SGLT-2 Inhibitors in Cancer Treatment—Mechanisms of Action and Emerging New Perspectives

Abstract

A new group of antidiabetic drugs, sodium-glucose cotransporter 2 inhibitors (SGLT-2 inhibitors), have recently been shown to have anticancer effects and their expression has been confirmed in many cancer cell lines. Given the metabolic reprogramming of these cells in a glucose-based model, the ability of SGLT-2 inhibitors to block the glucose uptake by cancer cells appears to be an attractive therapeutic approach. In addition to tumour cells, SGLT-2s are only found in the proximal tubules in the kidneys. Furthermore, as numerous clinical trials have shown, the use of SGLT-2 inhibitors is well-tolerated and safe in patients with diabetes and/or heart failure. In vitro cell culture studies and preclinical in vivo studies have confirmed that SGLT-2 inhibitors exhibit antiproliferative effects on certain types of cancer. However, the mechanisms of this action remain unclear. Even in those tumour cell types in which SGLT-2 is present, there is sometimes an SGLT-2-independent mechanism of anticancer action of this group of drugs. This article presents the current state of knowledge of the potential mechanisms of the anticancer action of SGLT-2 inhibitors and their possible future application in clinical oncology.

Unlocking the Full Potential of SGLT2 Inhibitors: Expanding Applications beyond Glycemic Control

“…They are well tolerated and safe, and have been found to be effective in treating heart failure in patients without diabetes. The expression of SGLT2 has been confirmed in various types of cancer cells, making them a promising target for therapy [ 124 ]. recent evidence suggests that SGLT2 inhibitors may have potential as an anti-cancer therapy.…”

“…recent evidence suggests that SGLT2 inhibitors may have potential as an anti-cancer therapy. The anticancer activity of SGLT2 inhibitors has been demonstrated in such cancers as liver, pancreatic, prostate, bowel, lung, and breast cancer [ 124 ]. Some types of cancer cells express SGLT2, and SGLT2 inhibitors have been shown to induce apoptosis or inhibit the proliferation of cancer cells at high concentrations in vitro [ 125 ].…”

“…Canagliflozin inhibits not only SGLT2 but also other glucose transporters such as GLUT1, which is overexpressed in HCC cells. Canagliflozin’s anticancer effect is not solely due to inhibiting glucose influx but also involves direct inhibition of protein phosphatase 2A (PP2A) activity [ 124 ]. The Wnt/β-catenin signaling pathway plays a crucial role in HCC development, and its excessive activation is a predisposing factor for HCC ( Figure 4 ).…”

How Sweet It Is: A Perspective on the Potential Anti-Tumor Role for SGLT2 Inhibitors

“…However, murine studies found no tumor promoter or progressor potential for dapaglafozin. 6 In addition, large meta-analyses consistently showed no increase in the overall risk of cancer or of specific cancer types. 6 Emerging evidence now suggests that SGLTs may actually play a vital role in tumor cell homeostasis, raising the attractive prospect that SGLT2is may possess anticancer properties.…”

“…6 In addition, large meta-analyses consistently showed no increase in the overall risk of cancer or of specific cancer types. 6 Emerging evidence now suggests that SGLTs may actually play a vital role in tumor cell homeostasis, raising the attractive prospect that SGLT2is may possess anticancer properties. 6,7 The link between cancer growth and glucose dates to the pioneering studies by Otto Warburg describing increased glucose uptake and preferential use of glycolysis for energy in tumor cells versus normal cells.…”