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

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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891029/
https://www.ncbi.nlm.nih.gov/pubmed/26802022
http://dx.doi.org/10.18632/oncotarget.6933
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author 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
author_facet 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
author_sort Peng, Mei
collection PubMed
description 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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spelling pubmed-48910292016-06-20 High efficacy of intravesical treatment of metformin on bladder cancer in preclinical model 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 Oncotarget Research Paper 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. Impact Journals LLC 2016-01-18 /pmc/articles/PMC4891029/ /pubmed/26802022 http://dx.doi.org/10.18632/oncotarget.6933 Text en Copyright: © 2016 Peng et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
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
High efficacy of intravesical treatment of metformin on bladder cancer in preclinical model
title High efficacy of intravesical treatment of metformin on bladder cancer in preclinical model
title_full High efficacy of intravesical treatment of metformin on bladder cancer in preclinical model
title_fullStr High efficacy of intravesical treatment of metformin on bladder cancer in preclinical model
title_full_unstemmed High efficacy of intravesical treatment of metformin on bladder cancer in preclinical model
title_short High efficacy of intravesical treatment of metformin on bladder cancer in preclinical model
title_sort high efficacy of intravesical treatment of metformin on bladder cancer in preclinical model
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891029/
https://www.ncbi.nlm.nih.gov/pubmed/26802022
http://dx.doi.org/10.18632/oncotarget.6933
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