Berberine Complex

$31.40
PAN77A

Panaxea’s Berberine Complex can be used in a broad range of treatment protocols, including Oncology and SIBO. Berberine benefits include: maintaining healthy cholesterol levels and glucose levels; eradicating unhealthy bacteria from the GI tract and reducing chronic inflammation.*

Supplement Facts

Serving Size: 2 capsules

Servings Per Container: 30

Amount Per Serving

% Daily Value

Berberine 840 mg
Corydalis Yanhusuo (methanol extract Corydalis Tuber alkaloids (10%) 160 mg
† Daily Value not established.

Other Ingredients: Vegetable cellulose (hypromellose); Vegetable Stearic Acid; Microcrystalline Cellulose and Vegetable Magnesium Stearate.

Does not contain: Wheat, gluten, soy, milk, eggs, fish, crustacean shellfish, tree nuts, peanuts

Berberine Complex 

60 x 500mg capsules

Product Overview

Berberine Complex contains an alkaloid that is present in a number of plants, including Berberis vulgaris (barberry), Berberis aristata (tree turmeric), Berberis aquifolium (Oregon grape), Hydrastis canadensis (goldenseal), and Coptis chinensis (goldthread). This traditional culinary and medicinal plant extract has shown benefits for supporting healthy glucose metabolism, maintenance of healthy lipid levels, and optimum inflammatory responses. Chronic inflammation underlies a wide range of disease states and is influenced by the modern life and diet, being overworked, stressed and having out of range weight parameters. Berberine Complex supports the regulation of a healthy inflammatory response and conditions resulting from chronic inflammation.*

Action

Supports healthy lipid levels* 

Helps promote healthy blood sugar function *

Regulates healthy inflammatory response function*

Suggested Use: 

Adult dosage: 2 caps 2 times daily on empty stomach. For optimal absorption and long term use add ProB)Plus (1 scoop a day)

For treatment of systemic inflammation alternate with ICC every 6 weeks (2 x 2 caps daily)

For SIBO

–       To clear mucosal inflammation and restore bowel function Add Gut Clear (2-3 caps twice daily)

–       To heal leaky gut and Inhibit return of pathogenic bacteria and fungi - add Dysbio (3-4 caps before sleep)  and Prebiotic Mix (1 scoop daily in juice, water or yogurt)

–       For constipation-predominant SIBO add Freely Moving (2-4 caps in the morning on empty stomach)

Warning: 

Do not use during pregnancy or lactation

*These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.

Berberine

Berberine is an isoquinoline alkaloid widely distributed in natural herbs, including Rhizoma Coptidis chinensis and Epimedium sagittatum (Sieb. et al Zucc.), a widely prescribed Chinese herb (Chen et al, 2008). It has a broad range of bioactivities, such as anti-inflammatory, anti-bacterial., anti-diabetes, anti-ulcer, sedation, protection of myocardial ischemia-reperfusion injury, expansion of blood vessels, inhibition of platelet aggregation, hepato-protective, and neuroprotective effects (Lau et al, 2001; Yu et al., 2005; Kulkarni & Dhir, 2010; Han et al, 2011; Ji, 2011). Berberine has been used in the treatment of diarrhoea, neurasthenia, arrhythmia and diabetes (Ji, 2011).

Diabetes Studies 

A Systemic Review and Meta-Analysis.Hui Dong, Nan Wang, Li Zhao, and Fuer Lu

Berberine protects against diabetes-induced complications

Aldose reductase is the rate-limiting enzyme of the polyol pathway that leads to conversion of glucose to sorbitol. Its increased activity, which results in abnormal activation of the polyol pathway, is implicated in the development of long-term complications of diabetes mellitus. Different plant species and their active components have shown potent in vitro and in vivo aldose reductase inhibitory activity. Among different phyto-constituents, alkaloids that contain isoquinoline/bis(isoquinoline)and related ring structures (such as berberine, palmatine, coptisine, and jateorrhizine) have shown very potent aldose reductase inhibitory activity. The structural activity relationship has revealed the importance of hydrophobic and hydrophilic groups of isoquinoline/bis(isoquinoline)for binding to an enzyme. The dioxymethylene group in the D ring (hydrophobic group) of these alkaloids binds tightly to the site adjacent to the anionic binding site (active site), while the methoxyl groups (polar) bind to the site adjacent to the nicotinamide ring of the coenzyme.

Berberine has molecular mechanisms of action and clinical efficacy and safety in patients with type 2 diabetes, hyperlipidaemia, heart diseases, cancers and inflammation and one of the advantages of berberine is its multiple-target effects in each of these diseases. The therapeutic efficacy of berberine may reflect a synergistic regulation of these targets, resulting in a comprehensive effect against these various chronic disorders. The safety of BBR may be due to its harmonious distribution into those targets (Yao et al, 2013).

Yin J. Xing H. Ye J. Efficacy of berberine in patients with type 2 diabetes mellitus. Metabolism May 2UU8:57(5):712-7

Berberine beneficial with blood glucose control in the treatment of type 2 diabetic patients and exhibits efficacy comparable with that of conventional oral hypoglycaemics.

A Systemic Review and Meta-Analysis. Hui Dong, Nan Wang, Li Zhao, and Fuer Lu

Blood Lipids - Cardiovascular

Berberine improves lipid dysregulation in obesity by controlling central and peripheral AMPK activity

Woo Sik Kim, et al, Am J Physiol Endocrinol Metab 296:E812-E819, 2009

Berberine Decreases Total Cholesterol and Triglycerides

Phytother Res 2011 May 9. doi; 10.1002/ptr.3493.

Berberine induced decline in circulating CD31+/CD42 microparticles is associated with improvement of endothelial function in humans

Reference

Eur J Pharmacol. 2009;614(1-3);77-83

Berberine improves lipid dysregulation in obesity by controlling central and peripheral AMPK activity

Reference

Woo Sik Kim, et al, Am J Physiol Endocrinol Metab 296:E812-E819, 2009

Berberine Decreases Total Cholesterol and Triglycerides

Reference

Phytotherapy Res 2011 May 9, doi; 10.1002/ptr.3493.

Berberine improves arterial endothelial function and suppresses pro-inflammatory cytokines.

Berberine induced decline in circulating CD31+/CD42 microparticles is associated with improvement of endothelial function in humans.

