:Genes, ras; D006720:Homozygote; D006801:Humans; D008297:Male; D008687:Metformin / Q000493:pharmacokinetics*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D060787:Neoplasm Grading; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases; D047368:Tumor Burden / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D008687:Metformin; D058570:TOR Serine-Threonine Kinases