{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T19:23:15Z","timestamp":1791228195532,"version":"4.1.0"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,12,11]],"date-time":"2024-12-11T00:00:00Z","timestamp":1733875200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>Pancreatic ductal adenocarcinoma (PDAC) is characterized by its poor prognosis. Traditional Japanese herbal medicine (Kampo), such as Juzentaihoto (a standardized combination of 10 herbal extracts), has shown immune modulatory effects, modulation of microcirculation, and amelioration of fatigue. It is administered to patients to prevent deterioration of cachexia and counteract side effects of chemotherapy. The effect of Juzentaihoto with or without standard chemotherapy (Gemcitabine) on survival and tumor microenvironment was studied in an immunocompetent pancreatic cancer mouse model. Following tumor development \u00b112 days after orthotopic implantation of murine pancreatic cancer cells (KPC) into the pancreas of C57BL\/6 mice, the mice were treated with Gemcitabine, Juzentaihoto, their combination (Gem\/Juz) or NaCl (Ctr.). Combination treatment significantly prolonged survival (+38%) of tumor bearing mice, compared to controls as well as Gemcitabine or Juzentaihoto monotherapy. Macrophage (CD68+) infiltration in pancreatic tumors was significantly enhanced in Gem\/Juz \u2013 treated animals, compared with controls (p &amp;lt; 0,001), with significant increases of both, macrophages (CD68+) and for lymphocytes (CD45+), especially at the tumor front. <jats:italic>In vitro<\/jats:italic>, Juz- or Gem\/Juz-treated KPC tumor cells secreted significantly more macrophage-chemoattractant cytokines, e.g., CCL2, CCL20, and CXCL2, whilst Juz- and Gem\/Juz-treated macrophages (MH-S) secreted cytokines of the M1 phenotype, e.g., IL6, TNF-\u03b1, and IL12. It has been shown that tumor cells recruit and polarize macrophages towards tumor-associated macrophages (TAM). Our results indicate a change in macrophage polarization which not only induced anti-tumor immune-cell activity and cytokine release, but also suggests amelioration of Gemcitabine efficacy as DNA-analogue and as partial antitumor antigen. We propose that the increased survival of tumor bearing mice after Gem\/Juz combination treatment is due to the restored cytotoxicity of Gemcitabine and changes in the tumor-microenvironment - induced by Juzentaihoto - such as an increased number of M1 macrophages.<\/jats:p>","DOI":"10.3389\/fonc.2024.1454291","type":"journal-article","created":{"date-parts":[[2024,12,11]],"date-time":"2024-12-11T12:23:05Z","timestamp":1733919785000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Prolonged survival by combination treatment with a standardized herbal extract from Japanese Kampo-medicine (Juzentaihoto) and gemcitabine in an orthotopic transplantation pancreatic cancer model"],"prefix":"10.3389","volume":"14","author":[{"given":"Joanna","family":"Napp","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paulina","family":"Siebel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans","family":"Rausch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenny","family":"Kuchta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Efferth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frauke","family":"Alves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Volker","family":"Ellenrieder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silke","family":"Cameron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,12,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21387","article-title":"Cancer statistics, 2017","volume":"67","author":"Siegel","year":"2017","journal-title":"CA: A Cancer J Clin"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.14951","article-title":"The landscape of pancreatic cancer therapeutic resistance mechanisms","volume":"12","author":"Chand","year":"2016","journal-title":"Int J Biol Sci"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2012.11.037","article-title":"A starring role for stellate cells in the pancreatic cancer microenvironment","volume":"144","author":"Apte","year":"2013","journal-title":"Gastroenterology"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2015.11.049","article-title":"Macrophages and pancreatic ductal adenocarcinoma","volume":"381","author":"Habtezion","year":"2016","journal-title":"Cancer Lett"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.28736","article-title":"Tumor-associated macrophages exhibit pro- and anti-inflammatory properties by which they impact on pancreatic tumorigenesis: Role of macrophages in pancreatic cancer","volume":"135","author":"Helm","year":"2014","journal-title":"Int J Cancer"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.00917","article-title":"Phytotherapy for cachexia: where do we stand","volume":"11","author":"Kuchta","year":"2020","journal-title":"Front Pharmacol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.imr.2022.100839","article-title":"Kampo medicines for supportive care of patients with cancer: A brief review","volume":"11","author":"Motoo","year":"2022","journal-title":"Integr Med Res"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.5582\/ddt.2012.v6.1.1","article-title":"Evidence-based research on traditional Japanese medicine, Kampo, in treatment of gastrointestinal cancer in Japan","volume":"6","author":"Gao","year":"2012","journal-title":"Drug Discovery Ther"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-014-2440-x","article-title":"Double-blind, placebo-controlled, randomized