{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T19:38:33Z","timestamp":1791920313292,"version":"4.3.4"},"reference-count":61,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,7,18]],"date-time":"2021-07-18T00:00:00Z","timestamp":1626566400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>The flowering plant genus Alisma, which belongs to the family Alismataceae, comprises 11 species, including Alisma orientale, Alisma\u00a0canaliculatum, and Alisma\u00a0plantago-aquatica. Alismatis rhizome (Ze xie in Chinese, Takusha in Japanese, and Taeksa in Korean, AR), the tubers of medicinal plants from Alisma species, have long been used to treat inflammatory diseases, hyperlipidemia, diabetes, bacterial infection, edema, oliguria, diarrhea, and dizziness. Recent evidence has demonstrated that its extract showed pharmacological activities to effectively reverse cancer-related molecular targets. In particular, triterpenes naturally isolated from AR have been found to exhibit antitumor activity. This study aimed to describe the biological activities and plausible signaling cascades of AR and its main compounds in experimental models representing cancer-related physiology and pathology. Available in vitro and in vivo studies revealed that AR extract possesses anticancer activity against various cancer cells, and the efficacy might be attributed to the cytotoxic and antimetastatic effects of its alisol compounds, such as alisol A, alisol B, and alisol B 23-acetate. Several beneficial functions of triterpenoids found in AR might be due to p38 activation and inhibition of the phosphatidylinositol 3-kinase (PI3K)\/protein kinase B (Akt)\/mammalian target of rapamycin (mTOR) signaling pathways. Moreover, AR and its triterpenes inhibit the proliferation of cancer cells that are resistant to chemotherapy. Thus, AR and its triterpenes may play potential roles in tumor attack, as well as a therapeutic remedy alone and in combination with other chemotherapeutic drugs.<\/jats:p>","DOI":"10.3390\/nu13072455","type":"journal-article","created":{"date-parts":[[2021,7,18]],"date-time":"2021-07-18T21:18:52Z","timestamp":1626643132000},"page":"2455","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Promising Anticancer Activities of Alismatis rhizome and Its Triterpenes via p38 and PI3K\/Akt\/mTOR Signaling Pathways"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9992-3942","authenticated-orcid":false,"given":"Eungyeong","family":"Jang","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea"},{"name":"Department of Internal Medicine, Kyung Hee University Korean Medicine Hospital, Seoul 02447, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4881-7357","authenticated-orcid":false,"given":"Jang-Hoon","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA A Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.ccr.2007.01.009","article-title":"A radical role for p38 MAPK in tumor initiation","volume":"11","author":"Kennedy","year":"2007","journal-title":"Cancer Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3803","DOI":"10.1200\/JCO.2014.59.0018","article-title":"Inhibition of the PI3K\/AKT\/mTOR pathway in solid tumors","volume":"34","author":"LoRusso","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1158\/1078-0432.CCR-15-1718","article-title":"A first-in-human phase I study of the oral p38 MAPK inhibitor, ralimetinib (LY2228820 Dimesylate), in patients with advanced cancer","volume":"22","author":"Patnaik","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.pharmthera.2013.12.004","article-title":"Molecular targets for cancer therapy in the PI3K\/AKT\/mTOR pathway","volume":"142","author":"Polivka","year":"2014","journal-title":"Pharmacol. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Mart\u00ednez-Lim\u00f3n, A., Joaquin, M., Caballero, M., Posas, F., and de Nadal, E. (2020). The p38 pathway: From biology to cancer therapy. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21061913"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"302426","DOI":"10.1155\/2013\/302426","article-title":"Therapeutic applications of herbal medicines for cancer patients","volume":"2013","author":"Yin","year":"2013","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.1517\/13543784.2012.727395","article-title":"Terpenoids: Natural products for cancer therapy","volume":"21","author":"Huang","year":"2012","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1872","DOI":"10.1002\/ptr.6933","article-title":"Alisma genus: Phytochemical constituents, biosynthesis, and biological activities","volume":"35","author":"Feng","year":"2021","journal-title":"Phytother. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"415097","DOI":"10.1155\/2014\/415097","article-title":"Ethanol extract of Alismatis rhizome inhibits adipocyte differentiation of OP9 cells","volume":"2014","author":"Park","year":"2014","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"363","DOI":"10.3389\/fchem.2020.00363","article-title":"Triterpenoids from Alisma species: Phytochemistry, structure modification, and bioactivities","volume":"8","author":"Wang","year":"2020","journal-title":"Front. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1097\/CAD.0b013e328330fd90","article-title":"Triterpenoids as new promising anticancer drugs","volume":"20","author":"Petronelli","year":"2009","journal-title":"Anti Cancer Drugs"},{"key":"ref_13","first-page":"16","article-title":"Anti-cancer effects of triterpenoids isolated form Alismatis rhizoma on HepG2 cells","volume":"34","author":"Xu","year":"2013","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.phytochem.2016.08.015","article-title":"Structures and biological activities of the triterpenoids and sesquiterpenoids from Alisma orientale","volume":"131","author":"Ma","year":"2016","journal-title":"Phytochemistry"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"80","DOI":"10.4161\/auto.2.2.2460","article-title":"Autophagy, mitochondrial quality control, and oncogenesis","volume":"2","author":"Jin","year":"2006","journal-title":"Autophagy"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2155","DOI":"10.7150\/ijms.55212","article-title":"Alisma canaliculatum Extract Affects AGS Gastric Cancer Cells by Inducing Apoptosis","volume":"18","author":"Kwon","year":"2021","journal-title":"Int. J. Med. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Choi, J., Ahn, S.S., Lim, Y., Lee, Y.H., and Shin, S.Y. (2018). Inhibitory effect of Alisma canaliculatum ethanolic extract on NF-\u03baB-dependent CXCR3 and CXCL10 expression in TNF\u03b1-exposed MDA-MB-231 breast cancer cells. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19092607"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Lou, C., Xu, X., Chen, Y., and Zhao, H. (2019). Alisol A suppresses proliferation, migration, and invasion in human breast cancer MDA-MB-231 cells. Molecules, 24.","DOI":"10.3390\/molecules24203651"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.3892\/or.2020.7654","article-title":"Alisol A is potentially therapeutic in human breast cancer cells","volume":"44","author":"Shi","year":"2020","journal-title":"Oncol. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1016\/j.ijbiomac.2018.05.158","article-title":"Study on antitumor molecular mechanism of Alisols based on p53DNA","volume":"116","author":"Xu","year":"2018","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1158\/1535-7163.MCT-09-0700","article-title":"Alisol B, a novel inhibitor of the sarcoplasmic\/endoplasmic reticulum Ca2+ ATPase pump, induces autophagy, endoplasmic reticulum stress, and apoptosis","volume":"9","author":"Law","year":"2010","journal-title":"Mol. Cancer Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.biopha.2016.12.088","article-title":"Antiproliferative activity of Alisol B in MDA-MB-231 cells is mediated by apoptosis, dysregulation of mitochondrial functions, cell cycle arrest and generation of reactive oxygen species","volume":"87","author":"Zhang","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/S0928-0987(03)00144-1","article-title":"Pharmacological evaluation of several major ingredients of Chinese herbal medicines in human hepatoma Hep3B cells","volume":"19","author":"Chou","year":"2003","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2870","DOI":"10.3748\/wjg.15.2870","article-title":"Alisol B acetate induces apoptosis of SGC7901 cells via mitochondrial and phosphatidylinositol 3-kinases\/Akt signaling pathways","volume":"15","author":"Xu","year":"2009","journal-title":"World J. Gastroenterol. WJG"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.canlet.2005.02.011","article-title":"Alisol B acetate, a triterpene from Alismatis rhizoma, induces Bax nuclear translocation and apoptosis in human hormone-resistant prostate cancer PC-3 cells","volume":"231","author":"Huang","year":"2006","journal-title":"Cancer Lett."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Kwon, M.J., Kim, J.N., Lee, M.J., Kim, W.K., Nam, J.H., and Kim, B.J. (2021). Apoptotic effects of alisol B 23-acetate on gastric cancer cells. Mol. Med. Rep., 23.","DOI":"10.3892\/mmr.2021.11887"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1016\/j.bbrc.2018.10.022","article-title":"Alisol B-23-acetate, a tetracyclic triterpenoid isolated from Alisma orientale, induces apoptosis in human lung cancer cells via the mitochondrial pathway","volume":"505","author":"Wang","year":"2018","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_28","first-page":"1187","article-title":"Alisol B 23-acetate inhibits the viability and induces apoptosis of non-small cell lung cancer cells via PI3K\/AKT\/mTOR signal pathway","volume":"20","author":"Liu","year":"2019","journal-title":"Mol. Med. