{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:44:13Z","timestamp":1760150653505,"version":"build-2065373602"},"reference-count":36,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,12,25]],"date-time":"2023-12-25T00:00:00Z","timestamp":1703462400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Foundation (NRF) of Korea","award":["2022R1A4A1025557","2021RIS-001"],"award-info":[{"award-number":["2022R1A4A1025557","2021RIS-001"]}]},{"DOI":"10.13039\/501100003725","name":"Ministry of Science and ICT","doi-asserted-by":"publisher","award":["2022R1A4A1025557","2021RIS-001"],"award-info":[{"award-number":["2022R1A4A1025557","2021RIS-001"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ministry of Education","award":["2022R1A4A1025557","2021RIS-001"],"award-info":[{"award-number":["2022R1A4A1025557","2021RIS-001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Cholangiocarcinoma (CCA) is a malignant biliary tract tumor with a high mortality rate and refractoriness to chemotherapy. Gemcitabine is an anti-cancer chemotherapeutic agent used for CCA, but the efficacy of gemcitabine in CCA treatment is limited, due to the acquisition of chemoresistance. The present study evaluated the chemosensitizing effects of Amurensin G (AMG), a natural sirtuin-1 inhibitor derived from Vitis amurensis, in the SNU-478 CCA cells. Treatment with AMG decreased the SNU-478 cell viability and the colony formation ability. Annexin V\/ Propidium iodide staining showed that the AMG increased apoptotic death. In addition, AMG downregulated anti-apoptotic Bcl-2 expression, while upregulating pro-apoptotic cleaved caspase-3 expression. Treatment with AMG decreased the migratory ability of the cells in a wound healing assay and transwell migration assay. It was observed that AMG decreased the gemcitabine-induced increase in CD44highCD24highCD133high cell populations, and the expression of the Sox-2 protein was decreased by AMG treatment. Co-treatment of AMG with gemcitabine significantly enhanced the production of reactive oxygen species, as observed through mitochondrial superoxide staining, which might be associated with the downregulation of the Sirt1\/Nrf2 pathway by AMG. These results indicate that AMG enhances the chemotherapeutic ability of gemcitabine by downregulating cancer stem-like properties in CCA cells. Hence, a combination therapy of AMG with gemcitabine may be an attractive therapeutic strategy for cholangiocarcinoma.<\/jats:p>","DOI":"10.3390\/nu16010073","type":"journal-article","created":{"date-parts":[[2023,12,25]],"date-time":"2023-12-25T23:00:12Z","timestamp":1703545212000},"page":"73","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Amurensin G Sensitized Cholangiocarcinoma to the Anti-Cancer Effect of Gemcitabine via the Downregulation of Cancer Stem-like Properties"],"prefix":"10.3390","volume":"16","author":[{"given":"Yun-Jung","family":"Na","sequence":"first","affiliation":[{"name":"Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Chungbuk, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong Kyu","family":"Lee","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Chungbuk, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1925-1198","authenticated-orcid":false,"given":"Kyung-Chul","family":"Choi","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Chungbuk, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1038\/s41575-020-0310-z","article-title":"Cholangiocarcinoma 2020: The next horizon in mechanisms and management","volume":"17","author":"Banales","year":"2020","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Wu, H.J., and Chu, P.Y. (2019). Role of cancer stem cells in cholangiocarcinoma and therapeutic implications. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20174154"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1056\/NEJMoa0908721","article-title":"Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer","volume":"362","author":"Valle","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"100737","DOI":"10.1016\/j.aohep.2022.100737","article-title":"Clinical treatment of cholangiocarcinoma: An updated comprehensive review","volume":"27","author":"Elvevi","year":"2022","journal-title":"Ann. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Pandit, B., and Royzen, M. (2022). Recent development of prodrugs of gemcitabine. Genes, 13.","DOI":"10.3390\/genes13030466"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5562","DOI":"10.2174\/0929867326666190816230650","article-title":"Small molecular gemcitabine prodrugs for cancer therapy","volume":"27","author":"Miao","year":"2020","journal-title":"Curr. Med. