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He-Wei Granule enhances anti-tumor activity of cyclophosphamide by changing tumor microenvironment

OBJECTIVE: He-Wei Granule (HWKL) is a modern product derived from the modified formulation of traditional Chinese medicine Banxia Xiexin Decoction (BXD), which remarkedly enhanced the anti-proliferation activity of cyclophosphamide (CTX) on HepG2 and SGC-7901 cell lines in vitro in our previous rese...

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Autores principales: Zhai, Jianxiu, Song, Zehai, Chang, Hang, Wang, Yuwei, Han, Na, Liu, Zhihui, Yin, Jun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9476702/
https://www.ncbi.nlm.nih.gov/pubmed/36120121
http://dx.doi.org/10.1016/j.chmed.2021.10.002
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author Zhai, Jianxiu
Song, Zehai
Chang, Hang
Wang, Yuwei
Han, Na
Liu, Zhihui
Yin, Jun
author_facet Zhai, Jianxiu
Song, Zehai
Chang, Hang
Wang, Yuwei
Han, Na
Liu, Zhihui
Yin, Jun
author_sort Zhai, Jianxiu
collection PubMed
description OBJECTIVE: He-Wei Granule (HWKL) is a modern product derived from the modified formulation of traditional Chinese medicine Banxia Xiexin Decoction (BXD), which remarkedly enhanced the anti-proliferation activity of cyclophosphamide (CTX) on HepG2 and SGC-7901 cell lines in vitro in our previous research. The aim of the study was to investigate the synergistic effects of HWKL and CTX using a transplanted H22 hepatocellular carcinoma mouse model. METHODS: The CTX-toxic-reducing efficacy of HWKL was evaluated by hematology indexes, organ indexes and marrow DNA detection. To investigate the underlying mechanisms, histopathology test, immunohistochemistry test and TUNEL staining were conducted. The efficacy of HWKL on the micro-vessel density (MVD) in tumor tissue was also evaluated by measuring CD34 level. RESULTS: High dose HWKL (6.75 g/kg) markedly attenuated CTX-induced hepatotoxicity and myelosuppression while significantly enhanced CTX anticancer efficacy in vivo. Further mechanism investigation suggested that high dose HWKL significantly increased cleaved Caspase 3 level and promoted apoptosis in tumor tissue by up-regulating Bax expression and down-regulating Bcl-2 and FasL expressions. Compared with CTX alone group, the decrease in LC-3B and Beclin 1 levels suggested that the autophagy in H22 carcinoma was significantly inhibited with addition of high dose HWKL. ELISA assay results indicated that the autophagy inhibition was achieved by decreasing p53 expression, blocking PI3K/AKT/mTOR pathway and recovering Th1/Th2 cytokine balance. In addition, CD34 and EGFR immunohistochemistry assay suggest that high dose HWKL could significantly decrease micro-vessel density (MVD) and inhibit angiogenesis in H22 carcinoma. CONCLUSION: It can be concluded that high-dose HWKL enhanced CTX efficacy by promoting apoptosis, inhibiting autophagy and angiogenesis in tumor tissue while significantly alleviated CTX-induced toxicity, and could be applied along with CTX in clinical treatment as a supplement agent.
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spelling pubmed-94767022022-09-16 He-Wei Granule enhances anti-tumor activity of cyclophosphamide by changing tumor microenvironment Zhai, Jianxiu Song, Zehai Chang, Hang Wang, Yuwei Han, Na Liu, Zhihui Yin, Jun Chin Herb Med Original Article OBJECTIVE: He-Wei Granule (HWKL) is a modern product derived from the modified formulation of traditional Chinese medicine Banxia Xiexin Decoction (BXD), which remarkedly enhanced the anti-proliferation activity of cyclophosphamide (CTX) on HepG2 and SGC-7901 cell lines in vitro in our previous research. The aim of the study was to investigate the synergistic effects of HWKL and CTX using a transplanted H22 hepatocellular carcinoma mouse model. METHODS: The CTX-toxic-reducing efficacy of HWKL was evaluated by hematology indexes, organ indexes and marrow DNA detection. To investigate the underlying mechanisms, histopathology test, immunohistochemistry test and TUNEL staining were conducted. The efficacy of HWKL on the micro-vessel density (MVD) in tumor tissue was also evaluated by measuring CD34 level. RESULTS: High dose HWKL (6.75 g/kg) markedly attenuated CTX-induced hepatotoxicity and myelosuppression while significantly enhanced CTX anticancer efficacy in vivo. Further mechanism investigation suggested that high dose HWKL significantly increased cleaved Caspase 3 level and promoted apoptosis in tumor tissue by up-regulating Bax expression and down-regulating Bcl-2 and FasL expressions. Compared with CTX alone group, the decrease in LC-3B and Beclin 1 levels suggested that the autophagy in H22 carcinoma was significantly inhibited with addition of high dose HWKL. ELISA assay results indicated that the autophagy inhibition was achieved by decreasing p53 expression, blocking PI3K/AKT/mTOR pathway and recovering Th1/Th2 cytokine balance. In addition, CD34 and EGFR immunohistochemistry assay suggest that high dose HWKL could significantly decrease micro-vessel density (MVD) and inhibit angiogenesis in H22 carcinoma. CONCLUSION: It can be concluded that high-dose HWKL enhanced CTX efficacy by promoting apoptosis, inhibiting autophagy and angiogenesis in tumor tissue while significantly alleviated CTX-induced toxicity, and could be applied along with CTX in clinical treatment as a supplement agent. Elsevier 2021-10-07 /pmc/articles/PMC9476702/ /pubmed/36120121 http://dx.doi.org/10.1016/j.chmed.2021.10.002 Text en © 2021 Tianjin Press of Chinese Herbal Medicines. Published by ELSEVIER B.V.se Herbal Medicines. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Zhai, Jianxiu
Song, Zehai
Chang, Hang
Wang, Yuwei
Han, Na
Liu, Zhihui
Yin, Jun
He-Wei Granule enhances anti-tumor activity of cyclophosphamide by changing tumor microenvironment
title He-Wei Granule enhances anti-tumor activity of cyclophosphamide by changing tumor microenvironment
title_full He-Wei Granule enhances anti-tumor activity of cyclophosphamide by changing tumor microenvironment
title_fullStr He-Wei Granule enhances anti-tumor activity of cyclophosphamide by changing tumor microenvironment
title_full_unstemmed He-Wei Granule enhances anti-tumor activity of cyclophosphamide by changing tumor microenvironment
title_short He-Wei Granule enhances anti-tumor activity of cyclophosphamide by changing tumor microenvironment
title_sort he-wei granule enhances anti-tumor activity of cyclophosphamide by changing tumor microenvironment
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9476702/
https://www.ncbi.nlm.nih.gov/pubmed/36120121
http://dx.doi.org/10.1016/j.chmed.2021.10.002
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