Reference: Eur J Pharmacol. 2009;614(1-3);77-83

Berberine Lowers serum cholesterol

Kong W, identified berberine (BBR), a compound isolated from a Chinese herb, as a new cholesterol-lowering drug. Oral administration of BBR in 32 hypercholesterolemia patients for 3 months reduced serum cholesterol by 29%, triglycerides by 35% and LDL-cholesterol by 25%. Treatment of hyperlipidemic hamsters with BBR reduced serum cholesterol by 40% and LDL-cholesterol by 42%, with a 3.5-fold increase in hepatic LDLR mRNA and a 2.6-fold increase in hepatic LDLR protein. Using human hepatoma cells, they show that BBR up regulates LDLR expression independent of sterol regulatory element binding proteins, but dependent on ERK activation. BBR elevates LDLR expression through a post-transcriptional mechanism that stabilises the mRNA. Using a heterologous system with luciferase as a reporter, they further identify the 5' proximal section of the LDLR mRNA 3' untranslated region responsible for the regulatory effect of BBR. These findings show BBR as a new hypolipidaemic drug with a mechanism of action different from that of statin drugs (Kong et al, 2004).

Blood Sugar / Glucose Metabolism

A new review of several studies shows that the plant alkaloid Berberine can lower blood glucose as effectively as the drug metformin at similar doses (500mg 3x daily) Panaxea standardized 97% Berberine.

Berberine offers Antiobesity Effects & has Significant Beneficial Effects on TYPE II Diabetes.

Yin J. Xing H. Ye J. Efficacy of berberine in patients with type 2 diabetes mellitus. Metabolism May 2UU8:57(5):712-7

PCOS Studies

The use of berberine in women with PCOS is very promising, even if more clinical studies are needed to confirm the safety and the efficacy of the berberine associated with other pharmacological compounds used in long-term therapy of PCOS.

Reference

Rondanelli M, Infantino V, Riva A, et al. Polycystic ovary syndrome management: a review of the possible amazing role of berberine. Arch Gynecol Obstet. 2020;301(1):53-60. doi:10.1007/s00404-020-05450-4

Berberine benefits PCOS women with metabolic configurations . 

Reference

Eur J Endorinol, 2012 Jan;166(1);99-105

Berberine is safe to use in premenopausal women who want to get pregnant and showed few side effects in all the cited studies. In conclusion, the use of berberine for PCOS is safe and promising. 

The use of berberine for women with polycystic ovary syndrome undergoing IVF treatment

Objective: Previous studies have indicated that berberine is an effective insulin sensitizer with comparable activity to metformin (Diabetes 2006, 55, 2256). Reduced insulin sensitivity is reportedly a factor adversely affecting the outcome of IVF in patients with polycystic ovary syndrome (PCOS) (Human Reproduction 2006, 21, 1416). Our objective was to evaluate the clinical, metabolic and endocrine effects of berberine vs metformin in PCOS women scheduled for IVF treatment and to explore the potential benefits to the IVF process.

Design: We performed a prospective study in 150 infertile women with PCOS undergoing IVF treatment. Patients were randomized to receive berberine, metformin or placebo tablets for 3 months before ovarian stimulation.

Measurements: The clinical, endocrine, metabolic parameters and the outcome of IVF.

Results: Compared with placebo, greater reductions in total testosterone, free androgen index, fasting glucose, fasting insulin and HOMA-IR, and increases in SHBG, were observed in the berberine and metformin groups. Three months of treatment with berberine or metformin before the IVF cycle increased the pregnancy rate and reduced the incidence of severe ovarian hyperstimulation syndrome. Furthermore, treatment with berberine, in comparison with metformin, was associated with decreases in BMI, lipid parameters and total FSH requirement, and an increase in live birth rate with fewer gastrointestinal adverse events.

Conclusions: Berberine and metformin treatments prior to IVF improved the pregnancy outcome by normalizing the clinical, endocrine and metabolic parameters in PCOS women. Berberine has a more pronounced therapeutic effect and achieved more live births with fewer side effects than metformin.

Cancer

Berberine Induced Apoptosis of Human Osteosarcoma Cells by Inhibiting Phosphoinositide 3 Kinase/Protein Kinase B (PI3K/Akt) Signal Pathway Activation.

Osteosarcoma is a malignant tumour with high mortality but effective therapy has not yet been developed. Berberine, an isoquinoline alkaloid component in several Chinese herbs including Huang lian, has been shown to induce growth inhibition and the apoptosis of certain cancer cells. The aim of this study was to determine the role of berberine on human osteosarcoma cell lines U2OS and its potential mechanism. Berberine treatment caused dose-dependent inhibiting proliferation and inducing apoptosis of U20S cell. Mechanistically, berberine inhibits PI3K/AKT activation that, in turn, results in up-regulating the expression of Bax, and PARP and down regulating the expression of Bcl-2 and caspase3. In all, berberine can suppress the proliferation and induce the apoptosis of U2OS cell through inhibiting the PI3K/Akt signalling pathway activation. Berberine can suppress the proliferation and induce the apoptosis of U2OS cell through inhibiting the PI3K/Akt signalling pathway activation.

Cancer: Nasopharyngeal carcinoma

Action: Anti-inflammatory, inhibits STAT3

Growth inhibitory effects of berberine on multiple types of human cancer cells have been reported. Berberine inhibits invasion, induces cell cycle arrest and apoptosis in human cancer cells. The anti-inflammatory property of berberine, involving inhibition of Signal Transducer and Activator of Transcription 3 (STAT3) activation, has also been documented.

Berberine effectively inhibited the tumorigenicity and growth of an EBV-positive nasopharyngeal carcinoma (NPC) cell line (C666-1).

In vitro, berberine inhibited both constitutive and IL-6-induced STAT3 activation in NPC cells. Inhibition of STAT3 activation by berberine induced growth inhibition and apoptotic response in NPC cells. Tumour-associated fibroblasts were found to secret IL-6 and the conditioned medium harvested from the fibroblasts also induced STAT3 activation in NPC cells. Inhibition of tumorigenic growth of NPC cells in vivo was also correlated with effective inhibition of STAT3 activation.

Angiogenesis, Chemo-enhancing

Inhibition of tumour invasion and metastasis is an important aspect of berberine’s anti-cancer activities (Tang et al, 2009; Ho et al, 2009). A few studies have reported berberine’s inhibition of tumour angiogenesis (Jie et al, 2011; Hamsa & Kuttan, 2012). In addition, its combination with chemotherapeutic drugs or irradiation could enhance the therapeutic effects (Youn et al, 2008; Hur et al, 2009).

Cell-cycle Arrest

The potential molecular targets and mechanisms of berberine are rather complicated. Berberine interacts with DNA or RNA to form a berberine-DNA or a berberine-RNA complex, respectively (Islam & Kumar. 2009; Li et al, 2012). Berberine is also identified as an inhibitor of several enzymes, such as N-acetyltransferase (NAT), cyclooxygenase-2 (COX-2), and telomerase (Sun et al., 2009).

