High efficacy of intravesical treatment of metformin on bladder cancer in preclinical model

• Published in: Oncotarget 2016-02, Vol.7 (8), p.9102-9117
• Main Authors: Peng, Mei, Su, Qiongli, Zeng, Qing, Li, Le, Liu, Zhihong, Xue, Lei, Cheng, Yan, Huang, Yanjun, Tao, Ting, Lv, Hongwei, Li, Xiaohui, Tao, Xiaojun, Guo, Peng, Chen, Alex F, Yang, Xiaoping
• Format: Article
• Language: English
• Subjects: Administration, Intravesical; AMP-Activated Protein Kinases - metabolism; Animals; Antineoplastic Agents - therapeutic use; Biomarkers, Tumor; Cell Line, Tumor; Cell Proliferation - drug effects; Drug Evaluation, Preclinical; Enzyme Activation - drug effects; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; Humans; Hypoglycemic Agents - therapeutic use; Kaplan-Meier Estimate; Lactic Acid - blood; Metformin - administration & dosage; Metformin - therapeutic use; Mice; Mice, Inbred C57BL; Phosphorylation - drug effects; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Research Paper; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; Urinary Bladder - pathology; Urinary Bladder Neoplasms - drug therapy
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.6933

Anticancer potential of metformin has been extensively studied. However, its anticancer clinical use remains yet to be approved since sufficient concentration on target organs could not be achieved via conventional administration. To overcome this drawback, we aim to examine the efficiency of novel intravesical treatment of metformin on syngeneic orthotopic preclinical model. Three human and one murine bladder cancer cell lines were tested in vitro for inhibitory sensitivity by MTT and cologenic assays. AMPK pathway including AKT, Erk and S6K was examined by western blot and further explored by regulating activated levels using specific inhibitors. In vivo efficacy was determined by Kaplan-Meier survival curves and measurements of body and bladder weights plus tumor biomarkers. Lactic acid and metformin levels of plasma were measured by standard procedures. The results demonstrated that metformin activated AMPK and decreased phosphorylation of Akt and Erk. Furthermore, combinations of metformin with either Akt or Erk inhibitors synergistically diminished cancer proliferation, suggesting the involvement of Akt- and Erk- related pathways. Intravesical metformin 26 and 104 mg/kg, twice per week demonstrated a rapid elimination of the implanted tumor without any evidence of toxicity. In contrast, oral treatment at a dose of 800mg/kg/d exhibited little efficacy whereas severe toxicity existed if the dosage is higher. Collectively, intravesical metformin displays potent inhibition on bladder cancer in vitro and this preclinical study reveals the profound therapeutic application of metformin with durable tolerance via intravesical administration route.