Effects of sulfonylureas on tumor growth: a review of the literature.
Pasello Giulia,Urso Loredana,Conte Pierfranco,Favaretto Adolfo
The oncologist
Type 2 diabetes mellitus patients are at higher cancer risk, probably because of hyperinsulinemia and insulin growth factor 1 pathway activation. The effects of antidiabetic drugs on cancer risk have been described and discussed in several studies suggesting opposite effects of the biguanide metformin and sulfonylureas on cancer incidence and mortality. The anticancer mechanisms of metformin have been clarified, and some clinical studies, particularly in breast cancer patients, have been published or are currently ongoing; however, data about the effects of sulfonylureas on cancer growth are less consistent. The aims of this work are to review preclinical evidence of second-generation sulfonylureas effects on tumor growth, to clarify the potential mechanisms of action, and to identify possible metabolic targets for patient selection. Most evidence is on the adenosine triphosphate-sensitive potassium channels inhibitor glibenclamide, which interacts with reactive oxygen species production thus inducing cancer cell death. Among diarylsulfonylureas, next-generation DW2282 derivatives are particularly promising because of the proapoptotic activity in multidrug-resistant cells.
10.1634/theoncologist.2013-0177
Repurposing metabolic regulators: antidiabetic drugs as anticancer agents.
Molecular biomedicine
Drug repurposing in cancer taps into the capabilities of existing drugs, initially designed for other ailments, as potential cancer treatments. It offers several advantages over traditional drug discovery, including reduced costs, reduced development timelines, and a lower risk of adverse effects. However, not all drug classes align seamlessly with a patient's condition or long-term usage. Hence, repurposing of chronically used drugs presents a more attractive option. On the other hand, metabolic reprogramming being an important hallmark of cancer paves the metabolic regulators as possible cancer therapeutics. This review emphasizes the importance and offers current insights into the repurposing of antidiabetic drugs, including metformin, sulfonylureas, sodium-glucose cotransporter 2 (SGLT2) inhibitors, dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), thiazolidinediones (TZD), and α-glucosidase inhibitors, against various types of cancers. Antidiabetic drugs, regulating metabolic pathways have gained considerable attention in cancer research. The literature reveals a complex relationship between antidiabetic drugs and cancer risk. Among the antidiabetic drugs, metformin may possess anti-cancer properties, potentially reducing cancer cell proliferation, inducing apoptosis, and enhancing cancer cell sensitivity to chemotherapy. However, other antidiabetic drugs have revealed heterogeneous responses. Sulfonylureas and TZDs have not demonstrated consistent anti-cancer activity, while SGLT2 inhibitors and DPP-4 inhibitors have shown some potential benefits. GLP-1RAs have raised concerns due to possible associations with an increased risk of certain cancers. This review highlights that further research is warranted to elucidate the mechanisms underlying the potential anti-cancer effects of these drugs and to establish their efficacy and safety in clinical settings.
10.1186/s43556-024-00204-z
Cancer risk associated with use of metformin and sulfonylurea in type 2 diabetes: a meta-analysis.
Soranna Davide,Scotti Lorenza,Zambon Antonella,Bosetti Cristina,Grassi Guido,Catapano Alberico,La Vecchia Carlo,Mancia Giuseppe,Corrao Giovanni
The oncologist
OBJECTIVE:Oral antidiabetic drugs (including metformin and sulfonylurea) may play a role in the relationship between type 2 diabetes and cancer. To quantify the association between metformin and sulfonylurea and the risk of cancer, we performed a meta-analysis of available studies on the issue. MATERIALS AND METHODS:We performed a MEDLINE search for observational studies that investigated the risk of all cancers and specific cancer sites in relation to use of metformin and/or sulfonylurea among patients with type 2 diabetes mellitus. Fixed- and random-effect models were fitted to estimate the summary relative risk (RR). Between-study heterogeneity was tested using χ(2) statistics and measured with the I(2) statistic. Publication bias was evaluated using funnel plot and Egger's regression asymmetry test. RESULTS:Seventeen studies satisfying inclusion criteria and including 37,632 cancers were evaluated after reviewing 401 citations. Use of metformin was associated with significantly decreased RR of all cancers (summary RR 0.61, 95% confidence interval [CI] 0.54-0.70), colorectal cancer (0.64, 95% CI 0.54-0.76), and pancreatic cancer (0.38, 95% CI 0.14-0.91). With the exception of colorectal cancer, significant between-study heterogeneity was observed. Evidence of publication bias for metformin-cancer association was also observed. There was no evidence that metformin affects the risk of breast and prostate cancers, nor that sulfonylurea affects the risk of cancer at any site. CONCLUSIONS:Metformin, but not sulfonylurea, appears to reduce subsequent cancer risk. This has relevant implications in light of the exploding global epidemic of diabetes.
10.1634/theoncologist.2011-0462
Sulfonylurea and Cancer Risk Among Patients With Type 2 Diabetes: A Population-Based Cohort Study.