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"375","DOI":"10.21147\/j.issn.1000-9604.2019.02.12","article-title":"Alisol B 23-acetate-induced HepG2 hepatoma cell death through mTOR signaling-initiated G1 cell cycle arrest and apoptosis: A quantitative proteomic study","volume":"31","author":"Xia","year":"2019","journal-title":"Chin. J. Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"219","DOI":"10.4149\/gpb_2020005","article-title":"The effects of Alisol B 23-acetate in hepatocellular carcinoma via inducing cell apoptosis and inhibiting cell migration and invasion","volume":"39","author":"Li","year":"2020","journal-title":"Gen. Physiol. Biophys."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"228","DOI":"10.2174\/1871520614666140601213514","article-title":"Anti-proliferative activities of terpenoids isolated from Alisma orientalis and their structure-activity relationships","volume":"15","author":"Xu","year":"2015","journal-title":"Anti Cancer Agents Med. Chem."},{"key":"ref_32","first-page":"1041","article-title":"Activation of p34cdc2 coincident with taxol-induced apoptosis","volume":"5","author":"Donaldson","year":"1994","journal-title":"Cell Growth Differ."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"800","DOI":"10.1016\/j.phymed.2016.04.003","article-title":"Effects of alisol B 23-acetate on ovarian cancer cells: G1 phase cell cycle arrest, apoptosis, migration and invasion inhibition","volume":"23","author":"Zhang","year":"2016","journal-title":"Phytomedicine"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3242989","DOI":"10.1155\/2019\/3242989","article-title":"Network pharmacology-based study on the mechanism of Bushen-Jianpi decoction in liver cancer treatment","volume":"2019","author":"Wu","year":"2019","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1007\/BF02975158","article-title":"Cytotoxic triterpenoides from Alismatis rhizoma","volume":"24","author":"Lee","year":"2001","journal-title":"Arch. Pharmacal Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1554","DOI":"10.1016\/j.procbio.2011.04.007","article-title":"A novel lectin from fresh rhizome of Alisma orientale (Sam.) Juzep","volume":"46","author":"Shao","year":"2011","journal-title":"Process Biochem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/S0014-2999(01)00983-9","article-title":"Effect of alisol B acetate, a plant triterpene, on apoptosis in vascular smooth muscle cells and lymphocytes","volume":"419","author":"Chen","year":"2001","journal-title":"Eur. J. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"70239","DOI":"10.18632\/oncotarget.19605","article-title":"Alisol B 23-acetate induces autophagic-dependent apoptosis in human colon cancer cells via ROS generation and JNK activation","volume":"8","author":"Zhao","year":"2017","journal-title":"Oncotarget"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.cell.2011.09.024","article-title":"Tumor metastasis: Molecular insights and evolving paradigms","volume":"147","author":"Valastyan","year":"2011","journal-title":"Cell"},{"key":"ref_40","first-page":"1","article-title":"Molecular principles of metastasis: A hallmark of cancer revisited","volume":"5","author":"Fares","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_41","first-page":"743","article-title":"Inhibitory effect of Alisma orientalis on spontaneous metastasis of Lewis lung carcinoma and its mechanism","volume":"34","author":"Ma","year":"2003","journal-title":"Chin. Tradit. Drug"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Pires, B.R., Mencalha, A.L., Ferreira, G.M., de Souza, W.F., Morgado-D\u00edaz, J.A., Maia, A.M., Corr\u00eaa, S., and Abdelhay, E.S. (2017). NF-kappaB is involved in the regulation of EMT genes in breast cancer cells. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0169622"},{"key":"ref_43","first-page":"351","article-title":"Paradoxical effects of chemotherapy on tumor relapse and metastasis promotion","volume":"60","author":"Scala","year":"2019","journal-title":"Semin. Cancer Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1177\/107327480301000207","article-title":"Overcoming multidrug resistance in cancer: An update on the clinical strategy of inhibiting p-glycoprotein","volume":"10","author":"Thomas","year":"2003","journal-title":"Cancer Control"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"476974","DOI":"10.1155\/2014\/476974","article-title":"Regulations of P-glycoprotein\/ABCB1\/MDR1 in human cancer cells","volume":"2014","author":"Katayama","year":"2014","journal-title":"New J. Sci."