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  3. Remodeling the homeostasis of pro- and anti-angiogenic factors by Shenmai injection to normalize tumor vasculature for enhanced cancer chemotherapy

Remodeling the homeostasis of pro- and anti-angiogenic factors by Shenmai injection to normalize tumor vasculature for enhanced cancer chemotherapy

  • J Ethnopharmacol. 2021 Apr 24;270:113770. doi: 10.1016/j.jep.2020.113770.
Lingge Cheng 1,  Wenyue Liu 2,  Chongjin Zhong 3,  Ping Ni 4,  Suiying Ni 5,  Qizhi Wang 6,  Qixiang Zhang 7,  Jingwei Zhang 8,  Jiali Liu 9,  Meijuan Xu 10,  Xuequan Yao 11,  Xiaobo Cen 12,  Guangji Wang 13,  Chao Jiang 14,  Fang Zhou 15
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: [email protected].
  • 2 State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China; National Chengdu Center for Safety Evaluation of Drugs, State Key Lab of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].
  • 3 State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: [email protected].
  • 4 State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: [email protected].
  • 5 State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: [email protected].
  • 6 State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: [email protected].
  • 7 State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: [email protected].
  • 8 State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: [email protected].
  • 9 State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: [email protected].
  • 10 Department of Clinical Pharmacology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China. Electronic address: [email protected].
  • 11 Department of Digestive Tumor Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China. Electronic address: [email protected].
  • 12 National Chengdu Center for Safety Evaluation of Drugs, State Key Lab of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].
  • 13 State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: [email protected].
  • 14 Department of Digestive Tumor Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China. Electronic address: [email protected].
  • 15 State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: [email protected].
PMID: 33388426 DOI: 10.1016/j.jep.2020.113770
Abstract

Ethnopharmacological relevance: 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.

Aim of this study: This study aimed to investigate whether SMI can regulate tumor vasculature to improve chemotherapy efficacy and identify the underlying mechanism.

Materials and methods: 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.

Results: 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.

Conclusion: 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.

Keywords

Angiogenic factors; Angiostatin; Combined therapy; Histone H3 acetylation; Normalization of tumor vessels; Shenmai injection.

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