Frontiers in endocrinology
Background:Current evidence of the association between the use of sulfonylurea and cancer risk is highly conflicting and little evidence of this association is from the mainland Chinese population. This study aimed to evaluate the potential effects of sulfonylurea use on cancer risk among patients with type 2 diabetes mellitus (T2DM). Methods:A retrospective cohort study of T2DM patients who were new users of sulfonylurea or metformin was conducted using the Yinzhou Regional Health Care Database. A marginal structural Cox model was used to estimate the hazard ratio (HR) of cancer associated with the use of sulfonylurea compared with metformin, with time-varying confounders controlled by inverse probability weighting. Secondary analyses using different glucose-lowering drugs (GLDs) as comparator and sensitivity analyses for potential bias due to latency period, model misspecification, missing data, analyses strategy (intention-to-treat and per-protocol), and diagnosis validation were performed to examine the robustness of the results. Results:After fully controlling for time-varying confounding, baseline confounding, and competing risk, the use of sulfonylurea was not associated with the risk of any cancer (HR 1.09; 95% CI, 0.93-1.27), compared with the use of metformin. In the secondary analyses, compared with α - glucosidase inhibitors, thiazolidinediones, glinides, other GLDs except sulfonylure and insulin, and T2DM patients not treated with sulfonylureas, the HRs of the association between sulfonylurea use and cancer risk were 0.92 (95% CI; 0.78-1.08), 0.89 (95% CI; 0.66-1.19), 0.85 (95% CI; 0.71-1.02), 1.04 (95% CI; 0.89-1.22), and 1.07 (95% CI; 0.99-1.16), respectively. The results of analyses for various subgroups, risk of site-specific cancers, cumulative duration, dose-response relationship, and sensitivity analyses of different latency periods and missing data were generally consistent with the findings of the primary analyses. Conclusion:No association between sulfonylurea use and cancer risk was found in this study after properly controlling biases due to time-varying confounders and other sources. Further studies on the association between sulfonylurea use and the risk of cancer by using data from a Chinese population with higher representativeness are needed.
10.3389/fendo.2022.874344
Glibenclamide Targets Sulfonylurea Receptor 1 to Inhibit p70S6K Activity and Upregulate KLF4 Expression to Suppress Non-Small Cell Lung Carcinoma.
Xu Kexin,Sun Geng,Li Min,Chen Hongling,Zhang Zuhao,Qian Xixi,Li Ping,Xu Lin,Huang Wenbin,Wang Xuerong
Molecular cancer therapeutics
Sulfonylurea receptor 1 (SUR1) is the regulatory subunit of ATP-sensitive potassium channels (K channels) and the receptor of antidiabetic drugs, such as glibenclamide, which induce insulin secretion in pancreatic β cells. However, the expression and role of SUR1 in cancer are unknown. In this study, we found that SUR1 expression was elevated in human non-small cell lung carcinoma (NSCLC) tissues and cell lines. SUR1 silencing suppressed the growth of NSCLC cells, while SUR1 overexpression promoted cell growth. Targeting SUR1 with glibenclamide suppressed cell growth, cell-cycle progression, epithelial-mesenchymal transition (EMT), and cell migration. Moreover, SUR1 directly interacted with p70S6K and upregulated p70S6K phosphorylation and activity. In addition, glibenclamide inhibited p70S6K, and overexpression of p70S6K partially reversed the growth-inhibiting effect of glibenclamide. Furthermore, glibenclamide upregulated the expression of the tumor suppressor Krüppel-like factor 4 (KLF4), and silencing KLF4 partially reversed the inhibitory effect of glibenclamide on cell growth, EMT, and migration. We found that SUR1 targeted p70S6K to downregulate KLF4 expression by enhancing DNA-methyltransferase 1-mediated methylation of the KLF4 promoter. Finally, in xenograft mouse models, SUR1 expression silencing or glibenclamide treatment inhibited the growth of A549 tumors, downregulated p70S6K activity, and upregulated KLF4 expression. These findings suggested that SUR1 expression was elevated in some NSCLC tissues and functioned as a tumor enhancer. Targeting SUR1 with glibenclamide inhibited NSCLC through downregulation of p70S6K activity and subsequent upregulation of the expression of the tumor suppressor gene SUR1 can be developed as a new target for cancer therapy and glibenclamide has potential anticancer effects.
10.1158/1535-7163.MCT-18-1181
Anti-diabetic medications and the risk for colorectal cancer: A population-based nested case-control study.
Shin Cheol Min,Kim Nayoung,Han Kyungdo,Kim Bongseong,Jung Jin Hyung,Oh Tae Jung,Lee Dong Ho
Cancer epidemiology
BACKGROUND:To evaluate whether anti-diabetic medications are related to colorectal cancer (CRC) risk in type 2 diabetes patients. METHODS:The study was performed from a population-based prospective cohort provided by the National Health Insurance Corporation (2007-2014). Among the 2,084,602 patients newly diagnosed as type 2 diabetes in this period, the cases had incident CRC identified at least 3 years after the diagnosis, and the controls were matched to each case by age, sex, body mass index (BMI), fasting plasma glucose level, and year of the diagnosis. Conditional logistic regression was used to calculate the adjusted odds ratio (aOR) and its 95 % confidence intervals (CIs) for CRC by anti-diabetic medications. RESULTS:A total of 4,228 cases were identified and 4,228 controls were matched to the cases. Sulfonylurea use increased the risk for CRC [aOR (95 % CI), 1.14 (1.05-1.25)], showing an increasing trend with increasing cumulative doses (p for trend = 0.0008). In subgroup analysis, sulfonylurea use increased the CRC risk in DM patients ≥ 65 years, but not in the patients < 65 years. Among sulfonylurea drugs, gliclazide decreased the CRC risk [0.85 (0.72-1.00), p < 0.05], whereas glimepiride increased the risk significantly [1.14 (1.06-1.22)]. In contrast, metformin, meglitide, thiazolidinedione, dipeptidyl peptidase-4 inhibitors, and α-glucosidase inhibitor use did not modify the CRC risk. CONCLUSIONS:Our results suggest that sulfonylureas except for gliclazide increase the CRC risk in type 2 diabetic patients. Long-term follow-up studies are necessary to clarify the association of newer anti-diabetic medications with the CRC incidence.
10.1016/j.canep.2019.101658