Other mechanisms of berberine are mainly related to its effect on cell-cycle arrest and apoptosis, including regulation of cyclin-dependent kinase (CDK) family of proteins (Sun et al, 2009; Mantena, Sharma, & Katiyar, 2006) and expression regulation of B-cell lymphoma 2 (Bcl-2) family of proteins (such as Bax, Bcl-2, and Bcl-xL) (Sun et al, 2009), and caspases (Eom et al, 2010; Mantena, Sharma, & Katiyar, 2006). Furthermore, berberine inhibits the activation of the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and induces the formation of intracellular reactive oxygen species (ROS) in cancer cells (Sun et al, 2009; Eom et al, 2010). Interestingly, these effects might be specific for cancer cells (Sun et al, 2009).

Several studies have shown that berberine has anti-cancer potential by interfering with the multiple aspects of tumourigenesis and tumour progression in both in vitro and in vivo experiments. These observations have been well summarized in recent reports (Sun et al, 2009; Tan et al, 2011). Berberine inhibits the proliferation of multiple cancer cell lines by inducing cell-cycle arrest at the G1 or G 2 / M phases and by apoptosis (Sun et al, 2009; Eom et al, 2010; Burgeiro et al, 2011). In addition, berberine induces endoplasmic reticulum stress (Chang et al, 1990; Eom et al, 2010) and autophagy (Wang et al, 2010) in cancer cells.

However, compared with clinically prescribed anti-cancer drugs, the cytotoxic potency of berberine is much lower, with an IC50 generally at 10 µM to 100 µM depending on the cell type and treatment duration in vitro (Sun et al, 2009). Besides, berberine also induces morphologic differentiation in human teratocarcinoma (testes) cells (Chang et al, 1990).

Anti-metastatic

The effect of berberine on invasion, migration, metastasis, and angiogenesis is mediated through the inhibition of focal adhesion kinase (FAK), NF-κB, urokinase-type plasminogen-activator (u-PA), matrix metalloproteinase 2 (MMP-2), and matrix metalloproteinase 9 (MMP-9) (Ho et al, 2009; Hamsa & Kuttan. (2011); reduction of Rho kinase-mediated Ezrin phosphorylation (Tang et al., 2009); reduction of the expression of COX-2, prostaglandin E, and prostaglandin E receptors (Singh et al., 2011); down-regulation of hypoxia-inducible factor 1 (HIF-1), vascular endothelial growth factor (VEGF), pro-inflammatory mediators (Jie et al, 2011; Hamsa & Kuttan, 2012).

Berberine alkaloids, such as berberine, coptisine, and palmatine have strong antibacterial activity on Escherichia coli, and protect against ethanol-induced gastric lesions by inhibiting gastric acid secretions (Li et al, 2006; Yan et al, 2008).

Cancer: Multiple Myeloma

Action: Down-regulates miR-21 levels through IL6/STAT3

Berberine is known to modulate microRNA (miRNA) levels, although the mechanism for this action is unknown. Luo et al. previously demonstrate that the expression of 87 miRNAs is differentially affected by berberine in multiple myeloma cells. Among 49 miRNAs that are down regulated, nine act as oncomirs, including miR-21. Integrative analysis showed that 28 of the down-regulated miRNAs participate in tumour protein p53 (TP53) signalling and other cancer pathways. miR-21 is involved in all these pathways, and is one of the most important oncomirs to be affected by berberine in multiple myeloma cells.

They confirmed that berberine down-regulated miRNA-21 expression and significantly up-regulated the expression of programmed cell death 4 (PDCD4), a predicted miR-21 target. Depletion of PDCD4 by short interfering RNA could rescue berberine-induced cytotoxicity in multiple

Results suggest that berberine suppresses multiple myeloma cell growth, at least in part, by down-regulating miR-21 levels possibly through IL6/STAT3. This led to increased PDCD4 expression, which is likely to result in suppression of the p53-signalling pathway (Luo et al. 2014).

Anti-cancer: VEGF

Dehydrocorydaline, an alkaloid isolated from CM-ext, inhibits MCF-7 cell proliferation by inducing apoptosis mediated by regulating Bax/Bcl-2, activating caspases as well as cleaving PARP (Xu et al, 2012).

Several protoberberine alkaloids (including berberine) found in CM-ext significantly suppressed the VEGF-induced up regulation of matrix metalloproteinase 2 (MMP2) at both mRNA and protein levels. This finding provides insights into the anti-angiogenic effects of C. Yan hu suo and berberine, and offer scientific evidence for their traditional clinical application as a cancer treatment (Gao et al, 2009).

Breast cancer resistance protein (BCRP/ABCG2) plays an important role in determining the absorption and disposition of consumed xenobiotics including various drugs and dietary phytochemicals and is also one of the prominent efflux transporters involved in multidrug resistance (MDR). Berberine demonstrated significant inhibition of ABCG2-mediated transport (Tan et al, 2013). Berberine may suppress TPA-induced VEGF and FN as well as VEGF-induced FN through the inhibition of the PI-3K/AKT pathway in breast cancer cells (Kim et al, 2013a). Berberine may be used as a candidate drug for the inhibition of metastasis of human breast cancer (Kim et al, 2013b).

Action: Triggers Hypomethylation

Berberine reduces the proliferation and induces apoptosis in the multiple myeloma cell line, U266. Qing et al, (2014) explored the detailed mechanism by analysing the gene expression profiles in U266 treated with or without berberine. DNMT1 andDNMT3B, encoding for a highly conserved member of the DNA methyltransferases, decreased significantly. Results show that berberine can repress the expression of DNMT1 and DNMT3B, which triggers hypomethylation of TP53 by changing the DNA methylation level and the alteration of p53 dependent signal pathway in human multiple melanoma cell U266.

Berberine Targets AP-2/hTERT, NF-κB/COX-2, HIF-1α/VEGF and Cytochrome-c/Caspase Signalling to Suppress Human Cancer Cell Growth.