phase II study of TJ-14 (hangeshashinto) for gastric cancer chemotherapy-induced oral mucositis","volume":"73","author":"Aoyama","year":"2014","journal-title":"Cancer Chemother Pharmacol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1007\/s11418-016-0989-x","article-title":"Anticancer effect of a Kampo preparation Daikenchuto","volume":"70","author":"Nagata","year":"2016","journal-title":"J Nat Med"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1007\/s10147-013-0529-6","article-title":"Changes of Immunological parameters with administration of Japanese Kampo medicine (Juzen-Taihoto\/TJ-48) in patients with advanced pancreatic cancer","volume":"19","author":"Ikemoto","year":"2014","journal-title":"Int J Clin Oncol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2012\/957082","article-title":"First nationwide attitude survey of Japanese physicians on the use of traditional Japanese medicine (Kampo) in cancer treatment","volume":"2012","author":"Ito","year":"2012","journal-title":"Evidence-Based Complementary Altern Med"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.npep.2021.102188","article-title":"Application of Kampo medicines for the palliation of cancer cachexia","volume":"90","author":"Ohsawa","year":"2021","journal-title":"Neuropeptides"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1186\/1751-0759-8-6","article-title":"Kampo medicine for palliative care in Japan","volume":"8","author":"Okumi","year":"2014","journal-title":"BioPsychoSocial Med"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3389\/fnut.2021.702812","article-title":"Kampo medicine treatment for advanced pancreatic cancer: A case series","volume":"8","author":"Shimizu","year":"2021","journal-title":"Front Nutr"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2013\/981717","article-title":"Juzentaihoto Failed to Augment Antigen-Specific Immunity but Prevented Deterioration of Patients\u2019 Conditions in Advanced Pancreatic Cancer under Personalized Peptide Vaccine","volume":"2013","author":"Yutani","year":"2013","journal-title":"Evidence-Based Complementary Altern Med"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1055\/a-0625-7414","article-title":"Kampo-Medizin in der gastrointestinalen Onkologie","volume":"10","author":"Cameron","year":"2018","journal-title":"Z F\u00fcr Komplement\u00e4rmedizin"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1186\/1472-6882-12-118","article-title":"Protective effect of the Japanese trad med Juz on myelosuppression induced by the anticancer drug TS-1 and identification of a potential biomarker of this effect","volume":"12","author":"Ogawa","year":"2012","journal-title":"BMC Complement Altern Med"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/ecam\/nen081","article-title":"Suppressive effect of juzen-taiho-to on lung metastasis of B16 melanoma cells in vivo","volume":"2011","author":"Matsuda","year":"2011","journal-title":"Evidence-Based Complementary Altern Med"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1111\/j.1349-7006.1998.tb00550.x","article-title":"Oral administration of a kampo (Japanese herbal) medicine juzen-taiho-to inhibits liver metastasis of colon 26-L5 carcinoma cells","volume":"89","author":"Ohnishi","year":"1998","journal-title":"Japanese J Cancer Res"},{"key":"B21","volume-title":"Leitfaden Kampo-Medizin \u2013 JAPANische Phytotherapie","author":"Eberhard","year":"2003"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2013\/570848","article-title":"Role of Kampo medicine in integrative cancer therapy","volume":"570848","author":"Yamakawa","year":"2013","journal-title":"Evid Based Complement Alternat Med"},{"key":"B23","first-page":"115ff","article-title":"The Search for Active Ingredients of Juzen-taiho-to","volume-title":"Juzentaihoto (","author":"Kiyohara","year":"2005"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2005.04.023","article-title":"Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice","volume":"7","author":"Hingorani","year":"2005","journal-title":"Cancer Cell"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1002\/jlb.46.2.119","article-title":"MH-S, a murine alveolar macrophage cell line: morphological, cytochemical, and functional characteristics","volume":"46","author":"Mbawuike","year":"1989","journal-title":"J Leukocyte Biol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: an open-source platform for biological-image analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat Methods"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3791\/56979","article-title":"Utilizing high resolution ultrasound to monitor tumor onset and growth in genetically engineered pancreatic cancer models","volume":"56979","author":"Goetze","year":"2018","journal-title":"JoVE"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexmp.2011.11.007","article-title":"Radiation-induced damage in different segments of the rat intestine after external beam irradiation of the liver","volume":"92","author":"Cameron","year":"2012","journal-title":"Exp Mol Pathol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.bcp.2016.01.014","article-title":"Interactions of human P-glycoprotein transport substrates and inhibitors at the drug binding domain: Functional and molecular docking analyses","volume":"104","author":"Kadioglu","year":"2016","journal-title":"Biochem Pharmacol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1286","DOI":"10.1074\/jbc.M113.471060","article-title":"A machine learning-based prediction platform for P-glycoprotein