Sodium-glucose cotransporters: new targets of cancer therapy?

Abstract

Glucose, the key source of metabolic energy, is imported into cells by two categories of transporters: 1) facilitative glucose transporters (GLUTs) and 2) secondary active sodium-glucose cotransporters (SGLTs). Cancer cells have an increased demand for glucose uptake and utilisation compared to normal cells. Previous studies have demonstrated the overexpression of GLUTs, mainly GLUT1, in many cancer types. As the current standard positron emission tomography (PET) tracer 2-deoxy-2-(18F)fluoro-D-glucose (2-FDG) for imaging tumour cells via GLUT1 lacks in sensitivity and specificity, it may soon be replaced by the newly designed, highly sensitive and specific SGLT tracer α-methyl-4-(F-18)fluoro-4-deoxy-Dglucopyranoside (Me-4FDG) in clinical detection and tumour staging. This tracer has recently demonstrated the functional activity of SGLT in pancreatic, prostate, and brain cancers. The mRNA and protein expression of SGLTs have also been reported in colon/colorectal, lung, ovarian, head, neck, and oral squamous carcinomas. So far, SGLTs have been poorly investigated in cancer, and their protein expression and localisation are often controversial due to a lack of specific SGLT antibodies. In this review, we describe current knowledge concerning SGLT1 and SGLT2 (over)expression in various cancer types. The findings of SGLTs in malignant cells may help in developing novel cancer therapies with SGLT2 or SGLT1/SGLT2 inhibitors already used in diabetes mellitus treatment.

A guide to plasma membrane solute carrier proteins

“…Thus, targeting glucose transporters discussed above would provide a targeted strategy through which to disrupt the energetic supply of cancerous cells. The expression of both SLC2 and SLC5 proteins changes during the development of cancer, although the proteins thought to be the most significant contributors to these changes are SLC2A1, SLC2A3, and SLC5A1 [127][128][129]. Both SLC2A1 and SLC2A3 are expressed at significantly higher levels in most cancers, with higher expression of proteins found in more aggressive and proliferative cancers and lower protein expression being linked to higher survival rates of patients [130,131].…”

“…Higher expression of SLC2 proteins has also been linked to the development of chemotherapy resistance [128,132,133]. SLC5 proteins have been found expressed at higher levels in colon, lung, head, neck, and pancreatic cancers [127]. SLC5A1, as the main sodium-glucose transporter in the body, is often overexpressed in cancerous tissues, allowing these higher rates of aerobic glycolysis [129].…”

Lysine-mediated hydroxyethyl starch-10-hydroxy camptothecin micelles for the treatment of liver cancer

“…(Li and Zhao, 2019;Mohammed et al, 2019;Zhang et al, 2019). It is well known that the progression of the tumor requires a large amount of nutrients, including amino acids (AA), glucose, etc., which leads to overexpression of AA transporters and glucose transporters on the surface of tumor cells (Madunic et al, 2018;Hafliger and Charles, 2019;Ogawa et al, 2019;Sztandera et al, 2019). Moreover, transporter-mediated drug transport exhibited higher specificity and efficiency than receptor-ligand-mediated active targeting in terms of transport efficiency.…”

Dysplastic urothelial changes accompany empagliflozin administration in urinary bladder of experimental diabetes

“…CANA may even protect against certain (gastrointestinal, GI) cancers, yet it had been implicated in other tumours that may be secondary to glucose malabsorption . Interestingly, SGLT expression has been demonstrated in many carcinomas, and specifically, SGLT2 was detected in pancreatic, prostatic tumours and in glioblastoma suggesting SGLT2is as a novel antitumour therapy . Therefore, further studies should be performed to clarify the exact risk benefit of SGLT2 inhibition …”

“…25 Interestingly, SGLT expression has been demonstrated in many carcinomas, and specifically, SGLT2 was detected in pancreatic, prostatic tumours 26 and in glioblastoma suggesting SGLT2is as a novel antitumour therapy. 27,28 Therefore, further studies should be performed to clarify the exact risk benefit of SGLT2 inhibition. 10,29 In the current study, we hypothesized that the EMPAinduced increase in UC risk might be due to a preceding premalignant urothelial lesion.…”