SGLT2 inhibitor ipragliflozin attenuates breast cancer cell proliferation

Abstract

Cancer is currently one of the major causes of death in patients with type 2 diabetes mellitus. We previously reported the beneficial effects of the glucagon-like peptide-1 receptor agonist exendin-4 against prostate and breast cancer. In the present study, we examined the anti-cancer effect of the sodium-glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin using a breast cancer model. In human breast cancer MCF-7 cells, SGLT2 expression was detected using both RT-PCR and immunohistochemistry. Ipragliflozin at 1-50 μM significantly and dose-dependently suppressed the growth of MCF-7 cells. BrdU assay also revealed that ipragliflozin attenuated the proliferation of MCF-7 cells in a dose-dependent manner. Because the effect of ipragliflozin against breast cancer cells was completely canceled by knocking down SGLT2, ipragliflozin could act via inhibiting SGLT2. We next measured membrane potential and whole-cell current using the patch clamp technique. When we treated MCF-7 cells with ipragliflozin or glucose-free medium, membrane hyperpolarization was observed. In addition, glucose-free medium and knockdown of SGLT2 by siRNA suppressed the glucose-induced whole-cell current of MCF-7 cells, suggesting that ipragliflozin inhibits sodium and glucose cotransport through SGLT2. Furthermore, JC-1 green fluorescence was significantly increased by ipragliflozin, suggesting the change of mitochondrial membrane potential. These findings suggest that the SGLT2 inhibitor ipragliflozin attenuates breast cancer cell proliferation via membrane hyperpolarization and mitochondrial membrane instability.

SGLT-2i and Risk of Malignancy in Type 2 Diabetes: A Meta-Analysis of Randomized Controlled Trials

“…Interestingly, a study has implied that canagliflozin holds anti-proliferation effect on breast cancer cells by increasing phosphorylation of adenosine monophosphate activated protein kinase (AMPK) and reducing the phosphorylation of 70 kilodalton (kDa) ribosomal protein S6 kinase 1, thereby blocking cell cycle and inducing apoptosis ( 115 ). Besides, a study has manifested that ipragliflozin can inhibit the proliferation of breast cancer cells ( 116 ).…”

Diabetes, Antidiabetic Medications and Cancer Risk in Type 2 Diabetes: Focus on SGLT-2 Inhibitors

“…Due to their mechanism of action-improvement in hyperglycemia, insulin sensitivity, decreased body weight-there were also expectations for their beneficial effect on cancer risk. In vitro and animal studies show their significant potential for protection against cancer formation and progression [126][127][128][129][130][131][132][133][134][135][136][137]. However, randomized and observational studies, and their meta-analyzes, did not confirm these hopes [111][112][113][114][115][116][117][118][119][120][121][122][123][124][125].…”

“…Thus, inhibition of SGLT-2 may have a direct impact on cancer cells growth. Studies in vitro and in animal models documented such effect of dapagliflozin in case of CaKi-1 renal cell cancer line with high expression of SGLT-2 [128], canagliflozin in two cell lines of hepatocellular cancer [129], ipragliflozin, canagliflozin and dapagliflozin in breast cancer [130,131].…”

Emergence of SGLT2 Inhibitors as Powerful Antioxidants in Human Diseases

“…In addition, SGLT2 inhibitors have been shown to reduce free radical generation [ 24 ], suppress pro-oxidants (e.g., NADPH oxidase 4 [NOX4] and thiobarbituric acid-reactive substances [TBARS]) [ 25 , 26 ], and upregulate antioxidant systems such as superoxide dismutases (SODs) and glutathione (GSH) peroxidases [ 27 , 28 , 29 ]. SGLT2 inhibitors have been shown to suppress cellular proliferation by reducing oxidative stress in multiple types of cancer [ 30 , 31 , 32 , 33 , 34 ]. Detailed discussion addressing specific markers of pro-oxidants and antioxidants that are examined in various studies is presented in subsequent sections under different disease headings.…”