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Background: Interleukin-8 (IL-8) expression is associated with metastasis in a variety of cancer cells., Purpose: Here, we investigated the regulatory mechanism of IL-8 expression as well as the pharmacological effect of berberine (BBR) on IL-8 expression in triple-negative breast cancer (TNBC) cells., Methods: The clinical value of IL-8 was analyzed by from a public database [Kaplan‑Meier plotter database. IL-8 mRNA and protein expression was analyzed by real-time PCR and ELISA, respectively. Cell invasion was analyzed by Boyden chamber assay. Tumor cell growth was analyzed by colony forming assay., Results: Clinically, we observed that breast cancer patients with highly expressed IL-8 are associated with poor outcomes in areas such as relapse-free, overall, and distant metastasis-free survival. We showed that IL-8 expression is higher in TNBC cells than in non-TNBC cells. In addition, the rates of cell invasion were significantly increased by IL-8 treatment. These IL-8 levels were decreased by EGFR (Neratinib and Afatinib) and MEK (PD98059) inhibitors in TNBC cells. Finally, we observed that BBR dramatically suppresses IL-8 expression. In addition, BBR also inhibited cell invasiveness and anchorage-independent growth. Interestingly, our results showed that BBR down-regulates EGFR protein expression and dose-dependently inhibits MEK and ERK phosphorylation., Conclusion: Here, we demonstrate that BBR may be a promising drug to suppress cell invasiveness and growth of TNBC through IL-8-related mechanisms., (Copyright © 2018. Published by Elsevier GmbH.)

Background/aims: Berberine (BBR) is an isoquinoline alkaloid and is beneficial for the anticancer effect on a variety of human tumor cells. However, BBR's anti-angiogenesis property and its clinical potential as an inhibitor of tumor angiogenesis in breast cancer cells have not been fully elucidated. Here, we investigated the effect of BBR on TPA-induced VEGF and fibronectin (FN) as well as VEGF-induced FN in breast cancer cells., Methods: The secretion of VEGF protein was detected by ELISA. Fibronectin mRNA and protein expression was analyzed by Real-Time PCR and western blotting, respectively. The overexpressions of CA-MEK, and CA-Akt were examined by adenovirus system., Results: Our results showed that TPA, a tumor promoter, significantly increased the level of VEGF and FN expression in both MCF7 and T47D breast cancer cells. On the other hand, TPA-induced VEGF and FN expression was suppressed by LY294002, a PI-3K inhibitor. In contrast, the level of FN expression also significantly increased by constitutively active (CA)-AKT overexpression. We also found that TPA-induced VEGF and FN expression was decreased by BBR treatment. Finally, our results showed that VEGF augmented the expression of FN whereas VEGF-induced FN expression was decreased by BBR treatment., Conclusion: Taken together, we suggest that BBR 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. Therefore, we suggest that BBR may be used as a candidate drug for the inhibition of angiogenesis of human breast cancer., (© 2014 S. Karger AG, Basel.)

Background: Berberine (BBR) is one of the major alkaloids, and it has been reported to have a variety of pharmacologic effects, including inhibition of cell cycle progression. Here, we investigated the effect of BBR on the MMP-1 and MMP-9 expressions, which are predictors of metastasis and invasion in breast cancer cells., Methods: MMP-1 and MMP-9 mRNA expressions were analyzed by real-time PCR. The levels of MMP-1 protein and PKC-α phosphorylation were detected by Western blotting. MMP-9 protein expression was detected by gelatin zymography. Cell cycle was analyzed by FACS analysis. PKC-α knock-down was examined by PKC-α siRNA transfection., Results: The basal levels of both the MMP-1 and MMP-9 mRNA expressions were decreased by BBR treatment in a dose-dependent manner. In contrast, TPA, which is a tumor promoter, significantly increased the levels of the MMP-1 and MMP-9 mRNA and protein expressions in the MCF-7 breast cancer cells. We also observed that the TPA-induced MMP-1 and MMP-9 mRNA and protein expressions were prevented by BBR treatment. In addition, the TPA-induced MMP-1 and MMP-9 expressions were completely decreased by Go6983 and PKC-α siRNA, respectively. TPA-induced PKC-α phosphorylation was dose-dependently decreased by BBR treatment., Conclusion: The TPA-induced PKC-α phosphorylation is suppressed and then the MMP-1 and MMP-9 expressions are also inhibited by berberine. Therefore, we suggest that berberine may be used as a candidate drug for the inhibition of metastasis of human breast cancer., (Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.)

Berberine (BBR), an isoquinoline derivative alkaloid compound, has been reported to have anti-oxidant and anti-carcinogenic effects. A loss of functional p53 is involved with an increased risk of cancer proliferation and metastasis. Here, we investigated the effect of BBR on the transcriptional activity and the protein expression of p53 in p53-positive (wild- type, MCF7 cells) and p53-negative (mutant, MDA-MB231 cells) human breast cancer cells. Our results showed that the basal level of p53 mRNA and protein expression was increased by BBR treatment. However, tumor promoter, TPA, decreased the level of p53 mRNA and protein expression in MCF7 cells with wild-type p53. In addition, TPA-induced down-regulation of p53 mRNA and protein expression was increased by UO126, but not by SP600125 and SB203580. To verify the regulatory mechanism of p53 protein expression, we investigated the effects of proteasomal inhibitors (ALLN and MG132) or a lysosomal inhibitor (chloroquine) on TPA-induced down-regulation of p53. We observed that TPA-induced down-regulation of p53 protein was prevented by ALLN and MG132, but not by chloroquine. Further, we investigated the effect of BBR on TPA-induced down-regulation of p53 mRNA and protein levels. Interestingly, the levels of TPA-induced down-regulation of p53 mRNA and protein were prevented by BBR, but MDA-MB231 cells with mutated p53 were not affected. In addition, TPA-induced down-regulation of p53 mRNA was also prevented by BBR. Taken together, we suggest that BBR may be used as an effective ingredient for anticancer products, which trigger the transcriptional activity and the inhibition of the degradation of p53, a tumor suppressor gene, in human breast cancer.

