The SGLT2 inhibitor canagliflozin suppresses growth and enhances prostate cancer response to radiotherapy

Ali, Amr; Mekhaeil, Bassem; Biziotis, Olga-Demetra; Tsakiridis, Evangelia E.; Ahmadi, Elham; Wu, Jianhan; Wang, Simon; Singh, Kanwaldeep; Menjolian, Gabe; Farrell, Thomas; Mesci, Aruz; Liu, Stanley; Berg, Tobias; Bramson, Jonathan L.; Steinberg, Gregory R.; Tsakiridis, Theodoros

doi:10.1038/s42003-023-05289-w

Cited by 6 publications

(2 citation statements)

References 82 publications

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“…Likewise, the results of this study provided the first evidence that iSGLT2 treatment triggered S-phase cell cycle arrest and caspase-3-dependent apoptotic cell death in HCT 116 and HT-29 cells. In line with recent reports, SGLT2 inhibition suppressed glucose uptake, lactate release, ATP production and increased AMPK activation, opposing signaling pathways which contribute to metabolic reprogramming and tumor progression [ 34 , 35 , 63 ]. AMPK is generally phosphorylated to decrease energy consumption and restore energetic metabolism when ATP synthesis is impaired or its consumption is accelerated [ 64 ].…”

Section: Discussionsupporting

confidence: 85%

SGLT2 inhibitor promotes mitochondrial dysfunction and ER-phagy in colorectal cancer cells

Anastasio,

Donisi,

Del Vecchio

et al. 2024

Cell Mol Biol Lett

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Background Sodium-glucose transporter 2 (SGLT2) inhibitors (iSGLT2) are approved medications for type 2 diabetes. Recent studies indicate that iSGLT2 inhibit the growth of some cancer cells. However, the mechanism(s) remains to be fully elucidated. Methods The SGLT2 levels were determined in normal colon CCD 841 CoN and, HCT 116, HT-29, SW480 and LoVo colorectal cancer (CRC) cell lines by quantitative real-time PCR and western blot. The effect of iSGLT2 canagliflozin on cell proliferation was examined using CCK-8, as its role on CRC cells metabolism and tumorigenesis has been evaluated by XF HS Seahorse Bioanalyzer and flow cytometric analyses. Transient gene silencing experiments and analysis of protein–protein interaction network were conducted to evaluate the SGLT2 molecular targets in CRC cells. Results Data showed that the treatment with iSGLT2 (50 µM) for 72 h induced cell cycle arrest (p < 0.001), impaired glucose and energetic metabolism (p < 0.001), promoted apoptotic cell death and ER stress flowing into autophagy (p < 0.001) in HCT 116 and HT-29 cells. These cellular events were accompanied by sirtuin 3 (SIRT3) upregulation (p < 0.01), as also supported by SIRT3 transient silencing experiments resulting in the attenuation of the effects of iSGLT2 on the cellular metabolic/energetic alterations and the induction of programmed cell death. The identification and validation of dipeptidyl peptidase 4 (DPP4) as potential common target of SGLT2 and SIRT3 were also assessed. Conclusions These results deepened knowledge on the iSGLT2 contribution in limiting CRC tumorigenesis unveiling the SGLT2/SIRT3 axis in the cytotoxic mechanisms. Graphical Abstract

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Section: Discussionsupporting

confidence: 85%

SGLT2 inhibitor promotes mitochondrial dysfunction and ER-phagy in colorectal cancer cells

Anastasio,

Donisi,

Del Vecchio

et al. 2024

Cell Mol Biol Lett

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“…DM is also associated with cancer development through a complex mechanism. Treatment with SGLT-2 inhibitors can diminish the risk of cancer incidence in DM patients [138] because gliflozins have anticancer activity through various mechanisms, as previously shown [139][140][141][142][143][144][145]. Moreover, SGLT-2 inhibitors can protect DM patients against the cardiotoxic action of anticancer drugs [31].…”

Section: Sglt-2 Inhibitors In the Therapy Of Dm Complications And Com...mentioning

confidence: 96%

Risks and Benefits of SGLT-2 Inhibitors for Type 1 Diabetes Patients Using Automated Insulin Delivery Systems—A Literature Review

