Patients with diabetes mellitus are at increased risk of cancer development Metformin is a well-established, effective agent for the management of type 2 diabetes mellitus Epidemiological studies have identified an association between metformin use and a beneficial effect on cancer prevention and treatment, which has led to increasing interest in the potential use of metformin as an anticancer agent Basic science has provided a better understanding of the mechanism of action of metformin and the potential for metformin to modulate molecular pathways involved in cancer cell signaling and metabolism This article outlines the link between metformin and cancer, the potential for metformin in oncology, and limitations of currently available evidence

Metformin in Cancer Treatment and Prevention

Metformin as an adjuvant treatment for cancer: a systematic review and meta-analysis

// Young Kwang Chae 1,2,3 , Ayush Arya 3 , Mary-Kate Malecek 3 , Daniel Sanghoon Shin 4 , Benedito Carneiro 1,2,3 , Sunandana Chandra 1,2,3 , Jason Kaplan 1,2,3 , Aparna Kalyan 1,2,3 , Jessica K. Altman 1,2,3 , Leonidas Platanias 1,2,3,5 and Francis Giles 1,2,3 1 Northwestern Medicine Developmental Therapeutics Institute, Chicago, IL, USA 2 Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA 3 Northwestern University Feinberg School of Medicine, Chicago, IL, USA 4 David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA 5 Division of Hematology-Oncology, Department of Medicine, Jesse Brown VA Medical Center, Chicago, IL, USA Correspondence to: Young Kwang Chae, email: // Keywords : metformin, clinical trials, cancer Received : September 20, 2015 Accepted : March 06, 2016 Published : March 19, 2016 Abstract In recent years, several studies have presented evidence suggesting a potential role for metformin in anti-cancer therapy. Preclinical studies have demonstrated several anticancer molecular mechanisms of metformin including mTOR inhibition, cytotoxic effects, and immunomodulation. Epidemiologic data have demonstrated decreased cancer incidence and mortality in patients taking metformin. Several clinical trials, focused on evaluation of metformin as an anti-cancer agent are presently underway. Data published from a small number of completed trials has put forth intriguing results. Clinical trials in pre-surgical endometrial cancer patients exhibited a significant decrease in Ki67 with metformin monotherapy. Another interesting observation was made in patients with breast cancer, wherein a trend towards improvement in cancer proliferation markers was noted in patients without insulin resistance. Data on survival outcomes with the use of metformin as an anti-cancer agent is awaited. This manuscript will critically review the role of metformin as a potential cancer treatment.

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Repurposing metformin for cancer treatment: current clinical studies

Multiple epidemiological studies have documented an association between metformin, used for treatment of type 2 diabetes, and reduced cancer incidence and mortality. Cell line models may not accurately reflect the effects of metformin in the clinical setting. Moreover, findings from animal model studies have been inconsistent, whilst those from more recent epidemiological studies have tempered the overall effect size. The purpose of this review is to examine metformin's chemopreventive potential by outlining relevant mechanisms of action, the most recent epidemiologic evidence, and recently completed and ongoing clinical trials. Although repurposing drugs with excellent safety profiles is an appealing strategy for cancer prevention and treatment in the adjuvant setting, there is no substitute for well-executed, large randomised clinical trials to define efficacy and determine the populations that are most likely to benefit from an intervention. Thus, enthusiasm remains for understanding the role of metformin in cancer through ongoing clinical research.

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Repurposing metformin for the prevention of cancer and cancer recurrence

Since the initial observations made at the beginning of the last century, it has been established that solid tumors contain regions of low oxygenation (hypoxia). Tumor cells can survive in these hypoxic conditions and are a major factor in tumor radioresistance. This significance has resulted in hypoxia becoming the most cited biological topic in translational radiation oncology. Identifying hypoxic cells in human tumors has become paramount, and the ability to do this has been improved by the help of new imaging techniques and the use of predictive gene profiles. Substantial data confirm the presence of hypoxia in many types of human tumors, although with considerable heterogeneity among individual tumors. Various approaches have been investigated for eliminating the hypoxic population. These include increasing oxygen availability, directly radiosensitizing or killing the hypoxic cells, indirectly affecting them by targeting the tumor vascular supply, increasing the radiation dose to this resistant population, or by using radiation with a high linear energy transfer, for which hypoxia is believed to be less of an issue. Many of these approaches have undergone controlled clinical trials during the last 50 years, and the results have shown that hypoxic radiation resistance can indeed be overcome. Thus, ample data exists to support a high level of evidence for the benefit of hypoxic modification. However, such hypoxic modification still has no impact on general clinical practice. In this review we summarize the biological rationale, and the current activities and trials, related to identifying and overcoming hypoxia in modern radiotherapy.

