Remodeling the homeostasis of pro- and anti-angiogenic factors by Shenmai injection to normalize tumor vasculature for enhanced cancer chemotherapy.
Angiogenesis Inhibitors
/ administration & dosage
Angiostatins
/ biosynthesis
Animals
Antineoplastic Combined Chemotherapy Protocols
/ administration & dosage
Colorectal Neoplasms
/ drug therapy
Combined Modality Therapy
Drug Combinations
Drugs, Chinese Herbal
/ administration & dosage
Fluorouracil
/ administration & dosage
Histones
/ antagonists & inhibitors
Homeostasis
/ drug effects
Human Umbilical Vein Endothelial Cells
Humans
Male
Mice, Inbred BALB C
Mice, Nude
Neovascularization, Pathologic
/ drug therapy
Plasminogen Activator Inhibitor 1
/ genetics
Receptors, Fibroblast Growth Factor
/ genetics
Treatment Outcome
Tumor Microenvironment
/ drug effects
Vascular Endothelial Growth Factor A
/ genetics
Xenograft Model Antitumor Assays
Angiogenic factors
Angiostatin
Combined therapy
Histone H3 acetylation
Normalization of tumor vessels
Shenmai injection
Journal
Journal of ethnopharmacology
ISSN: 1872-7573
Titre abrégé: J Ethnopharmacol
Pays: Ireland
ID NLM: 7903310
Informations de publication
Date de publication:
24 Apr 2021
24 Apr 2021
Historique:
received:
27
10
2020
revised:
18
12
2020
accepted:
24
12
2020
pubmed:
4
1
2021
medline:
4
8
2021
entrez:
3
1
2021
Statut:
ppublish
Résumé
Normalization of the tumor vasculature can enhance tumor perfusion and the microenvironment, leading to chemotherapy potentiation. Shenmai injection (SMI) is a widely used traditional Chinese herbal medicine for the combination treatment of cancer in China. This study aimed to investigate whether SMI can regulate tumor vasculature to improve chemotherapy efficacy and identify the underlying mechanism. The antitumor effect of SMI combined with 5-florouracil (5-FU) was investigated in xenograft tumor mice. Two-photon microscopy, laser speckle contrast imaging and immunofluorescence staining were used to investigate the effects of SMI on tumor vasculature in vivo. The mRNA and protein expression of pro- and anti-angiogenic factors were measured by Q-PCR and ELISA. Histone acetylation and transcriptional regulation were detected by Western blot and ChIP assay. SMI promoted normalization of tumor microvessels within a certain time window, which was accompanied by enhanced blood perfusion and 5-FU distribution in tumors. SMI significantly increased the expression of antiangiogenic factor angiostatin and decreased the pro-angiogenic factors VEGF, FGF and PAI-1 by day 10. SMI combined with neoadjuvant chemotherapy in colorectal cancer patients also showed a significant increase in angiostatin and decrease in VEGF and FGF in surgically resected tumors when compared to the neoadjuvant chemotherapy group. Further in vitro and in vivo studies revealed that SMI downregulated VEGF, FGF and PAI-1 mRNA expression by inhibiting histone H3 acetylation at the promoter regions. The enhanced production of angiostatin was attributed to the regulation of the plasminogen proteolysis system via SMI-induced PAI-1 inhibition. SMI can remodel the homeostasis of pro- and anti-angiogenic factors to promote tumor vessel normalization, and thus enhance drug delivery and anti-tumor effect. This study provides additional insights into the pharmacological mechanisms of SMI on tumors from the perspective of vascular regulation.
Identifiants
pubmed: 33388426
pii: S0378-8741(20)33658-8
doi: 10.1016/j.jep.2020.113770
pii:
doi:
Substances chimiques
Angiogenesis Inhibitors
0
Drug Combinations
0
Drugs, Chinese Herbal
0
Histones
0
Plasminogen Activator Inhibitor 1
0
Receptors, Fibroblast Growth Factor
0
SERPINE1 protein, human
0
VEGFA protein, human
0
Vascular Endothelial Growth Factor A
0
fructus schizandrae, radix ginseng, radix ophiopogonis drug combination
0
Angiostatins
86090-08-6
Fluorouracil
U3P01618RT
Types de publication
Journal Article
Randomized Controlled Trial
Langues
eng
Sous-ensembles de citation
IM
Pagination
113770Informations de copyright
Copyright © 2021 Elsevier B.V. All rights reserved.