Coptidis Rhizoma: a comprehensive review of its traditional uses, botany, phytochemistry, pharmacology and toxicology

Wang, Jin; Wang, Lin; Lou, Guan-Hua; Zeng, Hai-Rong; Hu, Ju; Huang, Qin-Wan; Peng, Wei; Yang, Xiang-Bo

Urokinase-type plasminogen activator (uPA) and MMPs play important roles in cancer metastasis and angiogenesis, and inhibition of uPA and MMP could inhibit the migration and invasion of cancer cells. Berberine affected JNK, ERK1/2, p38 MAPK, P13K-Akt and NF-jB signalling pathways to inhibit the actions of MMP-2, MMP-9, MMP-1, and uPA in SCC-4 human tongue squamous carcinoma cells, hepatoma cells, and breast cancer cells (Ho et al. 2009; Bing et al. 2011; Kim et al. 2012; Kuo et al. 2012 ). NM23-H1 and SDF-1 are potential genes associated with tumour cell metastasis and previous research indicated that berberine could decrease NM23-H1 and SDF-1 expression; thus reducing the metastasis of leukaemia cells Liu et al. 2008) . It was reported that berberine (50 lM) could act as a RhoGTPases inhibitor in HONE1 human nasopharyngeal carcinoma cell (Tang et al. 2009 ). Inhibition of RhoGTPase by CRE, as well as by berberine (100-200 lM), might also result in blockade of ROCK signalling in hepatoma cells . The expression levels of two chemokine receptors (CXCR4 and CCR7), which are involved in the migration and metastasis of esophageal cancer cells, were decreased following the berberine treatment (Mishan et al. 2015) . Tumour angiogenesis, a process associated with invasion and metastasis, is an essential link in the control of tumour progression (Zhao and Adjei 2015) . In tumour angiogenesis, VEGF and hypoxia-inducible factor-1a (H1F-1a) play a key role in tumour progression. In vivo and in vitro studies revealed that the antiangiogenic activity of berberine was mediated by downregulating the expression of H1F-1, VEGF and proinflammatory mediators in hepatocellular carcinoma cells and breast cancer cells Hamsa & Kuttan 2012; Kim et al. 2013) . Berberine may also inhibit the adhesion of gastric cancer cells to endothelial cells by increasing the proportion of intercellular adhesion 8-32 mM (Iizuka et al. 2000) molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), thus reducing the risk of tumour angiogenesis induced by evodiamine (Shi et al. 2013 ). In addition, berberine showed anti-angiogenesis effects on animals that were orthotopically implanted with hepatocellular carcinoma (Tsang et al. 2015) . Coptisine at 150 mg/kg may reduce cancer metastasis risk by inhibiting the RAS-ERK pathway in HCT116 bearing mice . Chinese medicinal herbs can enhance the body's immune function, by inducing cytokines, interferon (IFN), lymphocyteactivated killer cells production and natural killer (NK) cell proliferation, thereby mediating tumor cell apoptosis. Importantly, CRE could markedly increase the IFN-b and TNF-a mRNA expression in breast cancer MCF-7 oestrogen receptor-positive cells (Kang et al. 2005 ) Furthermore, berberine was also capable of reducing the expression of caspase-1 and IL-1b in osteosarcoma cells, and inhibiting the growth of tumour cells, suggesting that the mechanism might involve downregulation of the caspase-1/IL-1b inflammatory signalling axis . A recent study showed that palmatine disrupted the interaction between pancreatic stellate cells and cancer cells in the tumour microenvironment, consequently resulting in the inhibition of cancer growth and migration, while inducing apoptosis by inhibiting survivin (Chakravarthy et al. 2018 ).