Antidiabetic drug use and prostate cancer risk in the Finnish Randomized Study of Screening for Prostate Cancer

Haring, Antti; Murtola, Teemu J.; Talala, Kirsi; Taari, Kimmo; Tammela, Teuvo L.J.; Auvinen, Anssi

doi:10.1080/21681805.2016.1271353

Cited by 46 publications

(45 citation statements)

References 31 publications

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“…While exact mechanisms behind this remain unclear, some hypothesized that it is linked to Metformin's inhibitory effects on cancer cell proliferation pathways [27]. Haring et al [28] and Häggström et al [29] independently conducted nationwide cohort studies to evaluate the risk of PCa among users of Metformin.…”

Section: Anti-diabetic Drugs (Metformin)mentioning

confidence: 99%

“…They first confirmed an inverse relationship between T2DM and PCa risk by comparing anti-diabetic drug users (n = 15,578) to non-users (n = 63,037). Specific effects of Metformin were then investigated through comparing the PCa risk between users of Metformin and other oral anti-diabetic drugs [28]. Due to the retrospective nature of the study, confounding covariates that may have influenced the results could not be controlled.…”

Section: Anti-diabetic Drugs (Metformin)mentioning

confidence: 99%

“…This is supported by the fact that baseline PSA was lower in Metformin users in the study. As PCa is commonly diagnosed based on biopsies performed for elevated PSA, lower baseline PSA could lead to fewer diagnostic biopsies performed and PCa detected [28]. Thus, the recorded risk reduction might be caused by detection bias, which lowers results reliability and validity.…”

Section: Anti-diabetic Drugs (Metformin)mentioning

confidence: 99%

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The Relationship between Type 2 Diabetes Mellitus and Risk of Prostate Cancer: Literature Review and Critical Appraisal

Chu¹

2018

J Diabetes Metab

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Background: Type 2 Diabetes Mellitus and Prostate Cancer are two common illnesses. However, there was not extensive research done to determine the relationship between the two diseases. Objective: This article aims to investigate the relationship between Type 2 Diabetes Mellitus and the risk of Prostate Cancer, and some possible underlying mechanisms. Method: Several papers published within 5 years in this area are critically appraised and reviewed, including meta-analyses with large scale cohorts. Results: Type 2 Diabetes Mellitus is linked to a moderately decreased risk of Prostate Cancer, as seen in recent evidences. Possible underlying mechanisms include changes in hormonal profiles, genetics, and use of diabetic drugs (Metformin). Conclusion: While Type 2 Diabetes Mellitus might be protective against Prostate Cancer risk, more evidence as to how confounding variables such as ethnicity, lifestyle, and co-morbidities modify the overall risk is needed, as related information in this area is scarce.

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Section: Anti-diabetic Drugs (Metformin)mentioning

confidence: 99%

Section: Anti-diabetic Drugs (Metformin)mentioning

confidence: 99%

Section: Anti-diabetic Drugs (Metformin)mentioning

confidence: 99%

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The Relationship between Type 2 Diabetes Mellitus and Risk of Prostate Cancer: Literature Review and Critical Appraisal

Chu¹

2018

J Diabetes Metab

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“…17 Importantly, there is evidence to show that the use of the antidiabetic drug metformin has a protective effect against cancer in general, but particularly against endometrial and prostate cancers. 18,19 A recent in vitro study showed that metformin can decrease cell survival by decreasing ROS production, partly through downregulation of NOX4 protein expression. 20 Moreover, NOX4 is involved in the inhibition of insulin signaling by inhibiting the phosphorylation of the insulin receptor.…”