Berberine (BBR), an isoquinoline derivative alkaloid isolated from Chinese herbs, has a long history of uses for the treatment of multiple diseases, including cancers. However, the precise mechanisms of actions of BBR in human lung cancer cells remain unclear. In this study, we investigated the molecular mechanisms by which BBR inhibits cell growth in human non-small-cell lung cancer (NSCLC) cells. Treatment with BBR promoted cell morphology change, inhibited cell migration, proliferation and colony formation, and induced cell apoptosis. Further molecular mechanism study showed that BBR simultaneously targeted multiple cell signaling pathways to inhibit NSCLC cell growth. Treatment with BBR inhibited AP-2α and AP-2β expression and abrogated their binding on hTERT promoters, thereby inhibiting hTERT expression. Knockdown of AP-2α and AP-2β by siRNA considerably augmented the BBR-mediated inhibition of cell growth. BBR also suppressed the nuclear translocation of p50/p65 NF-κB proteins and their binding to COX-2 promoter, causing inhibition of COX-2. BBR also downregulated HIF-1α and VEGF expression and inhibited Akt and ERK phosphorylation. Knockdown of HIF-1α by siRNA considerably augmented the BBR-mediated inhibition of cell growth. Moreover, BBR treatment triggered cytochrome-c release from mitochondrial inter-membrane space into cytosol, promoted cleavage of caspase and PARP, and affected expression of BAX and Bcl-2, thereby activating apoptotic pathway. Taken together, these results demonstrated that BBR inhibited NSCLC cell growth by simultaneously targeting AP-2/hTERT, NF-κB/COX-2, HIF-1α/VEGF, PI3K/AKT, Raf/MEK/ERK and cytochrome-c/caspase signaling pathways. Our findings provide new insights into understanding the anticancer mechanisms of BBR in human lung cancer therapy. Source 
Fu L, Chen w, Guo W et al. PLoS One. 2013 Jul 15;8(7):e69240. doi: 10.1371/journal.pone.0069240.

Angiogenesis, Chemo-enhancing

Inhibition of tumour invasion and metastasis is an important aspect of the anti-cancer activities of berberine (Tang et al, 2009; Ho et al, 2009). Several studies have reported the ability of berberine to inhibit tumour angiogenesis (Jie et al, 2011; Hamsa & Kuttan, 2012). In addition, its combination with chemotherapeutic drugs or irradiation could enhance the therapeutic effects (Youn et al, 2008; Hur et al, 2009).

Cell-cycle Arrest

The potential molecular targets and mechanisms of berberine are rather complicated. Berberine interacts with DNA or RNA to form a berberine-DNA or a berberine-RNA complex, respectively (Islam & Kumar, 2009; Li et al, 2012). Berberine has also been identified as an inhibitor of several enzymes, such as N-acetyltransferase (NAT), cyclooxygenase-2 (COX-2), and telomerase (Sun et al, 2009). Other mechanisms of berberine are mainly related to its effect on cell-cycle arrest and apoptosis, including regulation of cyclin-dependent kinase (CDK) family of proteins (Sun et al, 2009) (Mantena, Sharma, & Katiyar, 2006) and expression regulation of B-cell lymphoma 2 (Bcl-2) family of proteins (such as Bax, Bcl-2, and Bcl-xL), (Sun et al, 2009) and caspases (Eom et al, 2010), (Mantena, Sharma, & Katiyar, 2006). Furthermore, berberine inhibits the activation of the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and induces the formation of intracellular reactive oxygen species (ROS) in cancer cells (Sun et al, 2009), (Eom et al, 2010). Interestingly, these effects might be specific for cancer cells (Sun et al, 2009).

Several studies have shown that berberine has anti-cancer potential by interfering with the multiple aspects of tumourigenesis and tumour progression in both in vitro and in vivo experiments. These observations have been well summarized in recent reports (Sun et al, 2009; Tan et al, 2011). Berberine inhibits the proliferation of multiple cancer cell lines by inducing cell-cycle arrest at the G1 or G 2/M phases and by apoptosis (Sun et al, 2009; Eom et al, 2010; Burgeiro et al, 2011). In addition, berberine induces endoplasmic reticulum stress (Chang et al, 1990; Eom et al, 2010) and autophagy (Wang et al, 2010) in cancer cells.

However, compared with clinically prescribed anti-cancer drugs, the cytotoxic potency of berberine is much lower, with an IC50 generally at 10 µM to 100 µM depending on the cell type and treatment duration in vitro (Sun et al, 2009). In addition, berberine induces morphologic differentiation in human teratocarcinoma (testes) cells (Chang et al, 1990).

Anti-metastatic

The effect of berberine on invasion, migration, metastasis, and angiogenesis is mediated through the inhibition of focal adhesion kinase (FAK), NF-κB, urokinase-type plasminogen-activator (u-PA), matrix metalloproteinase 2 (MMP-2), and matrix metalloproteinase 9 (MMP-9) (Ho et al., 2009; Hamsa & Kuttan,2011); reduction of Rho kinase-mediated Ezrin phosphorylation (Tang et al., 2009); reduction of the expression of COX-2, prostaglandin E, and prostaglandin E receptors (Singh et al, 2011); down-regulation of hypoxia-inducible factor 1 (HIF-1), vascular endothelial growth factor (VEGF), pro-inflammatory mediators (Jie et al, 2011; Hamsa & Kuttan, 2012).

Hepatoma, Leukaemia

The cytotoxic effects of Coptis chinensis extracts, and their major constituents on hepatoma and leukaemia cells in vitro have been investigated. Four human liver cancer cell lines, namely HepG2, Hep3B, SK-Hep1 and PLC/PRF/5, and four leukaemia cell lines, namely K562, U937, P3H1 and Raji, were investigated. C. chinensis exhibited strong activity against SK-Hep1 (IC50 = 7 microg/mL) and Raji (IC50 = 4 microg/mL) cell lines. Interestingly, the two major compounds of C. chinensis, berberine and coptisine, showed a strong inhibition on the proliferation of both hepatoma and leukaemia cell lines. These results suggest that the C. chinensis extract and its major constituents berberine and coptisine possess active anti-hepatoma and anti-leukaemia activities (Lin, 2004).

Leukaemia

The steady-state level of nucleophosmin/B23 mRNA decreased during berberine-induced (25 g/ml, 24 to 96 hours) apoptosis of human leukaemia HL-60 cells. A decline in telomerase activity was also observed in HL-60 cells treated with berberine. A stable clone of nucleophosmin/B23 over-expressed in HL-60 cells was selected and found to be less responsive to berberine-induced apoptosis. Control vector–transfected cells (pCR3) exhibited morphological characteristics of apoptosis, and nucleophosmin/B23-over-expressed cells (pCR3-B23) became apoptotic after incubation with 15 g/ml berberine for 48 to 96 hours.

These results indicated that berberine-induced apoptosis is associated with the down-regulation of nucleophosmin/B23 and telomerase activity. Nucleophosmin/B23 may hence play an important role in the control of the cellular response to apoptosis induction (Hsing, 1999).