},{"key":"ref_46","first-page":"242","article-title":"Recurrence after surgery in patients with NSCLC","volume":"3","author":"Uramoto","year":"2014","journal-title":"Transl. Lung Cancer Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"9545","DOI":"10.3390\/ijms13089545","article-title":"Implication of tumor microenvironment in chemoresistance: Tumor-associated stromal cells protect tumor cells from cell death","volume":"13","author":"Castells","year":"2012","journal-title":"Int. J. Mol. Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1111\/j.1365-2141.2011.08752.x","article-title":"Early UK experience in the use of clofarabine in the treatment of relapsed and refractory paediatric acute lymphoblastic leukaemia","volume":"154","author":"Sibson","year":"2011","journal-title":"Br. J. Haematol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.phymed.2006.03.004","article-title":"Reversal of multidrug resistance in cancer cells by Rhizoma Alismatis extract","volume":"14","author":"Fong","year":"2007","journal-title":"Phytomedicine"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1016\/j.bcp.2004.05.021","article-title":"Reversal of P-glycoprotein-mediated multidrug resistance by Alisol B 23-acetate","volume":"68","author":"Wang","year":"2004","journal-title":"Biochem. Pharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Pan, G., Li, T., Zeng, Q., Wang, X., and Zhu, Y. (2016). Alisol F 24 acetate enhances chemosensitivity and apoptosis of MCF-7\/DOX Cells by inhibiting P-glycoprotein-mediated drug efflux. Molecules, 21.","DOI":"10.3390\/molecules21020183"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1016\/j.bbamcr.2007.03.010","article-title":"p38 MAP-kinases pathway regulation, function and role in human diseases","volume":"1773","author":"Cuenda","year":"2007","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_53","first-page":"1601","article-title":"Plumbagin induces G2\/M arrest, apoptosis, and autophagy via p38 MAPK-and PI3K\/Akt\/mTOR-mediated pathways in human tongue squamous cell carcinoma cells","volume":"9","author":"Pan","year":"2015","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.tibs.2014.04.004","article-title":"Emerging roles of the p38 MAPK and PI3K\/AKT\/mTOR pathways in oncogene-induced senescence","volume":"39","author":"Xu","year":"2014","journal-title":"Trends Biochem. Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1158\/0008-5472.CAN-18-2738","article-title":"AKT as a therapeutic target for cancer","volume":"79","author":"Song","year":"2019","journal-title":"Cancer Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1111\/j.1600-065X.2012.01099.x","article-title":"NF-\u03baB and the link between inflammation and cancer","volume":"246","author":"DiDonato","year":"2012","journal-title":"Immunol. Rev."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"4798","DOI":"10.1038\/sj.onc.1209608","article-title":"Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy","volume":"25","author":"Fulda","year":"2006","journal-title":"Oncogene"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"143","DOI":"10.3389\/fphar.2021.628690","article-title":"Activation of PI3K\/AKT\/mTOR Pathway Causes Drug Resistance in Breast Cancer","volume":"12","author":"Dong","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1898","DOI":"10.1038\/s12276-020-00527-1","article-title":"Hepatocellular carcinoma: Old friends and new tricks","volume":"52","author":"Kim","year":"2020","journal-title":"Exp. Mol. Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"601710","DOI":"10.3389\/fonc.2020.601710","article-title":"Etiology of Hepatocellular Carcinoma: Special Focus on Fatty Liver Disease","volume":"10","author":"Suresh","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2943162","DOI":"10.1155\/2019\/2943162","article-title":"Pharmacological activities of Alisma orientale against nonalcoholic fatty liver disease and metabolic syndrome: Literature review","volume":"2019","author":"Choi","year":"2019","journal-title":"Evid. Based Complement. Altern. Med."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/13\/7\/2455\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:31:29Z","timestamp":1760164289000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/13\/7\/2455"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,18]]},"references-count":61,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["nu13072455"],"URL":"https:\/\/doi.org\/10.3390\/nu13072455","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,18]]}}}