Prolonged survival by combination treatment with a standardized herbal extract from Japanese Kampo-medicine (Juzentaihoto) and gemcitabine in an orthotopic transplantation pancreatic cancer model
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...
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Frontiers Media S.A.
2024-12-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2024.1454291/full |
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| author | Joanna Napp Joanna Napp Joanna Napp Paulina Siebel Hans Rausch Kenny Kuchta Thomas Efferth Frauke Alves Frauke Alves Frauke Alves Volker Ellenrieder Silke Cameron |
| author_facet | Joanna Napp Joanna Napp Joanna Napp Paulina Siebel Hans Rausch Kenny Kuchta Thomas Efferth Frauke Alves Frauke Alves Frauke Alves Volker Ellenrieder Silke Cameron |
| author_sort | Joanna Napp |
| collection | DOAJ |
| description | 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/Juz – treated animals, compared with controls (p < 0,001), with significant increases of both, macrophages (CD68+) and for 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-microenvironment - induced by Juzentaihoto - such as an increased number of M1 macrophages. |
| format | Article |
| id | doaj-art-96cc2359c48944f9bf2c3f4faa247314 |
| institution | Kabale University |
| issn | 2234-943X |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj-art-96cc2359c48944f9bf2c3f4faa2473142024-12-11T10:56:32ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2024-12-011410.3389/fonc.2024.14542911454291Prolonged survival by combination treatment with a standardized herbal extract from Japanese Kampo-medicine (Juzentaihoto) and gemcitabine in an orthotopic transplantation pancreatic cancer modelJoanna Napp0Joanna Napp1Joanna Napp2Paulina Siebel3Hans Rausch4Kenny Kuchta5Thomas Efferth6Frauke Alves7Frauke Alves8Frauke Alves9Volker Ellenrieder10Silke Cameron11Clinic for Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen (UMG), Göttingen, GermanyTranslational Molecular Imaging, Max Planck Institute for Multidisciplinary Sciences (MPI-NAT), Göttingen, GermanyInstitute of Diagnostic and Interventional Radiology, University Medical Center Göttingen (UMG), Göttingen, GermanyClinic for Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen (UMG), Göttingen, GermanyPhytochem Reference Substances, Neu-Ulm, GermanyResearch Unit for Far Eastern Medicine, Department of Vegetation Analysis and Phytodiversity, Albrecht-von-Haller Institute for Plant Sciences, Georg-August-University Göttingen, Göttingen, GermanyInstitute of Pharmaceutical and Biomedical Sciences, Department of Pharmaceutical Biology, Johannes Gutenberg Universität Mainz, Mainz, GermanyTranslational Molecular Imaging, Max Planck Institute for Multidisciplinary Sciences (MPI-NAT), Göttingen, GermanyInstitute of Diagnostic and Interventional Radiology, University Medical Center Göttingen (UMG), Göttingen, GermanyClinic for Hematology and Medical Oncology, University Medical Center Göttingen (UMG), Göttingen, GermanyClinic for Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen (UMG), Göttingen, GermanyClinic for Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen (UMG), Göttingen, GermanyPancreatic 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/Juz – treated animals, compared with controls (p < 0,001), with significant increases of both, macrophages (CD68+) and for 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-microenvironment - induced by Juzentaihoto - such as an increased number of M1 macrophages.https://www.frontiersin.org/articles/10.3389/fonc.2024.1454291/fullKampo medicineJuzentaihotogemcitabinepancreatic ductal adenocarcinoma (PDAC)orthotopic transplantation PDAC mouse modelmurine KPC pancreatic tumor cells |
| spellingShingle | Joanna Napp Joanna Napp Joanna Napp Paulina Siebel Hans Rausch Kenny Kuchta Thomas Efferth Frauke Alves Frauke Alves Frauke Alves Volker Ellenrieder Silke Cameron Prolonged survival by combination treatment with a standardized herbal extract from Japanese Kampo-medicine (Juzentaihoto) and gemcitabine in an orthotopic transplantation pancreatic cancer model Frontiers in Oncology Kampo medicine Juzentaihoto gemcitabine pancreatic ductal adenocarcinoma (PDAC) orthotopic transplantation PDAC mouse model murine KPC pancreatic tumor cells |
| 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 |
| title_full | Prolonged survival by combination treatment with a standardized herbal extract from Japanese Kampo-medicine (Juzentaihoto) and gemcitabine in an orthotopic transplantation pancreatic cancer model |
| title_fullStr | Prolonged survival by combination treatment with a standardized herbal extract from Japanese Kampo-medicine (Juzentaihoto) and gemcitabine in an orthotopic transplantation pancreatic cancer model |
| title_full_unstemmed | Prolonged survival by combination treatment with a standardized herbal extract from Japanese Kampo-medicine (Juzentaihoto) and gemcitabine in an orthotopic transplantation pancreatic cancer model |
| title_short | Prolonged survival by combination treatment with a standardized herbal extract from Japanese Kampo-medicine (Juzentaihoto) and gemcitabine in an orthotopic transplantation pancreatic cancer model |
| title_sort | prolonged survival by combination treatment with a standardized herbal extract from japanese kampo medicine juzentaihoto and gemcitabine in an orthotopic transplantation pancreatic cancer model |
| topic | Kampo medicine Juzentaihoto gemcitabine pancreatic ductal adenocarcinoma (PDAC) orthotopic transplantation PDAC mouse model murine KPC pancreatic tumor cells |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2024.1454291/full |
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