SGLT2 Inhibitors as Potential Anticancer Agents

Abstract

Sodium-glucose cotransporter 2 (SGLT2) serves as a critical glucose transporter that has been reported to be overexpressed in cancer models, followed by increased glucose uptake in both mice and humans. Inhibition of its expression can robustly thwart tumor development in vitro and in vivo. SGLT2 inhibitors are a comparatively new class of antidiabetic drugs that have demonstrated anticancer effects in several malignancies, including breast, liver, pancreatic, thyroid, prostate, and lung cancers. This review aims to assess the extent of SGLT involvement in different cancer cell lines and discuss the pharmacology, mechanisms of action, and potential applications of SGLT2 inhibitors to reduce tumorigenesis and its progression. Although these agents display a common mechanism of action, they exhibit distinct affinity towards the SGLT type 2 transporter compared to the SGLT type 1 transporter and varying extents of bioavailability and half-lives. While suppression of glucose uptake has been attributed to their primary mode of antidiabetic action, SGLT2 inhibitors have demonstrated several mechanistic ways to combat cancer, including mitochondrial membrane instability, suppression of β-catenin, and PI3K-Akt pathways, increase in cell cycle arrest and apoptosis, and downregulation of oxidative phosphorylation. Growing evidence and ongoing clinical trials suggest a potential benefit of combination therapy using an SGLT2 inhibitor with the standard chemotherapeutic regimen. Nevertheless, further experimental and clinical evidence is required to characterize the expression and role of SGLTs in different cancer types, the activity of different SGLT subtypes, and their role in tumor development and progression.

Nasopharyngeal Carcinoma and Head and Neck Cancer in Patients with Type-2 Diabetes Mellitus receiving SGLT2I, DPP4I or GLP1a: A population-based cohort study

“…22 Previously, SGLT2I was proposed as an potential anti-tumour agents since sodium-glucose cotransporter 2 was over-expressed in multiple tumour models, including head and neck cancer. 23, 24 In this study, we found that SGLT2I was associated with lower risk of NPC compared to DPP4I.…”

Exploring the clinical utility of DPP-IV and SGLT2 inhibitors in papillary thyroid cancer: a literature review

“…SGLT2 inhibitors may affect the tumor microenvironment by altering the composition of immune cells, cytokine profiles, and angiogenesis. Investigating these potential effects in the context of antitumor treatment is crucial ( Basak et al, 2023 ; L et al, 2014 ; Bose et al, 2021 ). Given their metabolic and signaling effects, SGLT2 inhibitors may have synergy with existing cancer therapies, such as chemotherapy, immunotherapy, or targeted therapies.…”

“…SGLT2 inhibitor significance lies in its ability to sensitize TNBC cells to DOX, offering a potential strategy to enhance chemotherapy efficacy and overcome drug resistance in this challenging cancer subtype. Combining SGLT2 inhibitors with conventional treatments could enhance treatment efficacy and improve patient outcomes (Basak et al, 2023). The diagram illustrating the operational dynamics of the SGLT2 inhibitor, alongside the identification of prospective targets Frontiers in Pharmacology frontiersin.org in differentiated thyroid cancer, has been presented in Figure 3 (Figure 3).…”

“…Thus, recent research has shed light on the potential role of novel pharmacological medicaments, such as antihyperglycemic agents, in the treatment of PTC ( Li et al, 2020 ). Among these agents, Dipeptidyl Peptidase-IV (DPP-IV) inhibitors and Sodium-Glucose Cotransporter 2 (SGLT2) inhibitors have emerged as promising candidates ( Busek et al, 2022 ; Basak et al, 2023 ). DPP-IV and SGLT2 inhibitors are primarily known for their applications in the management of type 2 diabetes mellitus (T2DM).…”

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

“…Sodium-glucose cotransporter 2 (SGLT2) is a critical glucose transporter overexpressed in different cancer models, leading to increased glucose uptake in mice and humans [ 1 , 2 ]. SGLT2 has been found significantly expressed in lung cancer metastasis, pancreatic and prostate adenocarcinomas, high-grade glioblastoma patients, cisplatin-resistant hepatoblastoma, renal cell carcinoma and its increased expression is related to a poor prognosis and decreased overall survival rates [ 3 – 7 ].…”