Abstract
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.
Highlights
Bladder cancer is one of the most frequent cancers of the urinary tract, accounting for about 74,000 new cases and 16,000 deaths in the United States in 2015[1]
Alternative administration to achieve an effective dose is critical [13]. In this present study, we aim to explore the efficacy of metformin using intravesical administration to treat bladder cancer
We report pre-clinical results of intravesical treatment using a syngeneic orthotopic bladder cancer model and the molecular mechanism of mode of action is elaborated
Summary
Bladder cancer is one of the most frequent cancers of the urinary tract, accounting for about 74,000 new cases and 16,000 deaths in the United States in 2015[1]. The commonest way to prevent recurrence and progression is supplemented with intravesical chemotherapy or immunosuppressive agents [3,4]. These methods are largely restricted with various degrees of side effects such as bone marrow suppression, allergic reactions and etc[5]. There is an unmet demand to discover safe and effective drugs for treating bladder cancer. A widely prescribed drug for treating type II diabetes, is one of the most extensively recognized metabolism modulators. Epidemiological evidence indicates that metformin has a high potential efficacy as an anti-cancer drug [7,8,9,10]. Data collected from various xenograft cancer models suggest that metformin delays the progression and relapse of cancer but no much research in bladder cancer is available [11,12]
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