{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T12:50:08Z","timestamp":1778071808128,"version":"3.51.4"},"reference-count":32,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2019,9,18]],"date-time":"2019-09-18T00:00:00Z","timestamp":1568764800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>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)-4\u03b1, 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.<\/jats:p>","DOI":"10.3390\/molecules24183390","type":"journal-article","created":{"date-parts":[[2019,9,18]],"date-time":"2019-09-18T11:01:15Z","timestamp":1568804475000},"page":"3390","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Trilobatin, a Novel SGLT1\/2 Inhibitor, Selectively Induces the Proliferation of Human Hepatoblastoma Cells"],"prefix":"10.3390","volume":"24","author":[{"given":"Lujing","family":"Wang","sequence":"first","affiliation":[{"name":"Chongqing Key Lab of Medicinal Chemistry &amp; Molecular Pharmacology, Chongqing University of Technology, Chongqing 400054, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min","family":"Liu","sequence":"additional","affiliation":[{"name":"Chongqing Key Lab of Medicinal Chemistry &amp; Molecular Pharmacology, Chongqing University of Technology, Chongqing 400054, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fei","family":"Yin","sequence":"additional","affiliation":[{"name":"Chongqing Key Lab of Medicinal Chemistry &amp; Molecular Pharmacology, Chongqing University of Technology, Chongqing 400054, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuanqiang","family":"Wang","sequence":"additional","affiliation":[{"name":"Chongqing Key Lab of Medicinal Chemistry &amp; Molecular Pharmacology, Chongqing University of Technology, Chongqing 400054, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xingan","family":"Li","sequence":"additional","affiliation":[{"name":"Chongqing Key Lab of Medicinal Chemistry &amp; Molecular Pharmacology, Chongqing University of Technology, Chongqing 400054, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yucui","family":"Wu","sequence":"additional","affiliation":[{"name":"Chongqing Key Lab of Medicinal Chemistry &amp; Molecular Pharmacology, Chongqing University of Technology, Chongqing 400054, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cuilian","family":"Ye","sequence":"additional","affiliation":[{"name":"Chongqing Key Lab of Medicinal Chemistry &amp; Molecular Pharmacology, Chongqing University of Technology, Chongqing 400054, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianhui","family":"Liu","sequence":"additional","affiliation":[{"name":"Chongqing Key Lab of Medicinal Chemistry &amp; Molecular Pharmacology, Chongqing University of Technology, Chongqing 400054, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,9,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1186\/1476-4598-12-152","article-title":"Tumor glycolysis as a target for cancer therapy: Progress and prospects","volume":"12","author":"Geschwind","year":"2013","journal-title":"Mol. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5537","DOI":"10.1158\/1078-0432.CCR-12-2587","article-title":"Targeting cancer metabolism","volume":"18","author":"Teicher","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.pharmthera.2016.10.017","article-title":"The Na(+)-d-glucose cotransporters SGLT1 and SGLT2 are targets for the treatment of diabetes and cancer","volume":"170","author":"Koepsell","year":"2017","journal-title":"Pharmacol. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"E4111","DOI":"10.1073\/pnas.1511698112","article-title":"Functional expression of sodium-glucose transporters in cancer","volume":"112","author":"Scafoglio","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1002\/dmrr.532","article-title":"Phlorizin: A review","volume":"21","author":"Ehrenkranz","year":"2005","journal-title":"Diabetes Metab. Res. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5299","DOI":"10.1007\/s11033-011-1328-7","article-title":"Phloridzin reduces blood glucose levels and improves lipids metabolism in streptozotocin-induced diabetic rats","volume":"39","author":"Najafian","year":"2012","journal-title":"Mol. Biol. Rep."},{"key":"ref_7","first-page":"2287","article-title":"The efficacy of phloridzin and phloretin on tumor cell growth","volume":"13","author":"Nelson","year":"1993","journal-title":"Anticancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Wang, J., Huang, Y., Li, K., Chen, Y., Vanegas, D., McLamore, E.S., and Shen, Y. (2016). Leaf Extract from Lithocarpus polystachyus Rehd. Promote Glycogen Synthesis in T2DM Mice. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0166557"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1016\/j.jchromb.2015.08.045","article-title":"Preparative isolation, quantification and antioxidant activity of dihydrochalcones from Sweet Tea (Lithocarpus polystachyus Rehd.)","volume":"1002","author":"Sun","year":"2015","journal-title":"J. Chromatogr. B"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1016\/j.foodchem.2014.06.022","article-title":"Trilobatin attenuates the LPS-mediated inflammatory response by suppressing the NF-kappaB signaling pathway","volume":"166","author":"Fan","year":"2015","journal-title":"Food Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"21193","DOI":"10.3390\/molecules201219754","article-title":"Dihydrochalcone Compounds Isolated from Crabapple Leaves Showed Anticancer Effects on Human Cancer Cell Lines","volume":"20","author":"Qin","year":"2015","journal-title":"Molecules"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1038\/nature09580","article-title":"The mechanism of sodium and substrate release from the binding pocket of vSGLT","volume":"468","author":"Watanabe","year":"2010","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Perez, M., Praena-Fernandez, J.M., Felipe-Abrio, B., Lopez-Garcia, M.A., Lucena-Cacace, A., Garcia, A., Lleonart, M., Roncador, G., Marin, J.J., and Carnero, A. (2013). MAP17 and SGLT1 protein expression levels as prognostic markers for cervical tumor patient survival. