Association of Metformin, Other Antidiabetic Medications, and Statins With Incidence of Colon Cancer in Patients With Type 2 Diabetes

Erkinantti, Sami; Marttila, Mikko; Sund, Reijo; Arffman, Martti; Urpilainen, Elina; Puistola, Ulla; Hautakoski, Ari; Karihtala, Peeter; Läärä, Esa; Jukkola, Arja

doi:10.1016/j.clcc.2020.11.003

Cited by 5 publications

(4 citation statements)

References 39 publications

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“…Metformin was observed to inhibit the cell growth of various tumors such as lung cancer, breast cancer, colon cancer, prostate cancer, endometrial carcinoma, melanoma, leukemia, and pancreatic cancer [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ]. Our experiment showed that metformin affected cell viability and proliferation to different degrees in glioblastoma cell lines U87MG, LNZ-308, and LN-299.…”

Section: Discussionmentioning

confidence: 99%

“…A range of doses exists for biguanides to serve as diabeto-biguanides (for type 2 diabetes mellitus) or onco-biguanides (for cancers) [ 17 ]. Their potential influence on numerous cancers such as leukemia [ 18 ], colon cancer [ 19 ], melanoma [ 20 , 21 , 22 ], breast cancer [ 23 ], prostate cancer [ 24 ], pancreatic cancer [ 25 , 26 ], endometrial carcinoma [ 27 ], and lung cancer [ 28 ] has also been investigated. Metformin has also been associated with better overall and progression-free survival in high-grade glioma patients [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

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Exploring the Mechanism of Adjuvant Treatment of Glioblastoma Using Temozolomide and Metformin

Feng

Chang

Chen

et al. 2022

IJMS

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Glioblastoma is the most frequent and lethal primary central nervous system tumor in adults, accounting for around 15% of intracranial neoplasms and 40–50% of all primary malignant brain tumors, with an annual incidence of 3–6 cases per 100,000 population. Despite maximum treatment, patients only have a median survival time of 15 months. Metformin is a biguanide drug utilized as the first-line medication in treating type 2 diabetes. Recently, researchers have noticed that metformin can contribute to antineoplastic activity. The objective of this study is to investigate the mechanism of metformin as a potential adjuvant treatment drug in glioblastoma. Glioblastoma cell lines U87MG, LNZ308, and LN229 were treated with metformin, and several cellular functions and metabolic states were evaluated. First, the proliferation capability was investigated using the MTS assay and BrdU assay, while cell apoptosis was evaluated using the annexin V assay. Next, a wound-healing assay and mesenchymal biomarkers (N-cadherin, vimentin, and Twist) were used to detect the cell migration ability and epithelial–mesenchymal transition (EMT) status of tumor cells. Gene set enrichment analysis (GSEA) was applied to the transcriptome of the metformin-treated glioblastoma cell line. Then, DCFH-DA and MitoSOX Red dyes were used to quantify reactive oxygen species (ROS) in the cytosol and mitochondria. JC-1 dye and Western blotting analysis were used to evaluate mitochondrial membrane potential and biogenesis. In addition, the combinatory effect of temozolomide (TMZ) with metformin treatment was assessed by combination index analysis. Metformin could decrease cell viability, proliferation, and migration, increase cell apoptosis, and disrupt EMT in all three glioblastoma cell lines. The GSEA study highlighted increased ROS and hypoxia in the metformin-treated glioblastoma cells. Metformin increased ROS production, impaired mitochondrial membrane potential, and reduced mitochondrial biogenesis. The combined treatment of metformin and TMZ had U87 as synergistic, LNZ308 as antagonistic, and LN229 as additive. Metformin alone or combined with TMZ could suppress mitochondrial transcription factor A, Twist, and O6-methylguanine-DNA methyltransferase (MGMT) proteins in TMZ-resistant LN229 cells. In conclusion, our study showed that metformin decreased metabolic activity, proliferation, migration, mitochondrial biogenesis, and mitochondrial membrane potential and increased apoptosis and ROS in some glioblastoma cells. The sensitivity of the TMZ-resistant glioblastoma cell line to metformin might be mediated via the suppression of mitochondrial biogenesis, EMT, and MGMT expression. Our work provides new insights into the choice of adjuvant agents in TMZ-resistant GBM therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Exploring the Mechanism of Adjuvant Treatment of Glioblastoma Using Temozolomide and Metformin