Prostate Cancer

In vitro treatment of androgen-insensitive (DU145 and PC-3) and androgen-sensitive (LNCaP) prostate cancer cells with berberine inhibited cell proliferation and induced cell death in a dose-dependent (10-100 micromol/L) and time-dependent (24–72 hours) manner. Berberine significantly (P < 0.05-0.001) enhanced apoptosis of DU145 and LNCaP cells with induction of a higher ratio of Bax/Bcl-2 proteins, disruption of mitochondrial membrane potential, and activation of caspase-9, caspase-3, and poly(ADP-ribose) polymerase.

The effectiveness of berberine in checking the growth of androgen-insensitive, as well as androgen-sensitive, prostate cancer cells without affecting the growth of normal prostate epithelial cells indicates that it may be a promising candidate for prostate cancer therapy (Mantena, 2006).

In another study, the treatment of human prostate cancer cells (PC-3) with berberine-induced dose-dependent apoptosis; however, this effect of berberine was not seen in non-neoplastic human prostate epithelial cells (PWR-1E). Berberine-induced apoptosis was associated with the disruption of the mitochondrial membrane potential, release of apoptogenic molecules (cytochrome c and Smac/DIABLO) from mitochondria, cleavage of caspase-9, caspase-3 and PARP proteins.

Berberine-induced apoptosis was blocked in the presence of the anti-oxidant N-acetylcysteine, through the prevention of mitochondrial membrane potential disruption and subsequent release of cytochrome c and Smac/DIABLO. Taken together, these results suggest that berberine-mediated cell death of human prostate cancer cells is regulated by reactive oxygen species, and therefore suggests that berberine should be considered for further studies as a promising therapeutic candidate for prostate cancer (Meeran, 2008).

Gastric Cancer

Results showed that berberine induced ROS production for up to 6 hours of incubation. It was also found that berberine induced down regulation of MMP-1 -2, and -9 but did not affect the level of MMP-7. The mRNA levels of MMPs in gastric SNU-5 cells after treatment with berberine for 24 hours were investigated using a polymerase chain reaction and the results showed that berberine inhibited the gene expression of MMP-1, -2 and -9 in human SNU-5 cells but it did not affect MMP-7. In conclusion, berberine appears to exert its anticancer properties by inducing ROS production and prevention (Lin et al, 2008)

Neuroblastoma

Very few drugs have been developed for the treatment of malignant brain tumours. Berberine is known to pass through the blood-brain barrier (Ozaki et al, 1993; Wang et al, 2005). Choi et al, (2008) have found that berberine penetrated into the nucleus of both SK-N-SH and SK-N-MC cells. It could be therefore effective for the treatment of neuroblastoma.

Breast Cancer

DNA microarray technology has been used to understand the molecular mechanism underlying the anti-cancer effect of berberine carcinogenesis in two human breast cancer cell lines, the ER-positive MCF-7 and ER-negative MDA-MB-231 cells; specifically, whether berberine affects the expression of cancer-related genes. Treatment of the cancer cells with berberine markedly inhibited their proliferation in a dose- and time-dependent manner. The growth-inhibitory effect was much more profound in MCF-7 cell line than that in MDA-MB-231 cells.

IFN-β is among the most important anti-cancer cytokines. The up-regulation of this gene by berberine is, at least in part, responsible for its anti-proliferative effect. The results of this study implicate berberine as a promising extract for chemoprevention and chemotherapy of certain cancers (Kang, 2005).

Berberine was added to proliferating MCF-7 and MDA-MB-231 cells in culture. Following treatment, changes in cell growth characteristics such as proliferation, cell cycle duration, and the degree of apoptosis were assayed. Following berberine treatment, a time-dependent reduction in proliferation was observed in both cell lines at differing concentrations: 20 microM for MCF-7 and 10 microM for MDA-MB-231 cells. Results demonstrate that treatment with berberine inhibits growth in both MDA-MB-231 and MCF-7 cells. In addition, they show that this partly occurs through the induction of apoptosis in MDA-MB-231 cells, and through both cell cycle arrest and induction of apoptosis in MCF-7 cells (Kim et al, 2008).

Breast Cancer Metastasis

Berberine inhibits the growth of Anoikis-resistant MCF-7 and MDA-MB-231 breast cancer cell lines by inducing cell-cycle arrest. Anoikis, or detachment-induced apoptosis, may prevent cancer progression and metastasis by blocking signals necessary for survival of localized cancer cells. Resistance to anoikis is regarded as a prerequisite for metastasis; however, little is known about the role of berberine in anoikis-resistance.

The anoikis-resistant cells have a reduced growth rate and are more invasive than their respective adherent cell lines. The effect of berberine on growth was compared to that of doxorubicin, which is a drug commonly used to treat breast cancer, in both the adherent and anoikis-resistant cell lines. Berberine promoted the growth inhibition of anoikis-resistant cells to a greater extent than doxorubicin treatment. Treatment with berberine-induced cell-cycle arrest at G0/G1 in the anoikis-resistant MCF-7 and MDA-MB-231 cells was compared to untreated control cells. These results reveal that berberine can efficiently inhibit growth by inducing cell-cycle arrest in anoikis-resistant MCF-7 and MDA-MB-231 cells. Further analysis of these phenotypes is essential for understanding the effect of berberine on anoikis-resistant breast cancer cells, which would be relevant for the therapeutic targeting of breast cancer metastasis Kim et al., 2010).

Invasion of cancer cell induced by matrix metalloproteinase-9 (MMP-9) is one of pivotal steps in cancer metastasis. Kim et al, (2008) investigated how cell invasion was regulated by berberine (BBR). The basal level of MMP-9 activity and expression was dose-dependently increased by TNF-α, while TNF-α-induced MMP-9 gelatinase activity and expression was decreased by BBR.

Data showed that TNF-α-induced AP-1 DNA binding activity was inhibited by BBR. They investigated the effect of BBR on TNF-α-induced cell invasion. TNF-α-induced cell invasion was significantly decreased by BBR treatment. Taken together, we suggest that TNF-α-induced MMP-9 expression and cell invasion are decreased by BBR through the suppression of AP-1 DNA binding activity in MDA-MB-231 human breast cancer cells.

Melanoma

Berberine inhibits melanoma cancer cell migration by reducing the expressions of cyclooxygenase-2, prostaglandin E2 and prostaglandin E2 receptors. The effects and associated molecular mechanism of berberine on human melanoma cancer cell migration (melanoma cell lines A375 and Hs294) were probed in an in vitro cell migration assay. The assay indicated that over-expression of cyclooxygenase COX-2, its metabolite prostaglandin E2 (PGE2) and PGE2 receptors promote the migration of cells.