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.gendis.2015.07.003","article-title":"Promising molecular mechanisms responsible for gemcitabine resistance in cancer","volume":"2","author":"Jia","year":"2015","journal-title":"Genes. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"692940","DOI":"10.3389\/fcell.2021.692940","article-title":"Cancer stem cells: Emerging key players in immune evasion of cancers","volume":"9","author":"Lei","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1038\/s41392-020-0110-5","article-title":"Targeting cancer stem cell pathways for cancer therapy","volume":"5","author":"Yang","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.bbrc.2013.02.053","article-title":"Amurensin g induces autophagy and attenuates cellular toxicities in a rotenone model of parkinson\u2019s disease","volume":"433","author":"Ryu","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2041769","DOI":"10.1155\/2022\/2041769","article-title":"Papaver plants: Current insights on phytochemical and nutritional composition along with biotechnological applications","volume":"2022","author":"Butnariu","year":"2022","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.taap.2011.12.025","article-title":"Involvement of sirt1 in hypoxic down-regulation of c-myc and beta-catenin and hypoxic preconditioning effect of polyphenols","volume":"259","author":"Hong","year":"2012","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1007\/s12272-010-1015-6","article-title":"Leaf and stem of vitis amurensis and its active components protect against amyloid beta protein (25-35)-induced neurotoxicity","volume":"33","author":"Jeong","year":"2010","journal-title":"Arch. Pharm. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3625","DOI":"10.1016\/j.fct.2012.07.027","article-title":"Amurensin g inhibits angiogenesis and tumor growth of tamoxifen-resistant breast cancer via pin1 inhibition","volume":"50","author":"Kim","year":"2012","journal-title":"Food Chem. Toxicol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1111\/cas.12299","article-title":"Amurensin g enhances the susceptibility to tumor necrosis factor-related apoptosis-inducing ligand-mediated cytotoxicity of cancer stem-like cells of hct-15 cells","volume":"104","author":"Lee","year":"2013","journal-title":"Cancer Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1124\/mol.110.065961","article-title":"Amurensin g, a potent natural sirt1 inhibitor, rescues doxorubicin responsiveness via down-regulation of multidrug resistance 1","volume":"78","author":"Oh","year":"2010","journal-title":"Mol. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"121009","DOI":"10.1016\/j.lfs.2022.121009","article-title":"The role of kiss1 gene on the growth and migration of prostate cancer and the underlying molecular mechanisms","volume":"310","author":"Kim","year":"2022","journal-title":"Life Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"114780","DOI":"10.1016\/j.biopha.2023.114780","article-title":"Effects of ccn6 overexpression on the cell motility and activation of p38\/bone morphogenetic protein signaling pathways in pancreatic cancer cells","volume":"163","author":"Nam","year":"2023","journal-title":"Biomed. Pharmacother."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"935","DOI":"10.14348\/molcells.2022.0105","article-title":"Overexpression of kiss1 induces the proliferation of hepatocarcinoma and increases metastatic potential by increasing migratory ability and angiogenic capacity","volume":"45","author":"Kim","year":"2022","journal-title":"Mol. Cells"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1007\/s00534-012-0542-6","article-title":"Recent advances in cancer stem cell research for cholangiocarcinoma","volume":"19","author":"Kokuryo","year":"2012","journal-title":"J. Hepatobiliary Pancreat. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1038\/nrgastro.2016.51","article-title":"Expert consensus document: Cholangiocarcinoma: Current knowledge and future perspectives consensus statement from the european network for the study of cholangiocarcinoma (ens-cca)","volume":"13","author":"Banales","year":"2016","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.canlet.2016.08.023","article-title":"Gemcitabine treatment promotes pancreatic cancer stemness through the nox\/ros\/nf-kappab\/stat3 signaling cascade","volume":"382","author":"Zhang","year":"2016","journal-title":"Cancer Lett."