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Andrographolide reduced VEGFA expression in hepatoma cancer cells.

Andrographolide (Andro) is the main active compound in medicinal herb Andrographis paniculata Nees (Acanthaceae). Vascular endothelial growth factor A (VEGFA), a key pro-angiogenic factor, contributes greatly to tumor growth. The purpose of this study is to observe the inhibition of Andro on VEGFA expression in hepatoma cancer cells and its engaged mechanism. Andro decreased mRNA and protein expression of VEGFA in hepatoma Hep3B and HepG2 cells. Andro also decreased hypoxia-inducible factor 1-alpha (HIF-1α) protein expression and its subsequent nuclear translocation. Further results showed that Andro induced the polyubiquitination of HIF-1α protein, and proteasome inhibitor MG132 reversed Andro-induced decrease in the expression of HIF-1α protein and VEGFA mRNA and protein. Andro reduced the expression of metastasis-associated protein 1 (MTA1) and histone deacetylase 1 (HDAC1) in hepatoma cancer cells. SP600125, an inhibitor of c-Jun N-terminal kinase (JNK), reversed Andro-induced decrease in the expression of HIF-1α and VEGFA, but not MTA1 and HDAC1. Andro (10 mg/kg) inhibited tumor growth in mice implanted with hepatoma Hep3B cells in vivo, and reduced the expression of CD31, VEGFA and HIF-1α in tumor tissues. In conclusion, Andro inhibited hepatoma tumor growth by reducing HIF-1α expression and its-mediated VEGFA expression via inducing ubiquitination-mediated HIF-1α proteindegradation, and JNK and MTA1/HDAC1 may be involved in this process. Natural product Andro has huge potential in hepatoma cancer treatment.

Liang Shi, Guoqing Zhang, Zhiyong Zheng, Bin Lu, Lili Ji, Chem Biol Interact

In Vitro Study Jul 31, 2017

This evidence indicated that ginsenoside Rg3 was an effective multi-targets antitumor agent for the treatment of liver cancer.

Na/Hexchanger 1 (NHE1) plays a vital role in the oncogenesis and development of hepatocellular carcinoma (HCC) and has been regarded as a promising target for the treatment of HCC. Ginsenoside Rg3 (Rg3), a bioactive ginseng compound, is suggested to possess pleiotropic antitumor effects on HCC. However, the underlying mechanisms of Rg3 suppressing HCC remain unclear. In the present study, we uncovered a novel antitumor mechanism of Rg3 on HCC by decreasing NHE1 expression through in vivo and in vitro studies. Mechanistically, we demonstrated that epidermal growth factor (EGF) could dramatically upregulate NHE1 expression, while increasing the phosphorylated extracellular signal-regulated protein kinase (ERK1/2) level and hypoxia-inducible factor 1 alpha (HIF-1expression. In the presence of ERK1/2-specific inhibitor PD98059, EGF stimulated HIF-1and NHE1 expression was obviously blocked in addition, the presence of HIF-1-specific inhibitor 2-methoxyestradiol (2-MeOE2) blocked EGF stimulated NHE1 expression. Moreover, results from in vivo and in vitro studies indicate that Rg3 treatment markedly decreased the expression of EGF, EGF receptor (EGFR), phosphorylated ERK1/2 and HIF-1. Conclusively, these findings suggested that NHE1 was stimulated by EGF, and Rg3 could decrease NHE1 expression by integrally inhibiting EGF-EGFR-ERK1/2-HIF-signal axis in HCC. Together, our evidence indicated that Rg3 was an effective multi-targets antitumor agent for the treatment of HCC.

Xiao Li, Jiaywei Tsauo, Chong Geng, He Zhao, Xuelian Lei, Xiao Li, Am J Chin Med

Animal Study Jan 1, 2018

Ginkgolides mimic the effects of hypoxic preconditioning to protect C6 cells against ischemic injury.

