Combining combretastatin A4 phosphate with ginsenoside Rd synergistically inhibited hepatocellular carcinoma by reducing HIF-1α via PI3K/AKT/mTOR signalling pathway.

Abstract

OBJECTIVES:

Combretastatin A4 phosphate (CA4P), a vascular disrupting agent (VDA), can cause rapid tumour vessel occlusion. Subsequently, extensive necrosis is discovered in the tumour center, which induces widespread hypoxia and the rise of the α subunit of hypoxia-inducible factor-1 (HIF-1α). The aim of this study was to evaluate the inhibition of hepatocellular carcinoma growth by combining CA4P with HIF-1 α inhibitor and investigate the mechanism of this combination.

METHODS:

Ginsenoside Rd (Rd) was used in combination with CA4P to estimate the inhibition effect in HepG2 cells and HepG2 xenograft mouse model. The efficacy of anti-tumour was evaluated by tumour growth curve. The protein expression of HIF-1α and PI3K/AKT/mTOR signalling pathway were analysed by western blot.

KEY FINDINGS:

Combination of CA4P and Rd inhibited HepG2 cell proliferation and induced apoptosis in vivo and in vitro. It also increased the necrotic area of the tumour and delayed the tumour growth. Moreover, Rd down-regulated HIF-1α protein expression by inhibiting PI3K/AKT/mTOR signalling pathway.

CONCLUSIONS:

Combination of CA4P and Rd had synergistic anti-tumour effects. The mechanism may be related to the inhibition of HIF-1α by PI3K/AKT/mTOR signalling pathway. This strategy provides a new thought for the combinative therapy of VDAs.

• Authors: Xinxiu Yang, Meng Gao, Mengqi Miao, Cuihua Jiang, Dongjian Zhang, Zhiqi Yin, Yicheng Ni, Jing Chen, Jian Zhang
• Journal: The Journal of pharmacy and pharmacology (J Pharm Pharmacol) Vol. 73 Issue 2 Pg. 263-271 (Mar 04 2021) ISSN: 2042-7158 [Electronic] England
• PMID: 33793802 (Publication Type: Journal Article)
• Copyright: © The Author(s) 2020. Published by Oxford University Press on behalf of Royal Pharmaceutical Society. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Ginsenosides
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Stilbenes
• MTOR protein, human
• Phosphatidylinositol 3-Kinase
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• fosbretabulin
• ginsenoside Rd

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, pharmacology)
• Apoptosis (drug effects)
• Carcinoma, Hepatocellular (drug therapy, pathology)
• Drug Synergism
• Ginsenosides (administration & dosage, pharmacology)
• Hep G2 Cells
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Liver Neoplasms (drug therapy, pathology)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Phosphatidylinositol 3-Kinase (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction (drug effects)
• Stilbenes (administration & dosage, pharmacology)
• TOR Serine-Threonine Kinases (metabolism)
• Xenograft Model Antitumor Assays