Section: Introductionmentioning

confidence: 99%

NADPH oxidase 4 expression in the normal endometrium and in endometrial cancer

et al. 2019

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The aim of this study was to explore the role of NOX4 in the biology of the normal endometrium and endometrial cancer. NOX4 plays a key role in other adenocarcinomas and has been implicated in the pathogenesis of diabetes and obesity, which are important risk factors for endometrial cancer. NOX4 expression was assessed in 239 endometrial cancer and 25 normal endometrium samples by quantitative real-time polymerase chain reaction, in situ hybridization, and immunohistochemistry. DNA methylation of the NOX4 promoter was determined by means of MethyLight PCR. Data were correlated with clinicopathological parameters and analyzed in the context of diabetes and body mass index. In the normal endometrium, NOX4 microRNA expression was significantly higher in the secretory transformed compared with proliferative endometrium (p = 0.008). In endometrial cancer specimens, NOX4 expression did not differ between diabetic and non-diabetic patients, but was the highest in patients with a body mass index ł 26 (p = 0.037). The lowest NOX4 expression was found in carcinosarcomas (p = 0.007). High NOX4 expression predicted poorer clinical outcome with regard to overall survival, especially in non-diabetic patients and those with a body mass index . 20. Independent prognostic significance of NOX4 transcripts was retained in type I endometrial cancer and was the most meaningful in patients with a body mass index . 20. No prognostic impact was shown for NOX4 promoter methylation in endometrial cancer. For the first time, we demonstrate that NOX4 plays a considerable role in the cycle-dependent changes in the normal endometrium and in the biology of endometrial cancer.

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“…Inhibition of the mammalian target of rapamycin (mTOR) (18)(19)(20)(21) and of cyclin D1 contributes to the anti-cancer effect of MET (18). A recent epidemiological study has demonstrated that overall PCa risk decreases in diabetic patients treated with MET (HR=1.44, 95% CI=1.09-1.91) (22), while a single-arm phase II clinical trial has found that MET can delay the progression of metastatic PCa, as measured by prostate-specific antigen (PSA) doubling time (23). However important these findings may be, they have been obtained after only a short period of treatment with no control arm included in the studies.…”

mentioning

confidence: 99%

The Combination of Metformin and Valproic Acid Has a Greater Anti-tumoral Effect on Prostate Cancer Growth In Vivo than Either Drug Alone

Tran

Kichenadasse

Morel

et al. 2018

In Vivo

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Background/Aim: The hypoglycemic drug metformin (MET) and the anti-epileptic drug valproic acid (VPA) have individually shown anti-tumor effects in prostate cancer in vitro. The present study intended to investigate the efficacy of the combination of MET and VPA in prostate cancer treatment in a pre-clinical xenograft model. Materials and Methods: Prostate cancer cell lines were inoculated under the skin of BALB/c nude mice. The mice were treated with 200 μl/ml MET and/or 0.4% (w/v) VPA diluted in drinking water, or with vehicle control, and were monitored until the tumor volume reached 2,000 mm 3 . Evaluation of toxicity of the drug combination was determined in liver and kidney by histology. Results: In both LNCaP and PC-3 xenografts, MET combined with VPA significantly reduced tumor growth during the first 4 weeks following treatment, and delayed the time-to-tumor volume of 2,000 mm 3 by 90 days, as compared to MET or to VPA alone, and to vehicle control. There was no significant difference in total mouse weight, liver or kidney morphology in response to combination treatment (MET+VPA) compared to MET or VPA alone and vehicle control. Conclusion. The combination treatment of MET with VPA is more effective at slowing prostate tumor growth in vivo compared to either drug alone, in mouse xenografts. These pre-clinical results support previous in vitro data and also demonstrate the low toxicity of the combination of these drugs, suggesting that this may be a potential new therapy to be investigated in clinical trials for prostate cancer.

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Antidiabetic drug use and prostate cancer risk in the Finnish Randomized Study of Screening for Prostate Cancer

Abstract: Among antidiabetic drug users, metformin lowered the overall PCa risk, while the risk of metastatic disease was elevated in sulphonylurea users. As sulphonylureas stimulate insulin secretion, the results suggest that hyperinsulinemia may be a risk factor for PCa.

Cited by 46 publications

References 31 publications

The Relationship between Type 2 Diabetes Mellitus and Risk of Prostate Cancer: Literature Review and Critical Appraisal

The Relationship between Type 2 Diabetes Mellitus and Risk of Prostate Cancer: Literature Review and Critical Appraisal

NADPH oxidase 4 expression in the normal endometrium and in endometrial cancer

The Combination of Metformin and Valproic Acid Has a Greater Anti-tumoral Effect on Prostate Cancer Growth In Vivo than Either Drug Alone

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