Hypoxic preconditioning can play a significant neuroprotective role. However, it has not been employed clinically because of safety concerns. To find a safer preconditioning stimulus that is both practical and effective, we investigated whether ginkgolides are capable of preconditioning as hypoxia to protect C6 cells against ischemic injury. We demonstrated that both ginkgolides (37.5microg/mL) and hypoxia (1% O(2) for 16h) can significantly increase cell viabilities and expression of phosphorylated glycogen synthase kinase (p-GSK), phosphorylated extracellular signal-regulated kinase (p-ERK), hypoxia-inducible factor-1 alpha (HIF-1alpha) and erythropoietin (EPO) in ischemic cells. The inhibitors of mitogen-activated protein kinase (MAPK) or phosphatidylinositol 3'-kinase (PI3K) significantly but not completely reduced the enhanced expression of these proteins and cell viabilities induced by ginkgolides and hypoxic preconditioning. These indicated that ginkgolides could mimic hypoxic preconditioning by increasing expression of HIF-1alpha as well as its target protein EPO and that the ginkgolides and hypoxic preconditioning role might be partly mediated by the activation of the p42/p44-mitogen-activated protein kinase and phosphatidylinositol 3'-kinase/AKT/glycogen synthase kinase 3beta pathways. The similar tendency in the changes of protein expression, cell viabilities and responses to MAPK or PI3K inhibitors of the cells treated with ginkgolides and hypoxia suggests that ginkgolides and hypoxic preconditioning might operate by similar mechanisms. The findings also imply that ginkgolides might have the potential for clinical use to prevent injury in high-risk conditions.

Wei He, Ming Qian Zhong, Li Zhu, Qian Christopher, Fang Du, Wing Ho Yung, Ya Ke, Int J Biochem Cell Biol

In Vitro Study Jan 1, 2008

Ginkgolide B preconditioning protects neurons against ischaemia-induced apoptosis.

Ischaemic preconditioning (IP) has been reported to protect the brain against subsequent lethal ischaemia, but it has not been used clinically to prevent ischaemic injury because of safety concerns. The aim of the present study was to see whether Ginkgolide B (GB) is capable of preconditioning as IP to protect neurons against ischaemic injury; if so, which mechanism is involved. Cultured mouse cortical neurons at day 8 were pre-treated with GB (120 micromol/l) for 24 hrs or exposed to short-term ischaemia (1 hr) followed by 24-hr normal culture to induce IP before being treated with severe ischaemia (5 hrs). GB and IP significantly increased cell viability, expression of hypoxia-inducible factor-1 alpha (HIF-1alpha), erythropoietin (EPO), phosphorylated Bad at serine 136 (136p-Bad) and phosphorylated glycogen synthase kinase- 3beta at serine 9 (p-GSK-3beta), and decreased the percentage of apoptotic cells and the level of active caspase-3 in severely ischaemic neurons. Moreover, LY294002 that is a specific inhibitor of phosphatidylinositol 3-kinase (PI3K) significantly reduced the enhanced expression of HIF-1alpha, EPO and 136p-Bad induced by GB and IP. These results suggest that GB, like IP in neurons, is capable of preconditioning against ischaemia-induced apoptosis, the mechanism of which may involve the PI3K signalling pathway.

Xiaomei Wu, Zhongming Qian, Ya Ke, Fang Du, Li Zhu, J Cell Mol Med

Animal Study Jan 1, 2009

Ellagic acid, an inhibitor of CARM1, can suppress the proliferation and metastasis of TNBC.

Coactivator-associated arginine methyltransferase 1 (CARM1) promotes the development and metastasis of estrogen receptor alpha (ERα)-positive breast cancer. The function of CARM1 in triple-negative breast cancer (TNBC) is still unclear and requires further exploration. Here, we report that CARM1 promotes proliferation, epithelial-mesenchymal transition (EMT), and stemness in TNBC. CARM1 is upregulated in multiple cancers and its expression correlates with breast cancer progression. Genome-wide analysis of CARM1 showed that CARM1 is recruited by hypoxia-inducible factor 1 subunit alpha (HIF1A) and occupy the promoters of CDK4, Cyclin D1,β-catenin, HIF1A, MALAT1, and SIX1 critically involved in cell cycle, HIF-1 signaling pathway, Wnt signaling pathway, VEGF signaling pathway, thereby modulating the proliferation and invasion of TNBC cells. We demonstrated that CARM1 is physically associated with and directly interacts with HIF1A. Moreover, we found that ellagic acid, an inhibitor of CARM1, can suppress the proliferation and metastasis of TNBC by directly inhibiting CDK4 expression. Our research has determined the molecular basis of CARM1 carcinogenesis in TNBC and its effective natural inhibitor, which may provide new ideas and drugs for cancer therapy.

Dandan Feng, Jie Gao, Ruiqiong Liu, Wei Liu, Tianyang Gao, Yunkai Yang, Die Zhang, Tianshu Yang, Xin Yin, Hefen Yu, Wei Huang, Yan Wang, Protein Cell

Animal Study Mar 13, 2024