Moreover, berberine inhibited the activation of nuclear factor-kappa B (NF-kB), an up-stream regulator of COX-2.These results indicate that berberine inhibits melanoma cell migration by inhibition of COX-2, PGE2 and PGE2 receptors. This is an essential step in invasion and metastasis of cancer cells (Sing, 2011).

Nasopharyngeal carcinoma

Growth inhibitory effects of berberine on multiple types of human cancer cells have been reported. Berberine inhibits invasion, induces cell cycle arrest and apoptosis in human cancer cells. The anti-inflammatory property of berberine, involving inhibition of Signal Transducer and Activator of Transcription 3 (STAT3) activation, has also been documented. Berberine effectively inhibited the tumorigenicity and growth of an EBV-positive nasopharyngeal carcinoma (NPC) cell line (C666-1) (Sang et al, 2013). In vitro, berberine inhibited both constitutive and IL-6-induced STAT3 activation in NPC cells. Inhibition of STAT3 activation by berberine induced growth inhibition and apoptotic response in NPC cells. Tumour-associated fibroblasts were found to secret IL-6 and the conditioned medium harvested from the fibroblasts also induced STAT3 activation in NPC cells. Inhibition of tumorigenic growth of NPC cells in vivo was also correlated with effective inhibition of STAT3 activation (Sang et al, 2013).

Cell-cycle Arrest, Squamous-cell Carcinoma

The in vitro treatment of human epidermoid carcinoma A431 cells with berberine decreases cell viability and induces cell death in a dose (5-75 microM)- and time (12–72 hours)-dependent manner, which was associated with an increase in G1 arrest. G0/G1 phase of the cell-cycle is known to be controlled by cyclin dependent kinases (Cdk), cyclin kinase inhibitors (Cdki) and cyclins. Pre-treatment of A431 cells with the pan-caspase inhibitor (z-VAD-fmk) significantly blocked the berberine-induced apoptosis in A431 cells confirmed that berberine-induced apoptosis is mediated through activation of caspase 3-dependent pathway. Together, these results indicate that berberine may be effective as a chemotherapeutic agent against human epidermoid carcinoma A431 (squamous-cell) cells in vitro; further in vivo studies are required to determine whether berberine could be an effective chemotherapeutic agent for the management of non-melanoma skin cancers (Mantena, 2006).

Cervical Cancer, Radio-sensitizer

Cervical cancer remains one of the major killers amongst women worldwide. In India, a cisplatin based chemo/radiotherapy regimen is used for the treatment of advanced cervical cancer. Evidence shows that most of the chemotherapeutic drugs used in current clinical practice are radio-sensitizers. Natural products open a new avenue for treatment of cancer, as they are generally tolerated at high doses. Animal studies have confirmed the anti-tumorigenic activity of natural products, such as curcumin and berberine.

Berberine is a natural chemo-preventive agent, extracted from Berberis aristata, which has been shown to suppress and retard carcinogenesis by inhibiting inflammation.

The combined therapy of cisplatin/berberine and radiotherapy produced up-regulation of pro-apoptotic proteins Bax and p73, while causing down regulation of the anti-apoptotic proteins Bcl-xL, COX-2, cyclin D1. This additionally was accompanied by increased activity of caspase-9 and caspase-3, and reduction in telomerase activity. Results demonstrated that the treatment combination of berberine/cisplatin had increased induction of apoptosis relative to cisplatin alone (Komal, Singh, & Deshwal, 2013)

Cytotoxicity enhancement in mda-mb-231 cells by the combination treatment of tetrahydropalmatine and berberine derived from corydalis yanhusuo

Zhao Y et al. Journal of Intercultural Ethnopharmacology, vol. 3, no. 2, pp. 68–72, 2014.

Aim: Our previous works have demonstrated that Chinese herb medicine yanhusuo (Corydalis yanhusuo W. T. Wang) has strong anti-cancer proliferation effect in MDA-MB-231 cells. The goal of this study was to find out the synergic cytotoxicity effect of three natural compounds, tetrahydropalmatine (THP), berberine (Ber), and dehydrocorydaline (DHC), isolated from C. yanhusuo W. T. Wang. Materials and Methods: The IC50 of THP, Ber and DHC in single use, as well as in combination use at fixed ratios and doses was measured by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay. Isobologram, combination index and modified coefficient of drug interaction (CDI) methods were used for evaluation the combination effects of THP, Ber, and DHC in different ratio and concentration. Results: The results indicated that the combination of THP and Ber shown the strongest anti- cancer cell proliferation effect at the ratio of 2:3 (Ber: THP, the average CDI value was 0.5795). DHC and THP have additive cytotoxicity in MDA-MB-231 cells. However, there wasn’t any synergistic effect between Ber and DHC, and it even exhibited antagonistic effect when the percentage of DHC was >50%. Conclusion: Our findings suggested that the combination of THP and Ber might be beneficial for anti-proliferation of MDA-MB-231 breast cancer cells through a significant synergy effect.

Anti-oxidative; Breast, Liver and Colorectal Cancer

The effect of B. vulgaris extract and berberine chloride on cellular thiobarbituric acid reactive species (TBARS) formation (lipid peroxidation), diphenyle–alpha-picrylhydrazyl (DPPH) oxidation, cellular nitric oxide (NO) radical scavenging capability, superoxide dismutase (SOD), glutathione peroxidase (GPx), acetylcholinesterase (AChE) and alpha-gulcosidase activities were spectrophotometrically determined. Barberry crude extract contains 0.6 mg berberine/mg crude extract. Barberry extract showed potent anti-oxidative capacity through decreasing TBARS, NO and the oxidation of DPPH that is associated with GPx and SOD hyper activation. Both berberine chloride and barberry ethanol extract were shown to have inhibitory effect on the growth of breast, liver and colorectal cancer cell lines (MCF-7, HepG2 and CACO-2, respectively) at different incubation times starting from 24 hours up to 72 hours and the inhibitory effect increased with time in a dose-dependent manner.

This work demonstrates the potential of the barberry crude extract and its active alkaloid, berberine, for suppressing lipid peroxidation, suggesting a promising use in the treatment of hepatic oxidative stress, Alzheimer and idiopathic male factor infertility. As well, berberis vulgaris ethanol extract is a safe non-toxic extract as it does not inhibit the growth of PBMC that can induce cancer cell death (Abeer et al, 2013).

