The effect of metformin on the survival of colorectal cancer patients with type 2 diabetes mellitus

Tarhini, Zeinab; Manceur, Kamelia; Magné, Julien; Mathonnet, Muriel; Jost, Jérémy; Christou, Niki

doi:10.1038/s41598-022-16677-3

Cited by 20 publications

(17 citation statements)

References 27 publications

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“…Moreover, while lowering systemic glucose levels and improving secondary hyperinsulinemia, metformin prevents the latter effects on tumor growth and progression. However, its antineoplastic effect in CRC is quite controversial [9].…”

Section: Discussionmentioning

confidence: 99%

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Prognostic Impact of Type 2 Diabetes in Metastatic Colorectal Cancer

Baleiras¹,

Domingues²,

Severino³

et al. 2023

Cureus

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BackgroundDiabetes mellitus (DM) is a prognostic factor for some malignancies, but its clinical implications in metastatic colorectal cancer (mCRC) patients are less clear. Therefore, we conducted a retrospective study to evaluate the impact of pre-existing type 2 diabetes mellitus (T2DM) on the survival outcomes of patients with newly diagnosed mCRC. MethodologyWe retrospectively included patients with newly diagnosed mCRC between January 2017 and June 2021 and with pre-existing T2DM. Data on the characteristics of patients, clinicopathological features, and drug exposure were collected from the electronic medical records. The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS) and treatment-related adverse events (TRAEs). ResultsAmong 187 mCRC patients, 54 (28.8%) had T2DM. The median follow-up was 25 months. We observed 150 OS events and 168 PFS events. Diabetes significantly and negatively impacted PFS and OS. The median for PFS (mPFS) was eight and 16 months for T2DM and no T2DM patients, respectively (p < 0.0001; log-rank test). The median overall survival (mOS) was 15 and 29 months for T2DM and no T2DM patients, respectively (p < 0.0001; log-rank test). Patients with diabetes were more often overweight or obese (59.3% vs. 24.8%; p < 0.01) and had a poorer performance status (53.7% vs. 21.1% with Eastern Cooperative Oncology Group Performance Status 1; p < 0.01). Additionally, T2DM patients had more high-risk pathological features, including G3 grading tumors (27.7% vs. 12.0%; p = 0.01), lymph node involvement (p < 0.01), BRAF-mutated (35.1% vs. 6.8%; p < 0.01), and right-sided CRC (63.0% vs. 30.1%; p < 0.01). We found no statistically significant differences in TRAEs. Nevertheless, a significantly higher rate of grade 2-4 peripheral neuropathy (22.2% vs. 5.3%; p < 0.01) was reported in T2DM patients. ConclusionsT2DM is a negative prognostic factor for survival in mCRC. The paper provides empirical evidence in favor of the joint control of both pathologies. Further research is needed to establish the robustness of our results.

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Section: Discussionmentioning

confidence: 99%

“…Furthermore, hyperglycemia enhances resistance to 5-fluorouracil-induced apoptosis. Interestingly, various studies have shown a protective effect of metformin against cancer [9]. Metformin is an antidiabetic drug that decreases insulin resistance.…”

Section: Introductionmentioning

confidence: 99%

Prognostic Impact of Type 2 Diabetes in Metastatic Colorectal Cancer

Baleiras¹,

Domingues²,

Severino³

et al. 2023

Cureus

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“…Recently, metformin, which is recognized to treat T2DM, was shown that to have antitumor effects. In colorectal cancer (CRC), the use of metformin may improve disease-free survival and overall survival in CRC patients with T2DM [ 12 ]. In bladder cancer cells, metformin improves the antitumor effect of Olaparib through the STAT3/C-MYC pathway [ 13 ].…”

Section: Discussionmentioning

confidence: 99%

Metformin Suppresses Hepatocellular Carcinoma through Regulating Alternative Splicing of LGR4

Han

Miao

Jin

et al. 2022

Journal of Oncology

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Background and aims. Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related deaths worldwide. The role of leucine-rich repeats containing G protein-coupled receptor 4 (LGR4) in HCC remains unclear. Metformin can prevent and control the development of a variety of cancers, especially in HCC. Alternative splicing (AS) can produce many cancer-driving genes. We aim to uncover that metformin regulates HCC development through alternative splicing of LGR4. Methods. First, the expression of LGR4 in HCC tumor tissues and cell lines was detected by western blotting and immunofluorescence. The ability of cell proliferation, migration, and invasion was detected with CCK8, wound-healing, and transwell assays when overexpressing LGR4 or treating with metformin. The β-catenin expression was detected by immunofluorescence. In order to investigate novel AS-associated LGR4, we discarded LGR4 isoforms from GSO databases. We used siRNA to knock down the specific isoform to check the cell proliferation, migration, and invasion when treated with metformin. Results. The level of LGR4 expression was higher in HCC cell lines and tumor tissues. The HCC cell proliferation, migration, and invasion were increased when overexpressing LGR4, which could be reduced by metformin treatment. The GEO database (GSE190076) showed that LGR4 had switching properties in HCC cell lines treated with metformin. We used siRNA to knock down the specific isoform, and the result showed that the specific isoform siRNA could promote the inhibition of cell invasion caused by metformin treatment. Conclusions. LGR4 could promote the ability of cell proliferation, migration, and invasion in HCC, which could be reduced by metformin through alternative splicing.

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“…Metformin has been associated with decreased risk of CRC in diabetic patients and prognosis improvement in CRC patients with diabetes (162). For instance, Tarhini et al (2020) showed that the use of metformin in patients with both CRC and T2D is associated with improved overall survival (adjusted hazard ratios [aHR] = 0.45, 95% CI = 0.21 -0.96) and disease-free survival (aHR = 0.31; 95% CI = 0.18 -0.54) (163). Furthermore, metformin can be considered as a senolytic drug: metformin treatment has been associated with increased tumour cell apoptosis and inhibition of SASP secretion Potential combination therapies for colorectal cancer.…”

Section: Future Directionsmentioning

confidence: 99%

Pro-tumorigenic role of type 2 diabetes-induced cellular senescence in colorectal cancer

et al. 2022

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Colorectal cancer (CRC) is the second leading cause of cancer-related mortality worldwide. The disease still remains incurable and highly lethal in the advanced stage, representing a global health concern. Therefore, it is essential to understand the causes and risk factors leading to its development. Because age-related cellular senescence and type 2 diabetes (T2D) have been recognised as risk factors for CRC development, the recent finding that type 2 diabetic patients present an elevated circulating volume of senescent cells raises the question whether type 2 diabetes facilitates the process of CRC tumorigenesis by inducing premature cell senescence. In this review, we will discuss the mechanisms according to which T2D induces cellular senescence and the role of type 2 diabetes-induced cellular senescence in the pathogenesis and progression of colorectal cancer. Lastly, we will explore the current therapeutic approaches and challenges in targeting senescence.

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The effect of metformin on the survival of colorectal cancer patients with type 2 diabetes mellitus

Cited by 20 publications

References 27 publications

Prognostic Impact of Type 2 Diabetes in Metastatic Colorectal Cancer

Prognostic Impact of Type 2 Diabetes in Metastatic Colorectal Cancer

Metformin Suppresses Hepatocellular Carcinoma through Regulating Alternative Splicing of LGR4

Pro-tumorigenic role of type 2 diabetes-induced cellular senescence in colorectal cancer

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