The effect of metformin on cancer-specific survival outcomes in diabetic patients undergoing radical cystectomy for urothelial carcinoma of the bladder

Nayan, Madhur; Bhindi, Bimal; Yu, Julie; Hermanns, Thomas; Mohammed, Aza; Hamilton, Robert J.; Finelli, Antonio; Jewett, Michael A.S.; Zlotta, Alexandre R.; Fleshner, Neil; Kulkarni, Girish S.

doi:10.1016/j.urolonc.2015.05.024

Cited by 33 publications

(27 citation statements)

References 32 publications

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“…Moreover, a single-institution retrospective cohort study (January 1997 - June 2013) to examine the association between metformin use and oncologic outcomes in 421 of diabetic patients undergoing radical cystectomy for bladder cancer and the authors concluded that metformin improves recurrence-free survival and bladder cancer-specific survival in diabetic patients undergoing radical cystectomy [25]. In addition, retrospective study conducted on 1117 patients with NMIBC at four institutions between 1996 and 2007 concluded that Patients with diabetic mellitus and NMIBC who do not take metformin seem to be at an increased risk of disease recurrence and progression [26].…”

Section: Introductionmentioning

confidence: 99%

New insight for metformin against bladder cancer

El‐Arabey

2017

Genes and Environ

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International Agency for Research on Cancer (IARC) estimated that bladder cancer is the ninth most common cancer in the world, with 430,000 new cases and 165,000 deaths in 2012. Bladder cancer represents the fourth most common cancer in men and ninth most common cancer in women. It is the second most prevalent cancer in men 60 years of age or older in United States. Looking further down, continuing advancements in cancer research could potentially offer more choices for clinician and patient with longer survival and better quality of life. Although, bladder cancer represents an ideal tumor model to test and apply cancer prevention strategies; there are limited studies about application of metformin in the management of bladder cancer. Here, I will shed light on the proposed mechanisms of anti-carcinogenic effects of metformin and cohort of these mechanisms with the novel application of metformin as therapy of bladder cancer.

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Section: Introductionmentioning

confidence: 99%

New insight for metformin against bladder cancer

El‐Arabey

2017

Genes and Environ

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“…To date, several clinical trials have been conducted, with many still ongoing and recruiting patients (https:// clinicaltrials.gov/ct2/home) (Chae et al 2016). The results for some of these clinical studies are highly encouraging and demonstrate the potential of metformin in the prevention and treatment of various cancer types such as breast, pancreatic, gastric, colorectal, endometrial, prostate and bladder, either alone or in combination with other drugs (Niraula et al 2012, Spillane et al 2013, Hawkes et al 2014, Nayan et al 2015, Chae et al 2016, Lee et al 2016. Based on a meta-analysis that included 13,008 cancer patients with type 2 diabetes, an improvement in overall, and cancer-specific survival was observed in patients treated with metformin in comparison to other glucose-lowering drugs (Yin et al 2013).…”

Section: Introductionmentioning

confidence: 99%

The role of an anti-diabetic drug metformin in the treatment of endocrine tumors

Thakur

Daley

Kłubo-Gwieździńska

2019

Journal of Molecular Endocrinology

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Incidence of endocrine cancers is rising every year. Over the last decade, evidence has accumulated that demonstrates the anti-cancer effects of an anti-diabetic drug, metformin, in endocrine malignancies. We performed a literature review utilizing the PubMed, Medline and clinicaltrials.gov databases using the keyword ‘metformin’ plus the following terms: ‘thyroid cancer’, ‘thyroid nodules’, ‘parathyroid’, ‘hyperparathyroidism’, ‘adrenal adenoma’, ‘Cushing syndrome’, ‘hyperaldosteronism’, ‘adrenocortical cancer’, ‘neuroendocrine tumor (NET)’, ‘pancreatic NET (pNET)’, ‘carcinoid’, ‘pituitary adenoma’, ‘pituitary neuroendocrine tumor (PitNET)’, ‘prolactinoma’, ‘pheochromocytoma/paraganglioma’. We found 37 studies describing the preclinical and clinical role of metformin in endocrine tumors. The available epidemiological data show an association between exposure of metformin and lower incidence of thyroid cancer and pNETs in diabetic patients. Metformin treatment has been associated with better response to cancer therapy in thyroid cancer and pNETs. Preclinical evidence suggests that the primary direct mechanisms of metformin action include inhibition of mitochondrial oxidative phosphorylation via inhibition of both mitochondrial complex I and mitochondrial glycerophosphate dehydrogenase, leading to metabolic stress. Decreased ATP production leads to an activation of a cellular energy sensor, AMPK, and subsequent downregulation of mTOR signaling pathway, which is associated with decreased cellular proliferation. We also describe several AMPK-independent mechanisms of metformin action, as well as the indirect mechanisms targeting insulin resistance. Overall, repositioning of metformin has emerged as a promising strategy for adjuvant therapy of endocrine tumors. The mechanisms of synergy between metformin and other anti-cancer agents need to be elucidated further to guide well-designed prospective trials on combination therapies in endocrine malignancies.

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“…Although metformin is mainly considered as a antidiabetic agent [ 22 ], it has also showed anticancer effect in many cancer types, including melanoma [ 23 ], colon cancer [ 24 ], ovarian cancer [ 25 ], prostate cancer [ 26 ] and bladder cancer [ 27 ] by enhancing cancer cell apoptosis, inhibiting epithelial to mesenchymal transition (EMT) and targeting cancer stem cells. These effects were evidenced by the fact that metformin can also synergize with certain chemotherapeutic drugs [ 28 – 33 ].…”

Section: Introductionmentioning

confidence: 99%

Metformin represses bladder cancer progression by inhibiting stem cell repopulation via COX2/PGE2/STAT3 axis

et al. 2016

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Cancer stem cells (CSCs) are a sub-population of tumor cells playing essential roles in initiation, differentiation, recurrence, metastasis and development of drug resistance of various cancers, including bladder cancer. Although multiple lines of evidence suggest that metformin is capable of repressing CSC repopulation in different cancers, the effect of metformin on bladder cancer CSCs remains largely unknown. Using the N-methyl-N-nitrosourea (MNU)-induced rat orthotropic bladder cancer model, we demonstrated that metformin is capable of repressing bladder cancer progression from both mild to moderate/severe dysplasia lesions and from carcinoma in situ (CIS) to invasive lesions. Metformin also can arrest bladder cancer cells in G1/S phases, which subsequently leads to apoptosis. And also metformin represses bladder cancer CSC repopulation evidenced by reducing cytokeratin 14 (CK14+) and octamer-binding transcription factor 3/4 (OCT3/4+) cells in both animal and cellular models. More importantly, we found that metformin exerts these anticancer effects by inhibiting COX2, subsequently PGE2 as well as the activation of STAT3. In conclusion, we are the first to systemically demonstrate in both animal and cell models that metformin inhibits bladder cancer progression by inhibiting stem cell repopulation through the COX2/PGE2/STAT3 axis.

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The effect of metformin on cancer-specific survival outcomes in diabetic patients undergoing radical cystectomy for urothelial carcinoma of the bladder

Cited by 33 publications

References 32 publications

New insight for metformin against bladder cancer

New insight for metformin against bladder cancer

The role of an anti-diabetic drug metformin in the treatment of endocrine tumors

Metformin represses bladder cancer progression by inhibiting stem cell repopulation via COX2/PGE2/STAT3 axis

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