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1186\/s13018-022-03048-x","article-title":"Knockdown of cd44 inhibits proliferation, migration and invasion of osteosarcoma cells accompanied by downregulation of cathepsin s","volume":"17","author":"Kong","year":"2022","journal-title":"J. Orthop. Surg. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1038\/s41419-021-03733-5","article-title":"Sox2 promotes chemoresistance, cancer stem cells properties, and epithelial-mesenchymal transition by beta-catenin and beclin1\/autophagy signaling in colorectal cancer","volume":"12","author":"Zhu","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Thanee, M., Dokduang, H., Kittirat, Y., Phetcharaburanin, J., Klanrit, P., Titapun, A., Namwat, N., Khuntikeo, N., Wangwiwatsin, A., and Saya, H. (2021). Cd44 modulates metabolic pathways and altered ros-mediated akt signal promoting cholangiocarcinoma progression. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0245871"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.semcdb.2017.05.023","article-title":"Ros signalling in the biology of cancer","volume":"80","author":"Moloney","year":"2018","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.ccr.2011.01.038","article-title":"Cd44 variant regulates redox status in cancer cells by stabilizing the xct subunit of system xc(\u2212) and thereby promotes tumor growth","volume":"19","author":"Ishimoto","year":"2011","journal-title":"Cancer Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.omto.2019.07.005","article-title":"Ros\/kras\/ampk signaling contributes to gemcitabine-induced stem-like cell properties in pancreatic cancer","volume":"14","author":"Zhao","year":"2019","journal-title":"Mol. Ther. Oncolytics"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/2162-3619-2-17","article-title":"Cd133: A stem cell biomarker and beyond","volume":"2","author":"Li","year":"2013","journal-title":"Exp. Hematol. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"56324","DOI":"10.18632\/oncotarget.10838","article-title":"Microenvironment mediated alterations to metabolic pathways confer increased chemo-resistance in cd133+ tumor initiating cells","volume":"7","author":"Nomura","year":"2016","journal-title":"Oncotarget"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1016\/j.bcp.2012.03.014","article-title":"Amurensin g, a novel sirt1 inhibitor, sensitizes trail-resistant human leukemic k562 cells to trail-induced apoptosis","volume":"84","author":"Kim","year":"2012","journal-title":"Biochem. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1038\/s41419-020-2308-4","article-title":"Sirt1 inhibits chemoresistance and cancer stemness of gastric cancer by initiating an ampk\/foxo3 positive feedback loop","volume":"11","author":"An","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1177\/1947601912473826","article-title":"Emerging roles of sirt1 in cancer drug resistance","volume":"4","author":"Wang","year":"2013","journal-title":"Genes Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Alves-Fernandes, D.K., and Jasiulionis, M.G. (2019). The role of sirt1 on DNA damage response and epigenetic alterations in cancer. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20133153"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1089\/ars.2017.7290","article-title":"The role of sirtuins in antioxidant and redox signaling","volume":"28","author":"Singh","year":"2018","journal-title":"Antioxid. Redox Signal."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1098915","DOI":"10.3389\/fphar.2023.1098915","article-title":"Lanatoside c decelerates proliferation and induces apoptosis through inhibition of stat3 and ros-mediated mitochondrial membrane potential transformation in cholangiocarcinoma","volume":"14","author":"Zhang","year":"2023","journal-title":"Front. Pharmacol."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/16\/1\/73\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:41:49Z","timestamp":1760132509000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/16\/1\/73"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,25]]},"references-count":36,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,1]]}},"alternative-id":["nu16010073"],"URL":"https:\/\/doi.org\/10.3390\/nu16010073","relation":{},"ISSN":["2072-6643"],"issn-type":[{"type":"electronic","value":"2072-6643"}],"subject":[],"published":{"date-parts":[[2023,12,25]]}}}