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ORIGINAL RESEARCH article

Front. Oncol.
Sec. Gastrointestinal Cancers: Hepato Pancreatic Biliary Cancers
Volume 14 - 2024 | doi: 10.3389/fonc.2024.1454291
This article is part of the Research Topic The Growing Role of Immunotherapy and Combination Strategies in Pancreatic and Hepatobiliary Cancers View all 5 articles

Prolonged survival by combination treatment of a standardized herbal extract from Japanese Kampo-Medicine (Juzentaihoto) and Gemcitabine in an orthotopic transplantation pancreatic cancer model

Provisionally accepted
Joanna Napp Joanna Napp 1Paulina Siebel Paulina Siebel 2Hans Rausch Hans Rausch 3Kenny Kuchta Kenny Kuchta 4Thomas Efferth Thomas Efferth 5Frauke Alves Frauke Alves 6Volker Ellenrieder Volker Ellenrieder 7Silke Cameron Silke Cameron 2*
  • 1 Institute for Diagnostic and Interventional Radiology, University Medical Center Göttingen, Translational Molecular Imaging, Max-Planck-Institute for Multidisciplinary Sciences, Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Goettingen, Germany
  • 2 Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Goettingen, Germany
  • 3 Phytochem Reference Substances, Neu-Ulm, Germany
  • 4 Independent researcher, Göttingen, Germany
  • 5 Institute for Pharmaceutical and Biomedical Science, Faculty of Chemistry, Pharmacy, Geography and Geosciences, Johannes Gutenberg University Mainz, Mainz, Rhineland-Palatinate, Germany
  • 6 Translational Molecular Imaging, Max-Planck-Institute for Multidisciplinary Sciences, Department of Haematology and Medical Oncology, University Medical Center Göttingen, Institute for Diagnostic and Interventional Radiology, University Medical Center Goettingen, Goettingen, Lower Saxony, Germany
  • 7 Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Göttingen, Germany

The final, formatted version of the article will be published soon.

    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 ±12 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 / Juztreated animals, compared with controls (p < 0,001), with significant increases of both, macrophages (CD68+) and lymphocytes (CD45+), especially at the tumor front. In vitro, 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-α, 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-microenvironmentinduced by Juzentaihoto -such as an increased number of M1 macrophages.

    Keywords: Kampo medicine, juzentaihoto, gemcitabine, Pancreatic ductal adenocarcinoma (PDAC), orthotopic transplantation PDAC mouse model, murine KPC pancreatic tumor cells, Macrophages, Tumor Microenvironment

    Received: 24 Jun 2024; Accepted: 13 Nov 2024.

    Copyright: © 2024 Napp, Siebel, Rausch, Kuchta, Efferth, Alves, Ellenrieder and Cameron. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Silke Cameron, Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Goettingen, Germany

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