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0056169"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1712","DOI":"10.1002\/ijc.31193","article-title":"Sodium glucose cotransporter 2 inhibitor canagliflozin attenuates liver cancer cell growth and angiogenic activity by inhibiting glucose uptake","volume":"142","author":"Kaji","year":"2018","journal-title":"Int J. Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"6102","DOI":"10.1021\/ja108404p","article-title":"Imaging of EdU, an alkyne-tagged cell proliferation probe, by Raman microscopy","volume":"133","author":"Yamakoshi","year":"2011","journal-title":"J. Am. Chem. Soc."},{"key":"ref_16","first-page":"535","article-title":"Cell type specific applicability of 5-ethynyl-2\u2032-deoxyuridine (EdU) for dynamic proliferation assessment in flow cytometry","volume":"75","author":"Clarke","year":"2009","journal-title":"Cytometry A"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2415","DOI":"10.1073\/pnas.0712168105","article-title":"A chemical method for fast and sensitive detection of DNA synthesis in vivo","volume":"105","author":"Salic","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Okada, M., and Shi, Y.B. (2017). Cell Proliferation Analysis during Xenopus Metamorphosis: Using 5-Ethynyl-2-Deoxyuridine (EdU) to Stain Proliferating Intestinal Cells. Cold Spring Harb. Protoc., 2017.","DOI":"10.1101\/pdb.prot097717"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e31","DOI":"10.1093\/nar\/gkp023","article-title":"A rapid non-radioactive technique for measurement of repair synthesis in primary human fibroblasts by incorporation of ethynyl deoxyuridine (EdU)","volume":"37","author":"Limsirichaikul","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1111\/j.1745-7254.2007.00531.x","article-title":"Involvement of hepatitis B X-interacting protein (HBXIP) in proliferation regulation of cells","volume":"28","author":"Wang","year":"2007","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1258\/ebm.2010.010179","article-title":"Hepatitis B x-interacting protein induces HepG2 cell proliferation through activation of the phosphatidylinositol 3-kinase\/Akt pathway","volume":"236","author":"Wang","year":"2011","journal-title":"Exp. Biol. Med. (Maywood)"},{"key":"ref_22","first-page":"2553","article-title":"The effect of arsenic trioxide on the expression of Hsc and HNF4 in nuclear matrix proteins in HepG2 cells","volume":"21","author":"Yu","year":"2001","journal-title":"Anticancer Res."},{"key":"ref_23","first-page":"5","article-title":"Comparative protein structure modeling using Modeller","volume":"5","author":"Eswar","year":"2006","journal-title":"Curr. Protoc. Bioinform."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1007\/BF00124474","article-title":"Scoring noncovalent protein-ligand interactions: A continuous differentiable function tuned to compute binding affinities","volume":"10","author":"Jain","year":"1996","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1007\/s12154-015-0131-7","article-title":"Design and activity of AP endonuclease-1 inhibitors","volume":"8","author":"Feng","year":"2015","journal-title":"J. Chem. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1021\/ci5007189","article-title":"Structural insight into tetrameric hTRPV1 from homology modeling, molecular docking, molecular dynamics simulation, virtual screening, and bioassay validations","volume":"55","author":"Feng","year":"2015","journal-title":"J. Chem. Inf. Model."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/s00894-018-3790-9","article-title":"An insight into paracetamol and its metabolites using molecular docking and molecular dynamics simulation","volume":"24","author":"Wang","year":"2018","journal-title":"J. Mol. Model."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1038\/s41401-019-0217-9","article-title":"Structural insight into the serotonin (5-HT) receptor family by molecular docking, molecular dynamics simulation and systems pharmacology analysis","volume":"40","author":"Wang","year":"2019","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"eaat5933","DOI":"10.1126\/scitranslmed.aat5933","article-title":"Sodium-glucose transporter 2 is a diagnostic and therapeutic target for early-stage lung adenocarcinoma","volume":"10","author":"Scafoglio","year":"2018","journal-title":"Sci. Transl. Med."},{"key":"ref_30","first-page":"164","article-title":"Expression of glucose transporters in cancers","volume":"1835","author":"Szablewski","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1002\/med.10033","article-title":"Flavonoids: Promising anticancer agents","volume":"23","author":"Ren","year":"2003","journal-title":"Med. Res. Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1111\/j.1349-7006.2001.tb01175.x","article-title":"SGLT gene expression in primary lung cancers and their metastatic lesions","volume":"92","author":"Ishikawa","year":"2001","journal-title":"Jpn. J. Cancer Res."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/18\/3390\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:21:21Z","timestamp":1760188881000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/18\/3390"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,18]]},"references-count":32,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2019,9]]}},"alternative-id":["molecules24183390"],"URL":"https:\/\/doi.org\/10.3390\/molecules24183390","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,18]]}}}