Elian,

Popovici,

Karampelas

et al. 2024

IJMS

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The primary treatment for autoimmune Diabetes Mellitus (Type 1 Diabetes Mellitus-T1DM) is insulin therapy. Unfortunately, a multitude of clinical cases has demonstrated that the use of insulin as a sole therapeutic intervention fails to address all issues comprehensively. Therefore, non-insulin adjunct treatment has been investigated and shown successful results in clinical trials. Various hypoglycemia-inducing drugs such as Metformin, glucagon-like peptide 1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, amylin analogs, and Sodium-Glucose Cotransporters 2 (SGLT-2) inhibitors, developed good outcomes in patients with T1DM. Currently, SGLT-2 inhibitors have remarkably improved the treatment of patients with diabetes by preventing cardiovascular events, heart failure hospitalization, and progression of renal disease. However, their pharmacological potential has not been explored enough. Thus, the substantial interest in SGLT-2 inhibitors (SGLT-2is) underlines the present review. It begins with an overview of carrier-mediated cellular glucose uptake, evidencing the insulin-independent transport system contribution to glucose homeostasis and the essential roles of Sodium-Glucose Cotransporters 1 and 2. Then, the pharmacological properties of SGLT-2is are detailed, leading to potential applications in treating T1DM patients with automated insulin delivery (AID) systems. Results from several studies demonstrated improvements in glycemic control, an increase in Time in Range (TIR), a decrease in glycemic variability, reduced daily insulin requirements without increasing hyperglycemic events, and benefits in weight management. However, these advantages are counterbalanced by increased risks, particularly concerning Diabetic Ketoacidosis (DKA). Several clinical trials reported a higher incidence of DKA when patients with T1DM received SGLT-2 inhibitors such as Sotagliflozin and Empagliflozin. On the other hand, patients with T1DM and a body mass index (BMI) of ≥27 kg/m2 treated with Dapagliflozin showed similar reduction in hyperglycemia and body weight and insignificantly increased DKA incidence compared to the overall trial population. Additional multicenter and randomized studies are required to establish safer and more effective long-term strategies based on patient selection, education, and continuous ketone body monitoring for optimal integration of SGLT-2 inhibitors into T1DM therapeutic protocol.

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SGLT2 inhibition and three urological cancers: Up‐to‐date results

Lin,

Ning,

Xiang

et al. 2024

Diabetes Metabolism Res

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ObjectiveTo identify the causal role of sodium‐glucose cotransporter 2 (SGLT2) inhibition on three urological cancers.MethodsSix single nucleotide polymorphisms associated with the expression level of SLC5A2, a proxy for SGLT2 inhibition, from a recent publication were extracted. Three common urological cancers, including bladder cancer, prostate cancer and kidney cancer, were analysed. The main cohort of bladder cancer was derived from UK Biobank (1279 cases and 372,016 controls). The prostate cancer cohort was from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium (79,148 cases and 61,106 controls). The kidney cancer phenotype was from the UK Biobank cohort of 463,010 individuals (1114 cases and 461,896 controls). Primary and sensitivity analysis were performed to validate the results. In vitro analysis was also incorporated to validate the Mendelian randomisation results.ResultsIn primary analysis, SGLT2 inhibition was associated with reduced risk of bladder cancer (OR: 0.98, 95% CI: 0.97–0.99) per unit lowering of HbA1c level. A protective association was also observed for prostate cancer with odds ratio = 0.31 (95% CI = 0.21–0.47). However, we did not discover a causal relationship between SGLT2 inhibition and kidney cancer (OR: 1.00, 95% CI: 0.99–1.00). Sensitivity analysis and in vitro validation did not support the causal role of SGLT2 inhibition in increasing cancer risk.ConclusionsWe did not find any evidence that SGLT2 inhibition could increase the risk of the three cancers. Even in some analysis, SGLT2 inhibition tended to show protective effects on the three urological cancers.

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The SGLT2 inhibitor canagliflozin suppresses growth and enhances prostate cancer response to radiotherapy

Cited by 6 publications

References 82 publications

SGLT2 inhibitor promotes mitochondrial dysfunction and ER-phagy in colorectal cancer cells

SGLT2 inhibitor promotes mitochondrial dysfunction and ER-phagy in colorectal cancer cells

Risks and Benefits of SGLT-2 Inhibitors for Type 1 Diabetes Patients Using Automated Insulin Delivery Systems—A Literature Review

SGLT2 inhibition and three urological cancers: Up‐to‐date results

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