High efficacy of intravesical treatment of metformin on bladder cancer in preclinical model
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Mei Peng1, Qiongli Su1, Qing Zeng2, Le Li3, Zhihong Liu4, Lei Xue4, Yan Cheng5, Yanjun Huang1, Ting Tao1, Hongwei Lv3, Xiaohui Li5, Xiaojun Tao1, Peng Guo6, Alex F. Chen3,5, Xiaoping Yang1
1Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, P.R. China 410013
2Department of Urology Surgery, Third Affiliated Hospital, Central South University, Changsha, Hunan, P.R. China 410023
3Third Affiliated Hospital and the Institute of Vascular Disease and Translational Medicine, Central South University, Changsha, Hunan, P.R. China 410023
4Department of Pathology, Hunan Provincial Cancer Hospital, Changsha, Hunan, P.R. China 410023
5School of Pharmacy, Central South University, Changsha, Hunan, P.R. China 410023
6Institute of Urology, Xi’an Jiaotong University, Xi’an, Shaanxi, P.R. China 710061
Xiaoping Yang, e-mail: Xiaoping.Yang@hunnu.edu.cn
Keywords: metformin, bladder cancer, localized administration, AMPK, preclinical model
Received: August 19, 2015 Accepted: January 02, 2016 Published: January 18, 2016
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.
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