Anti-cancer

Total alkaloid extract (TAE) from Corydalis yanhusuo (YHS) significantly induced the mRNA expression and enzyme activity of CYP2E1 and CYP3A1 in the rat liver, lung, and intestine. Furthermore, enzyme activity correlated well with mRNA expression. The results of the present dose–response study in rats suggest that potential CYP2E1 and CYP3A drug-drug interactions are unlikely at clinical dosages of TAE, but need to be considered when high dosages of TAE or TAE-containing products are co-administered with substrates of CYP1A2 or CYP2C11. Complex herb (drug)-drug interactions may ensue from the co-administration of YHS with other drugs, which is mediated by CYP2E1 and CYP3A1 enzymes (Yan et al, 2014). Dehydrocorydaline, an alkaloid isolated from CM-ext, inhibits MCF-7 cell proliferation by inducing apoptosis mediated by regulating Bax/Bcl-2, activating caspases as well as cleaving PARP (Xu et al, 2012).

Several protoberberine alkaloids (including berberine) found in CM-ext significantly suppressed the VEGF-induced up regulation of matrix metalloproteinase 2 (MMP2) at both mRNA and protein levels. This finding provides insights into the anti-angiogenic effects of C. yanhusuo and berberine, and offer scientific evidence for their traditional clinical application as a cancer treatment (Gao et al, 2009).

Osteosarcoma

Berberine Induced Apoptosis of Human Osteosarcoma Cells by Inhibiting Phosphoinositide 3 Kinase/Protein Kinase B (PI3K/Akt) Signal Pathway Activation.

Osteosarcoma is a malignant tumour with high mortality but effective therapy has not yet been developed. Berberine, an isoquinoline alkaloid component in several Chinese herbs including Huang Lian, has been shown to induce growth inhibition and the apoptosis of certain cancer cells. The aim of this study was to determine the role of berberine on human osteosarcoma cell lines U2OS and its potential mechanism. Berberine treatment caused dose-dependent inhibiting proliferation and inducing apoptosis of U20S cell. Mechanistically, berberine inhibits PI3K/AKT activation that, in turn, results in up-regulating the expression of Bax, and PARP and down-regulating the expression of Bcl-2 and caspase3. In all, berberine can suppress the proliferation and induce the apoptosis of U2OS cell through inhibiting the PI3K/Akt signalling pathway activation.

Berberine can suppress the proliferation and induce the apoptosis of U2OS cell through inhibiting the PI3K/Akt signalling pathway activation.

Plasminogen Activator Inhibitor 1 (PAI-1)

High concentrations of plasminogen activator inhibitor (PAI-1), an endogenous inhibitor of uPA, also correlate with poor prognosis in patients with breast cancer, including the subgroup with node-negative disease (Duffy, 2002). Several studies revealed a paradoxical association between elevated levels of PAI-1 in blood and tissue samples of cancer patients and an unfavourable clinical outcome and poor response to therapy. The production of PAI-1 by endothelial cells (EC), fibroblasts, adipocytes, smooth muscle cells, and macrophage cells in the tumour microenvironment was stimulated by pro-tumorigenic factors such as transforming growth factor (TGF)-β, IL-6, and TNF-α added further evidence supporting a pro-tumourigenic role (Brown, 2010).

In a study by Pierpaoli et al. (2013), PAI-1 expression increased after a 24 hour treatment with 50 μM berberine, with a 3.3-fold increase, and increased by 10-fold after 48 hours in SK-BR-3 (HER-2/ neu) cells. PAI-1 expression only had a slight 2.3-fold increase at 24 hours with a berberine derivative called NAX012. PAI-1 has been used to assess Ras-induced senescence in previous studies, making it a marker of cellular senescence.

Berberine (25 μM) also induced apoptosis in this cell line as well as MCF-7 (ER+/PR+) cells by instigating the mitochondrial intrinsic pathway, and up regulating cytochrome c, p53 and p27 (Patil, Kim, & Jayaprakasha, 2010). Similarly, p53 was upregulated in conjunction with other cellular senescence markers in SK-BR-3 cells by berberine treatment after 24 and 48 hours.

NF-κB

Nuclear factor-kappaB (NF-κB) is usually viewed as a critical component to bridge inflammation and cancer because it can induce more than 200 genes related to inflammation and cancer (Yoon & Baek, 2005). NF-κB is a key orchestrator of innate immunity/inflammation and aberrant NF-κB regulation has been observed in many cancers (Karin, 2006). NF-κB induces the expression of inflammatory cytokines, adhesion molecules, key enzymes in the prostaglandin synthase pathway (COX-2), nitric oxide (NO) synthase and angiogenic factors. In addition, by inducing antiapoptotic genes (e.g. Bcl2), it promotes survival in tumour cells and in epithelial cells targeted by carcinogens. NF-κB is involved in tumour initiation and progression in tissues (Pikarsky et al, 2004). Activated NF-κB has been detected more prominently in ER-negative breast tumours than ER+ breast tumours and mostly in ER-negative and ErbB2-positive tumours (Nakshatri, Bhat-Nakshatri, Martin, Goulet, & Sledge, 1997; Biswas, 2004). Genes involved in the NF-κB signalling pathway such as SP-1, have also been associated with poor prognosis in doxorubicin-treated TNBC (Kim et al, 2016).

Berberine treatment (10−100 μM) affected the cell viability of triple negative MDA-MB-231 and ER+ MCF-7 cells in a dose- and time-dependent manner. A 6−28% reduction in cell viability was observed at 24 hours and a 14−52% reduction was observed at 48 hours in MCF-7 cells. Berberine treatment inhibits cell growth by modulating the expression of cell cycle regulatory proteins (cyclins A, D1, and E), whilst up regulating p21 protein levels in MCF-7 cells. Berberine also affected the Akt signalling pathway, which is a mediator of metastatic potential in cancer cells. Akt mRNA and protein levels were significantly reduced after treatment with 50 μM of berberine in MCF-7 and T-47D cells after 48 hours. Protein levels of cyclin D1, cyclin E, NF-κB (p65), and c-Jun were also reduced in MDA-MB-231 cells after treatment with Berberine. NF-κB and AP-1 (c-Fos and c-Jun) are critical downstream signalling molecules in the Akt pathway, which regulate MM-2 and -9 expression (Kuo et al, 2012).

TNF-α

Tumour necrosis factor-alpha (TNF-α) is an important inflammatory factor that acts as a master switch in establishing an intricate link between inflammation and cancer. A wide variety of evidence has pointed to a critical role of TNF-α in tumour proliferation, migration, invasion and angiogenesis (Wu & Zhou, 2010). Adhesion of cancer cell to endothelial cells and the subsequent trans-endothelial migration are key steps in metastasis. Liang et al, (2007) tested the hypothesis that lectin-like oxidised-low-density lipoprotein (oxLDL) receptor-1 (LOX-1), a key mediator of vascular inflammation and atherosclerosis expressed on endothelial cell surface, mediates breast cancer cell/endothelial cell interactions. They showed that up-regulation of endothelial LOX-1 by TNF-α promoted the adhesion and trans-endothelial migration of MDA-MB-231 breast cancer cells. Thus, endothelial LOX-1 could present a novel pathway in breast cancer metastasis.