modulators and its validation by molecular docking","volume":"8","author":"Kadioglu","year":"2019","journal-title":"Cells"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.471060","article-title":"CD163 Binding to Haptoglobin-Hemoglobin Complexes Involves a Dual-point Electrostatic Receptor-Ligand Pairing","volume":"288","author":"Nielsen","year":"2013","journal-title":"J Biol Chem"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19103217","article-title":"The role of chemokines in wound healing","volume":"19","author":"Ridiandries","year":"2018","journal-title":"IJMS"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.21873\/anticanres.14355","article-title":"FOLFIRINOX versus gemcitabine-based therapy for pancreatic ductal adenocarcinoma: lessons from patient-derived cell lines","volume":"40","author":"Begg","year":"2020","journal-title":"Anticancer Res"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/nri887","article-title":"NF-\u03baB, chemokine gene transcription and tumour growth","volume":"2","author":"Richmond","year":"2002","journal-title":"Nat Rev Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v20.i11.2979","article-title":"Differential gene expression of chemokines in KRAS and BRAF mutated colorectal cell lines: Role of cytokines","volume":"20","author":"Khan","year":"2014","journal-title":"WJG"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v27.i46.7956","article-title":"T cells in pancreatic cancer stroma","volume":"27","author":"Goulart","year":"2021","journal-title":"WJG"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3390\/cancers16010081","article-title":"Inflammation-associated cytotoxic agents in tumorigenesis","volume":"16","author":"Arnhold","year":"2023","journal-title":"Cancers"},{"key":"B38","first-page":"3563","article-title":"Immune cells in primary and metastatic gastrointestinal stromal tumors (GIST)","volume":"7","author":"Cameron","year":"2014","journal-title":"Int J Clin Exp Pathol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-4005","article-title":"Distinct role of macrophages in different tumor microenvironments","volume":"66","author":"Lewis","year":"2006","journal-title":"Cancer Res"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2004.09.015","article-title":"The chemokine system in diverse forms of macrophage activation and polarization","volume":"25","author":"Mantovani","year":"2004","journal-title":"Trends Immunol"},{"key":"B41","doi-asserted-by":"publisher","first-page":"1390","DOI":"10.1016\/j.cmet.2019.02.001","article-title":"Macrophage-released pyrimidines inhibit gemcitabine therapy in pancreatic cancer","volume":"29","author":"Halbrook","year":"2019","journal-title":"Cell Metab"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2015-309193","article-title":"Dual prognostic significance of tumour-associated macrophages in human pancreatic adenocarcinoma treated or untreated with chemotherapy","volume":"65","author":"Di Caro","year":"2016","journal-title":"Gut"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-06-2073","article-title":"High macrophage infiltration along the tumor front correlates with improved survival in colon cancer","volume":"13","author":"Forssell","year":"2007","journal-title":"Clin Cancer Res"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6605465","article-title":"Pre-treatment with chemotherapy can enhance the antigenicity and immunogenicity of tumours by promoting adaptive immune responses","volume":"102","author":"Liu","year":"2010","journal-title":"Br J Cancer"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1007\/s00432-003-0492-0","article-title":"Increased expression of CEA and MHC class I in colorectal cancer cell lines exposed to chemotherapy drugs","volume":"129","author":"Ohtsukasa","year":"2003","journal-title":"J Cancer Res Clin Oncol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2018.1438107","article-title":"Gemcitabine alters the proteasome composition and immunopeptidome of tumour cells","volume":"7","author":"Gravett","year":"2018","journal-title":"OncoImmunology"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0215(19971114)73:4<556:AID-IJC17>3.0.CO;2-7","article-title":"GM-CSF and B7-1 (CD80) co-stimulatory signals co-operate in the induction of effective anti-tumor immunity in syngeneic mice","volume":"73","author":"Sumimoto","year":"1997","journal-title":"Int J Cancer"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2014.07.001","article-title":"Isoliquiritigenin, a flavonoid from licorice, blocks M2 macrophage polarization in colitis-associated tumorigenesis through downregulating PGE2 and IL-6","volume":"279","author":"Zhao","year":"2014","journal-title":"Toxicol Appl Pharmacol"},{"key":"B49","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2012\/945714","article-title":"Suppressive effect of juzentaihoto on vascularization induced by B16 melanoma cells in vitro and in vivo","volume":"2012","author":"Ishikawa","year":"2012","journal-title":"Evidence-Based Complementary Altern Med"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2024.1454291\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,11]],"date-time":"2024-12-11T12:23:22Z","timestamp":1733919802000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2024.1454291\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,11]]},"references-count":49,"alternative-id":["10.3389\/fonc.2024.1454291"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2024.1454291","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,11]]},"article-number":"1454291"}}