Trilobatin, a Novel SGLT1/2 Inhibitor, Selectively Induces the Proliferation of Human Hepatoblastoma Cells

Abstract

Studies have indicated that Na+-d-glucose co-transporter (SGLT) inhibitors had anti-proliferative activity by attenuating the uptake of glucose in several tumor cell lines. In this study, the molecular docking showed that, trilobatin, one of the dihydrochalcones from leaves of Lithocarpus polystachyus Rehd., might be a novel inhibitor of SGLT1 and SGLT2, which evidently attenuated the uptake of glucose in vitro and in vivo. To our surprise, we observed that trilobatin did not inhibit, but promoted the proliferation of human hepatoblastoma HepG2 and Huh 7 cells when it was present at high concentrations. At the same time, incubation with high concentrations of trilobatin arrested the cell cycle at S phase in HepG2 cells. We also found that treatment with trilobatin had no significant effect on the expression of hepatitis B x-interacting protein (HBXIP) and hepatocyte nuclear factor (HNF)-4α, the two key regulators of hepatocyte proliferation. Taken together, although trilobatin worked as a novel inhibitor of SGLTs to attenuate the uptake of glucose, it also selectively induced the cell proliferation of HepG2 cells, suggesting that not all the SGLT inhibitors inhibited the proliferation of tumor cells, and further studies are needed to assess the anti-cancer potentials of new glucose-lowering agents.

Sodium-glucose cotransporter-2 inhibitors: Understanding the mechanisms for therapeutic promise and persisting risks

“…In recent years, investigators have also begun to study the potential effects of SGLT2 inhibitors on cancer in preclinical studies. In vitro studies have demonstrated that SGLT2 inhibitors, at high doses, inhibit cell division in liver (159)(160)(161), lung (162,163), kidney (164), prostate (163), and breast cancer (165,166) potentially by inhibiting tumor cell glucose uptake (161) and/or oxidation (167). Even more exciting, SGLT2 inhibitors inhibit tumor growth in vivo (159,161,164,166,(168)(169)(170)(171)(172), by a mechanism that remains under debate.…”

Complex Positive Effects of SGLT-2 Inhibitor Empagliflozin in the Liver, Kidney and Adipose Tissue of Hereditary Hypertriglyceridemic Rats: Possible Contribution of Attenuation of Cell Senescence and Oxidative Stress

“…Interestingly, in higher concentrations, (10 µM) canagliflozin also protected against liver carcinogenesis [ 41 , 42 ]. Some of the novel SGLT inhibitors, such as tofogliflozin [ 43 ] or trilobatin [ 44 ], also promoted liver proliferation. These results indicate an overall positive effect of SGLT inhibitors in the liver, and our data add another important piece of information with the potential role of empagliflozin in the amelioration of liver cell senescence.…”

Dapagliflozin Inhibits Cell Adhesion to Collagen I and IV and Increases Ectodomain Proteolytic Cleavage of DDR1 by Increasing ADAM10 Activity

“…As canagliflozin is metabolized and excreted by UGT1A9 and UDP glucuronosyltransferase family 2 member B4 (UGT2B4), we speculate that cancer cells expressing SGLT2 combined with low levels of UGT1A9 and UGT2B4, will make these tumor cells sensitive to canagliflozin. Since not all SGLT inhibitors suppress the proliferation of tumor cells [19], further studies are needed to assess the anti-cancer potentials of new glucose-lowering agents. In addition, we have observed that unmetabolized dapagliflozin increased ADAM10 activity that proteolytically cleaves DDR1 resulting in the loss of cell adhesion.…”