The impact of hypoxia and its modification of the outcome of radiotherapy.

Association of metformin use with cancer incidence and mortality: A meta-analysis

Background: The purpose of the meta-analysis is to explore the association between vitamin D receptor polymorphisms (including four gene loci: Taq-I, Bsm-I, Apa-I, and Fok-I) for susceptibility to periodontitis (either chronic [CP] or aggressive [AP]). Up to now, there has been only one systematic review focusing on this topic. We obtained some different findings compared with the previously published literature.Methods: Nineteen case-control studies were identified through a search of multiple electronic databases (from January 1, 1999 to June 30, 2011). The pooled odds ratios (ORs) and 95% confidence intervals (CIs) using codominant, dominant, and recessive genetic models from meta-analysis were the main outcome measure. The Harbord test was used to detect the publication bias for each group.Results: Eighteen identified articles met the eligibility criteria. Through overall analyses, no statistical association was found between polymorphisms of the four gene loci and periodontitis. However, based on sub...

Association between vitamin D receptor polymorphisms and periodontitis: a meta-analysis.

Metabolic Syndrome (MS) is increasingly becoming a major worldwide clinical and public health issue. Thus it is extremely important to study the history of MS and search for the most likely component contributing to start the cascade of confusions of MS. A longitudinal cohort was involved which included the data of 7510 individuals who had at least two routine health check-ups in a six-year follow-up. Based on the data, a Markov model with each chain containing seven states (no component state, four isolated states, 2-component state, and MS state) was built. Annual transition probability was the mean of five probabilities for the transition between the given states between each pair of consecutive years. The transition probabilities from the no component state to MS were higher in men than that in women in four age groups. In the young people (men <60 years and women <50 years), the probabilities to the overweight or obesity state and dyslipidemia state were the first two biggest probabilities in transition from no component to the rest six states. However, in the elderly population, the probabilities to hypertension state and 2-component state increased, even surpassed the above two states. The individuals initiating with 2-component states and the isolated hyperglycemia state were more likely to develop MS than the others. The Markov model was able to give a better description of the evolutionary history of MS, and to predict the future course based on past evidence. The occurrence of the MS process mostly began with overweight or obesity and dyslipidemia in young people. In the elderly population, many individuals initiating with hypertension or 2 components besides the above two states. Individuals with the isolated hyperglycemia had greater chances to develop MS than other isolated MS’ components.

https://link.springer.com/content/pdf/10.1186%2F1471-2458-14-1033.pdf

Description and prediction of the development of metabolic syndrome in Dongying City: a longitudinal analysis using the Markov model

Longitudinal Changes in Liver Aminotransferases Predict Metabolic Syndrome in Chinese Patients with Nonviral Hepatitis

Background: Increasing serum levels of uric acid (SUA) after menopause in women brought up a hypothesis that estrogenic effect may protectively regulate SUA. Estrogenic effect is a major etiology of uterine fibroids and fibrocystic breast disease. The study aimed to explore SUA among patients suffering from these diseases to enhance the hypothesis. Methods : Overall , 1349 female participants were selected into three cases: CaseⅠhaving uterine fibroids (n=568), CaseⅡ having fibrocycstic breast disease (n=608) and CaseⅢ having uterine fibroids combining with fibrocycstic breast disease (n=173); 4206 participants without these diseases were selected as controls. Based on health check-up data from 2011 to 2012, in Dongying Shengli Oilfield Central Hospital, a cross-sectional study was conducted to examine the difference in SUA between the case and control. We adjusted covariates by generalized linear regression mode. Results : From 19 to 44 yr, SUA of CaseⅠ to CaseⅢ were lower than controls by 8.46 umol/L ( P =0.011), 5.88umol/L ( P =0.014) and 9.39 umol/L ( P =0.059), respectively. From 45-54 yr, no significant differences were between three cases and controls. In CaseⅠand its control: from 54-59 yr, differences were not significant; from 60 to 72 yr, SUA in CaseⅠwas lower than the control by 32.02umol/L ( P =0.003). Conclusion : Participants of uterine fibroids and fibrocystic breast disease had a lower SUA except the stage of menopause, which indirectly supported that estrogenic effect, may protectively decrease SUA.

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Shumei Wang

Papers

Association of metformin use with cancer incidence and mortality: A meta-analysis

Association between vitamin D receptor polymorphisms and periodontitis: a meta-analysis.

Description and prediction of the development of metabolic syndrome in Dongying City: a longitudinal analysis using the Markov model

Longitudinal Changes in Liver Aminotransferases Predict Metabolic Syndrome in Chinese Patients with Nonviral Hepatitis

Lower Serum Levels of Uric Acid in Uterine Fibroids and Fibrocystic Breast Disease Patients in Dongying City, China.