Sodium glucose cotransporter 2 inhibitor canagliflozin attenuates liver cancer cell growth and angiogenic activity by inhibiting glucose uptake

Abstract

Sodium-glucose cotransporter 2 inhibitors (SGLT2-Is) comprise a new class of antidiabetic agents that inhibit glucose reabsorption in the renal proximal tubules. Although a recent report demonstrated the potential ability of SGLT2-Is to attenuate cancer growth of SGLT2-expressing cancer cells, little is known about the effects of SGLT2-Is on hepatocellular carcinoma (HCC). Here, we investigate the anti-cancer properties of a SGLT2-I, canagliflozin, against human liver cancer cells. SGTL2 mRNA and protein expression were detected in Huh7 and HepG2 cells, although not in HLE as well as primary human hepatocytes and hepatic stellate cells. Canagliflozin exerted antiproliferative effects on SGLT2-expressing Huh7 and HepG2 cells in a dose-dependent manner by inhibiting glycolytic metabolism including glucose uptake, lactate and intracellular ATP production. This agent also induced G2/M arrest and apoptosis with inhibited phosphorylation of ERK, p38 and AKT and cleavage of caspase3. Xenograft tumor growth assay showed that oral administration of canagliflozin (10 mg/kg/day) significantly reduced subcutaneous tumor burdens in a glycemic status-independent manner, and attenuated intratumor vascularization in Huh7- and HepG2-derived xenograft tumors in BALB/c nude mice. In vitro, canagliflozin suppressed the increased human umbilical vein endothelial cell (HUVEC) proliferation and tubular formation which were observed in Huh7 or HepG2 co-cultures. By contrast, canagliflozin had no effect on tumor growth and intratumor angiogenesis in SGLT2-null HLE-derived xenograft models. These results indicate that SGLT2-I therapy is a potential new strategy for the treatment of HCC.

Synthetic lethality targeting LKB1 mutant and EGFR wild type human non-small cell lung cancer cells by glucose starvation and SGLT2 inhibition

“…As mentioned above, the SGLT family proteins are involved in the active uptake of glucose, with predominant expression in intestine and kidney (Vrhovac et al, 2015). Moreover, it has been reported that functional SGLT2 expression is detected in various cancer types, including lung, pancreatic, prostate, colon, and liver cancers (Ishikawa et al, 2001;Kaji et al, 2018;Saito et al, 2015;Scafoglio et al, 2015;Scafoglio et al, 2018;Villani et al, 2016). Indeed, all 6 NSCLC cell lines expressed SGLT2 (Figure 6A).…”

“…Invokana is the clinical tablet form of canagliflozin which is currently used to treat type 2 diabetes. In a BALB/c nude mice xenograft model, daily oral gavage of Invokana (100 mg/kg/day), a dosage reported by others in study of its anti-tumor activity (Friess et al, 2005;Kaji et al, 2018;Villani et al, 2016;Zhang et al, 2012), significantly mitigated tumor growth of H460 and A549 cell lines, but not that of HCC827 (Figures 6E and S6D). Consistent with reduced tumor growth, in Invokana-treated H460 and A549 xenograft tumors, the proliferation marker Ki67 was much weaker, whereas no obvious difference was detected in HCC827 xenograft tumor (Figures 6F and S6E).…”

“…Indeed, all 6 NSCLC cell lines expressed SGLT2 (Figure 6A). Targeting SGLT2 by its inhibitors has been shown to inhibit tumor cell growth in pancreatic, prostate, colon, liver and lung cancers (Kaji et al, 2018;Saito et al, 2015;Scafoglio et al, 2015;Scafoglio et al, 2018;Villani et al, 2016). Thus, it is of interest and importance to investigating whether SGLT2 inhibitors would mimic the effect of glucose starvation in selective killing of the EGFR-WT/LKB1-mutant NSCLC cells.…”

Clinical response to sodium glucose co‐transporter 2 inhibitor ipragliflozin in a patient with metastatic renal cell carcinoma

“…A recent study reported that dapagliflozin, an SGLT2 inhibitor, reduces the viability of renal cell carcinoma cell lines, thus regulating the cell cycle and apoptosis in vitro and in vivo . In liver cancer cells, canaglifrozin inhibits cell growth by not only inhibiting glucose uptake but also by affecting intratumor angiogenesis . It is possible that ipragliflozin affects both glucose uptake and tumor angiogenesis.…”

“…3 In liver cancer cells, canaglifrozin inhibits cell growth by not only inhibiting glucose uptake but also by affecting intratumor angiogenesis. 5 It is possible that ipragliflozin affects both glucose uptake and tumor angiogenesis.…”