Coptis chinensis extracts or C. rhizoma (Chinese pinyin: Huang Lian) were used to treat ER+ MCF7 cells. The cells were treated with 10 μg/ml of Coptis extract for 72 hours, which resulted in 60 to 70% inhibition of cell growth and 35.6% cell death via apoptosis. Cell cycle arrest was also induced at G0/ G1 phase after 24 hours treatment with 5 μg/ml of Coptis extract. Gene expression profiling revealed that there was a ∼200-fold increase in IFN-β expression and a 17-fold up regulation of TNF-α. IFN-β mediates growth inhibitory effects of the extract as revealed through a proliferation assay comparing Coptis treated cells to IFN-β antibody plus Coptis treated cells (Kang, 2005).

The effect of berberine on TNF-α-induced MMP-9 expression and cell invasion in MDA-MB-231 breast cancer cells was investigated. TNF-α-induced cell invasion was significantly (P<0.01) down regulated by 10 μM berberine in the TNBC cells. The MMP-9 promoter has several transcription factor-binding motifs, including AP-1 and NF-κB. Activated AP-1 binds to its response element on the MMP-9 promoter to increase the transcription of MMP-9. TNF-α-induced AP-1 DNA binding activity was significantly decreased by berberine. Additionally, berberine may down-regulate TNF-α-induced MMP-9 gelatinase activity/expression indirectly by inhibiting ERK and p38 pathways in MDA-MB-231 cells. TNF-α-induced cell invasion is prevented by berberine treatment in MDA-MB-231 human breast cancer cells (Kim et al, 2008).

Cytokines

The mixture of cytokines produced in the tumour microenvironment, have an important role in cancer pathogenesis. Cytokines that are released in response to infection, inflammation and immunity can function to inhibit tumour development and progression. Alternatively, cancer cells can respond to host-derived cytokines that promote growth, attenuate apoptosis and facilitate invasion and metastasis (Dranoff, 2004).

Prognostic analysis revealed that high expression of the cytokine MCP-1, as well as VEGF, was a significant indicator of early relapse in primary breast cancer. MCP-1 concentration was significantly correlated with the level of potent angiogenic factors VEGF, TP, TNF-α, and IL-8, as well as a positively associated with IL-6 and -10 (Ueno et al, 2000).

MCF-7 cells were treated with 10 to 160 μM berberine for 24 hours. An MTT assay revealed that growth was inhibited dose dependently, with 36% cells inhibited at 160 μM. The migration of cells was affected to a larger degree after treatment with Berberine. A wound healing assay determined that 80 μM of Berberine could reduce migration significantly to 40% of the control. The underlying mechanisms involved in decreased cell migration in response to berberine were investigated through chemokine receptor gene expression. One of the receptors found to be down regulated by Berberine, CXCR1, binds to pro-inflammatory chemokine’s IL-8/CXCL8 and CXCL6, and has been implicated in the proliferation and metastasis of breast cancer stem cells (Ginestier et al., 2010). Furthermore, the nuclear translocation of NF-κB, results in IL-8 secretion of breast cancer cells. IL-8 may directly activate CXCR1, leading to the promotion of migration and invasion in breast cancer cells (Jiang et al, 2013). Alternatively, the NF-κB may also be activated by chemokine receptor activation. Berberine may also inhibit NF-κB through the down regulation of chemokine receptors, leading to the inhibition of cell migration. Berberine also down regulated other key chemokine’s associated with cancer progression; CXCR4 at 10 μM and above; CCR9 at 20 μM and above; and CCR6 at 40 μM (Ahmadiankia et al, 2016).

VEGF

VEGF is a sub-family of growth factors, specifically the platelet-derived growth factor family of cystine-knot growth factors. They are important signalling proteins involved in both vasculogenesis and angiogenesis (the growth of blood vessels from pre-existing vasculature) (Ferrara & Gerber, 2002). VEGF is critical for vascularisation of tissues, including tumours (Loureiroa & D’Amore, 2005).

VEGF over-expression in breast cancer cells potently increased intra-tumour lymph-angiogenesis, resulting in significantly enhanced metastasis to regional lymph nodes and to lungs. These results establish the occurrence and biological significance of intra-tumour lymph-angiogenesis in breast cancer and identify VEGF as a molecular link between tumour lymph-angiogenesis and metastasis (Skobe et al, 2001) VEGF in breast cancer is not limited to angiogenesis, and that VEGF signalling in breast carcinoma cells is important for the ability of these cells to evade apoptosis and progress towards invasive and metastatic disease. VEGF and VEGF receptor-based therapeutics, in addition to targeting angiogenesis, may also target tumour cells directly (Mercurio et al, 2005).

ZR-75-30 cells, an ER+ breast cancer cell line (Schulte et al, 2012), were treated with 0.78–3.12 µM of berberine. Berberine significantly decreased cell migration of ZR-75-30 cells by down regulating MMP-2 and -9. Berberine also inhibited cell growth in a number of cell lines in a dose-dependent manner, but the IC50 value for ZR-75-30 cells was the lowest at 5.26 μM. Ephrin-B2 signalling mediates cell contact-dependent repulsion, which regulates cell migration. Berberine strongly down regulated the expression of ephrin-B2 and its PDZ binding proteins (Syntenin-1 and PICK1) in ZR-75-30 cells. Ephrin-B2 is required for VEGFR2 internalization and signalling, thus the phosphorylation of several key regulators, were investigated via western blot. Berberine significantly decreased phosphorylation of VEGFR2, as well as downstream protein expression of AKT and Erk1/2 in ZR-75-30 cells in a dose-dependent manner (Ma et al, 2017).

Anti-inflammatory

Berberine is an isoquinoline alkaloid widely distributed in natural herbs, including Rhizoma Coptidis chinensis and Epimedium sagittatum, a widely prescribed Chinese herb (Chen et al, 2008). It has a broad range of bioactivities, such as anti-inflammatory, anti-bacterial, anti-diabetes, anti-ulcer, sedation, protection of myocardial ischemia-reperfusion injury, expansion of blood vessels, inhibition of platelet aggregation, hepato-protective, and neuroprotective effects (Lau et al, 2001; Yu et al, 2005; Kulkarni & Dhir, 2010; Han et al, 2011; Ji, 2011). Berberine has been used in the treatment of diarrhoea, neurasthenia, arrhythmia, diabetes (Ji, 2011).