Invasion of cancer cell induced by matrix metalloproteinase-9 (MMP-9) is one of pivotal steps in cancer metastasis. Herein, we investigated how cell invasion was regulated by berberine (BBR), an isoquinoline derivative alkaloid compound, in MDA-MB-231 human breast cancer cells. The basal level of MMP-9 activity and expression was dose-dependently increased by TNF-alpha, while TNF-a-induced MMP-9 gelatinase activity and expression was decreased by BBR. To investigate regulatory mechanism of TNF-alpha-induced MMP-9 expression, we pretreated cells with UO126 (MEK inhibitor), SB203580 (p38 inhibitor) and SP600125 (JNK inhibitor), respectively. Interestingly, TNF-alpha-induced MMP-9 activity and expression was decreased by UO126 and SB203580, but not by SP600125. Therefore, we further examined the effects of BBR on TNF-alpha-induced AP-1 DNA binding activity which is a downstream target of ERK and p38. Our data showed that TNF-alpha-induced AP-1 DNA binding activity was inhibited by BBR. Finally, we investigated the effect of BBR on TNF-alpha-induced cell invasion. TNF-alpha-induced cell invasion was significantly decreased by BBR treatment. Taken together, we suggest that TNF-alpha-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.

Matrix metalloproteinases (MMPs) induction and type I procollagen reduction in photoaging of the skin due to exposure to ultraviolet (UV) irradiation. Therefore, regulation of these genes has been suggested to be a useful tool to abolish skin aging. In this study, antioxidative plant ingredients used in traditional Chinese medicine, berberine (BBR) was investigated for their capacity to regulate MMP-1 and type I procollagen expression in human dermal fibroblasts. Our results showed that both basal and UV-induced MMP-1 expression was decreased by BBR. On the other hand, type I procollagen expression was dose-dependently increased by it. In addition, UV-induced reduction of type I procollagen expression is recovered by it. Therefore, we suggest that BBR may be a possible candidate for anti-skin aging agent.

Berberine is a plant ingredient that has anti-inflammatory and anti-oxidative effects. Matrix metalloproteinase-9 (MMP-9) and interleukin-6 (IL-6) are known to be highly induced by ultraviolet (UV) light and may play important roles in UV-induced skin inflammation and the skin aging process. In this study, we investigated the effects of berberine on MMP-9 and IL-6 expression in normal human keratinocytes (NHK). Our results demonstrated that berberine dose-dependently inhibited basal and TPA-induced expression and activity of MMP-9, and also suppressed TPA-induced IL-6 expression. Berberine prevented TPA-induced ERK activation and AP-1 DNA binding activity. Therefore, berberine may be used as an effective ingredient for anti-skin aging products, which can prevent skin inflammation and the degradation of extracellular matrix proteins, including collagen, by MMPs.

The effects of berberine on the behavior of breast tumors have not yet been established. To determine whether this compound is useful in the treatment of breast cancer, we analyzed the impact of berberine on the human breast cancer cell lines MCF-7 and MDA-MB-231 cells. 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. Annexin V staining showed an increase in apoptosis in both cell lines of 31 % in MCF-7 and 12 % in MDA-MB-231 cells compared to their respective controls. In addition, 12 % of the MCF-7 cells were arrested at G0/G1, compared to 62 % of control cells. These 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. Thus, berberine may be a novel therapeutic drug for breast cancer.

Background/Aims: Transforming growth factor-beta proteins (TGF-βs) are multifunctional growth factors and powerful modulators of the epithelial-mesenchymal transition (EMT) in a variety of cancer types including breast and lung cancer cells. Here, we demonstrated the inhibitory effect of berberine (BBR) on tumor growth and metastasis of triple negative breast cancer (TNBC) cells via suppression of TGF-β1 expression. Methods: The levels of mRNA expression were analyzed by real-time PCR. The levels of MMP-2, MMP-9 and TGF-β1 protein expression were analyzed by zymography and confocal microscopy, respectively. Cell migration was analyzed by wound healing assay. Tumorigenicity of TNBC cells such as tumor growth and metastasis was analyzed using xenograft models. Results: In a clinical data set, aberrant TGF-β1 expression was associated with poor prognosis of breast cancer patients. Our in vitro results using TNBC cells showed that the expression levels of matrix metalloproteinase (MMP)-2 and MMP-9 and the capacity for cell migration were increased by TGF-β1 treatment. In contrast, basal levels of MMP-2 and MMP-9 were suppressed by a specific TGF-β receptor I inhibitor, SB431542. In addition, TGF-β1–induced MMP-2 and MMP-9 expression and cell migration were decreased by SB431542. Interestingly, we showed for the first time that BBR decreased the level of TGF-β1, but not TGF-β2, in TNBC cells. Furthermore, BBR significantly decreased the level of MMP-2 expression as well as the capacity for cell migration in TNBC cells. Finally, we examined the effect of BBR on in vivo tumor growth and lung metastasis in MDA-MB231 and 4T1 breast cancer xenograft models and showed that both were significantly decreased following BBR treatment. Conclusion: BBR suppresses tumorigenicity of TNBC cells through inhibition of TGF-β1 expression. Therefore, we demonstrate that BBR could be a promising drug for treatment of TNBC. [ABSTRACT FROM AUTHOR]