Feng

Chang

Chen

et al. 2022

IJMS

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“…The cancer mortality rate in patients with diabetes is 1.41 times that of patients without diabetes ( 59 ). Studies have shown that metformin reduced the incidence of cancer by 30-50%, especially pancreatic cancer ( 60 ), hepatocellular carcinoma ( 61 ) and colon cancer ( 62 ). Febbraro et al ( 63 ) conducted a retrospective cohort study on 341 patients with ovarian cancer and found that, the 5-year progression-free survival rate of diabetic patients taking metformin was higher than diabetic patients who did not take metformin and non-diabetic patients., but the 5-year overall survival rates were not significantly different.…”

Section: Metformin As An Antitumor Candidate Drugmentioning

confidence: 99%

Metformin: A promising drug for human cancers (Review)

Huang

Zhao

et al. 2022

Oncol Lett

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Small-molecule chemical drugs are of great significance for tumor-targeted and individualized therapies. However, the development of new small-molecule drugs, from basic experimental research and clinical trials to final application in clinical practice, is a long process that has a high cost. It takes at least 5 years for most drugs to be developed in the laboratory to prove their effectiveness and safety. Compared with the development of new drugs, repurposing traditional non-tumor drugs can be a shortcut. Metformin is a good model for a new use of an old drug. In recent years, the antitumor efficacy of metformin has attracted much attention. Epidemiological data and in vivo , and in vitro experiments have shown that metformin can reduce the incidence of cancer in patients with diabetes and has a strong antagonistic effect on metabolism-related tumors. Recent studies have shown that metformin can induce autophagy in esophageal cancer cells, mainly by inhibiting inflammatory signaling pathways. In recent years, studies have shown that the antitumor functions and mechanisms of metformin are multifaceted. The present study aims to review the application of metformin in tumor prevention and treatment.

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“…Supplemental digital content 1, http://links.lww.com/ACD/ A419 showed study characteristics. Eight case-control studies [11][12][13][14][15][16][17][18] (including 22050 CRC patients and 48 4594 controls), 19 cohort studies [9,10,[19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] (including 43 7688 metformin users and 118 3331 no-metformin users) and 1 randomized controlled trial (RCT) (including 71 metformin users and 62 no-metformin users) detected the effect of metformin use on the risk of CRC in DM. Additionally, 2 case-control studies [36,37] (including 400 CRC patients and 345 controls) and 6 cohort studies [38][39][40][41][42][43] (including 3938 metformin users and 3338 no-metformin users) detected the effect of metformin use on all-cause mortality of CRC in DM.…”

Section: Study Characteristicsmentioning

confidence: 99%

Effect of metformin use on the risk and prognosis of colorectal cancer in diabetes mellitus: a meta-analysis

Wang

Shi

2021

Anti-Cancer Drugs

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Whether metformin is a protective factor of colorectal cancer (CRC) among CRC patients is still not entirely clear. Thus, we conducted this systemic review and metaanalysis to provide a comprehensive review of associations between metformin therapy and CRC risk or survival outcomes for clinical decisions. Articles published before July 2021 were searched in databases (PubMed and Web of Science). Odds ratio (OR)/risk ratio (RR) or hazard ratio (HR) and their confidence intervals (CIs) were computed using STATA 12.0 software. Q test and I 2 were conducted to explore heterogeneities between studies. The present meta-analysis showed that metformin use was associated with decreased risk and lower all-cause mortality of CRC in diabetes mellitus (DM) with random-effects models (risk: OR/RR = 0.71, 95% CI, 0.64-0.80, I 2 = 89.3%, P < 0.001; allcause mortality: HR = 0.72, 95% CI, 0.62-0.83, I 2 = 60.1%, P = 0.014). In addition, the study showed that metformin use was associated with a lower CRC-specific mortality in DM in cohort studies with a fixed-effects model (HR = 0.80, 95% CI, 0.70-0.92, I 2 = 34.7%, P = 0.190). Overall, in this meta-analysis, we found that metformin may be a protective factor for CRC risk and prognosis in patients with DM. Further well-designed, large-scale clinical studies are needed to evaluate the accuracy of our findings and more preclinical experiments are needed to reveal the underlying mechanism of metformin.

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Association of Metformin, Other Antidiabetic Medications, and Statins With Incidence of Colon Cancer in Patients With Type 2 Diabetes

Cited by 5 publications

References 39 publications

Exploring the Mechanism of Adjuvant Treatment of Glioblastoma Using Temozolomide and Metformin

Exploring the Mechanism of Adjuvant Treatment of Glioblastoma Using Temozolomide and Metformin

Metformin: A promising drug for human cancers (Review)

Effect of metformin use on the risk and prognosis of colorectal cancer in diabetes mellitus: a meta-analysis

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