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

Lujing Wang,Min Liu,Yuanqiang Wang,Jianhui Liu,Xingan Li,Fei Yin,Cuilian Ye,Yucui Wu

doi:10.3390/molecules24183390

Lujing Wang, Min Liu + Show 6 more

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https://doi.org/10.3390/molecules24183390

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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.

Highlights

A large body of evidence showed that tumor cells were easy to adapt to aerobic glycolysis through up-regulation of glucose uptake systems and changes in the expression of metabolic enzymes, which were potential targets for antitumor therapies [1]
It has been identified that the Na+ -D-glucose co-transporters SGLT1 and SGLT2 are expressed in various tumors, which provides an effective way to attenuate the uptake of glucose and inhibit the growth of tumor cells [2,3,4]
The binding pocket was near residue Tyr290, which was the key residue for receptor and ligand interaction [12]. Both of trilobatin and phloridzin kept the similar pose, especially, the saccharide group had a conformation like glucose transported by SGLT2, which meant the inhibitor could block the interaction between SGLT2 and glucose

Summary

Introduction

A large body of evidence showed that tumor cells were easy to adapt to aerobic glycolysis through up-regulation of glucose uptake systems and changes in the expression of metabolic enzymes, which were potential targets for antitumor therapies [1]. It has been identified that the Na+ -D-glucose co-transporters SGLT1 and SGLT2 are expressed in various tumors, which provides an effective way to attenuate the uptake of glucose and inhibit the growth of tumor cells [2,3,4]. Phloridzin, a nonselective SGLT1/SGLT2 inhibitor, was demonstrated to inhibit glucose intestinal absorption and renal resorption, resulting in the normalization of blood glucose and overall reduction of glycaemia in animal models [5,6]. Phloridzin had been shown a significant in vivo anti-proliferative activity in bladder carcinoma cells that were subcutaneously transplanted from the Fischer 344 male rat’s model, which inhibited the growth of mammary adenocarcinoma cells subcutaneously transplanted into Fischer 344 female rats [7]. Trilobatin, an isomer of phloridzin (Figure 1A), was revealed to have lower toxicity and better solubility, with significant anti-hyperglycemic [8], anti-oxidative [9] and anti-inflammatory

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Conclusion