Berberine induces autophagic cell death and mitochondrial apoptosis in liver cancer cells: The cellular mechanism

Wang, Ning; Feng, Yibin; Zhu, Meifen; Tsang, Chi-Man; Man, Kwan; Tong, Yao; Tsao, Sai‐Wah

doi:10.1002/jcb.22869

Cited by 262 publications

(190 citation statements)

References 47 publications

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“…Based on the findings outlined above, it is reasonable to hypothesize that berberine induces autophagic cell death, at least in part, through downregulating CD147 and the subsequent inhibition of the Akt signaling pathway, which increases the level of autophagy. A recent study confirmed that berberine suppresses the activity of Akt in HCC cells, (16) which supports this hypothesis. Although a variety of studies have confirmed that berberine exerts its anticancer effects by inducing tumor cell apoptosis, the molecular mechanisms involved are not fully understood.…”

Section: Discussionsupporting

confidence: 60%

“…These results shed further light on the antineoplastic activity of berberine and are in agreement with other recent reports. (16,33) It is interesting that co-incubation of cells with both 3-MA and z-DEVD-fmk did not completely prevent berberine-induced cell death. This suggests that berberine induces not only autophagic cell death and apoptosis, but also some other types of death, such as necrosis.…”

Section: Discussionmentioning

confidence: 99%

“…(11)(12)(13) Previous studies confirm the anti-tumor effects of berberine on HCC. (14)(15)(16) Berberine acts by inhibiting proliferation and inducing apoptosis in HCC cells. It can also inhibit the migration of HCC cells by downregulating the Rho ⁄ ROCK signaling pathway.…”

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confidence: 99%

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Berberine induces cell death in human hepatoma cells in vitro by downregulating CD147

Hou

Xu²,

Liu

et al. 2011

Cancer Science

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The isoquinoline plant alkaloid berberine has anti-tumor effects on a variety of carcinoma cells, mainly through inhibition of cell proliferation, apoptosis induction and cell cycle arrest. However, the mechanisms underlying its role in tumor progression are unknown. In the present study, we investigated the molecular mechanisms involved in berberine-induced cell death in human hepatoma carcinoma cell (HCC) lines HepG2 and SMMC7721. Our results showed that berberine inhibited tumor cell viability in a dose-and time-dependent manner, and induced cell death via apoptosis and autophagy. Moreover, berberine treatment significantly inhibited CD147 expression by HCC cells in a dosedependent manner. Overexpression of CD147 protein markedly reduced berberine-induced cell death. Our data provide the first experimental evidence that berberine induces cell death in HCC cells via downregulation of CD147 and suggest a new mechanism to explain its anti-tumor effects. (Cancer Sci 2011; 102: 1287-1292 B erberine is an isoquinoline alkaloid found in a number of important medicinal plant species such as Berberis aristata and Berberis aquifolium, and has antibacterial,(1) anti-hypertensive, (2) anti-inflammatory, (3) anti-diabetic (4) and anti-hyperlipidemic effects.(5) Recently, researchers have become interested in the anti-neoplastic activities of berberine and have demonstrated its anticancer effects against a variety of human cancer cells both in vitro and in vivo through suppression of tumor cell proliferation, induction of tumor cell apoptosis, and inhibition of both tumor invasion and metastasis.(6,7) These findings suggest that berberine is a promising candidate for clinical use in cancer chemotherapy.Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide and the third leading cause of death from cancer because of its very poor prognosis. More than 1 million cases of HCC occur in the world each year.(8) Hepatocellular carcinoma is highly resistant to conventional systemic therapies and the prognosis for patients with advanced HCC remains poor. Although a lot of progress has been made in terms of chemotherapy, which provides significant survival benefits for patients with HCC, it is associated with significant side-effects, highlighting the need for therapeutic strategies that target tumor cells without compromising normal tissue function.(9,10) Thus, the development of novel systemic agents from natural products with low toxicity and few side-effects is being actively pursued. (11)(12)(13) Previous studies confirm the anti-tumor effects of berberine on HCC. (14)(15)(16) Berberine acts by inhibiting proliferation and inducing apoptosis in HCC cells. It can also inhibit the migration of HCC cells by downregulating the Rho ⁄ ROCK signaling pathway.(17) However, the exact mechanisms underlying the anti-tumor effects of berberine are still unknown. CD147, a glycosylated immunoglobulin super family transmembrane protein, is highly expressed by HCC cells. Several in vitro studies suggest that CD147 promotes...

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

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Berberine induces cell death in human hepatoma cells in vitro by downregulating CD147

Hou

Xu²,

Liu

et al. 2011

Cancer Science

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“…It can effectively induce glioblastoma cells to undergo cellular senescence. Interestingly, while berberine has been reported to exert its cytotoxic effect by inducing apoptosis in numerous types of cancer cells (13,16,18,19), none of the glioblastoma cell lines we tested in this study showed signs of increased apoptosis in response to berberine treatment. Therefore, induction of cellular senescence is probably the major mechanism by which berberine exerts its antitumor effect against glioblastoma cells.…”

Section: Discussionmentioning

confidence: 62%

“…Berberine can induce apoptosis in a variety of cancer cells (12,13,(18)(19)(20). We, therefore, determined whether berberine could also induce apoptosis of glioblastoma cells.…”

Section: Berberine Induces Cellular Senescence Of Glioblastoma Cellsmentioning

confidence: 99%

Berberine Induces Senescence of Human Glioblastoma Cells by Downregulating the EGFR–MEK–ERK Signaling Pathway

Zhao

et al. 2015

Molecular Cancer Therapeutics

110

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Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor and has a poor prognosis. We, here, report a potent antitumor effect of berberine, an isoquinoline alkaloid, on GBM. Berberine was found to have an IC 50 that is much lower than temozolomide in vitro in U87, U251, and U118 glioblastoma cells. Although previous studies showed that berberine primarily exerts its anticancer effect by inducing cell-cycle arrest, apoptosis, and autophagy, we observed that the antitumor effect of berberine on glioblastoma cells was primarily achieved through induction of cellular senescence. In glioblastoma cells treated with berberine, the level of epidermal growth factor receptor (EGFR) was greatly reduced. Examination of the activities of the kinases downstream of EGFR revealed that the RAF-MEK-ERK signaling pathway was remarkably inhibited, whereas AKT phosphorylation was not altered. Pharmacologic inhibition or RNA interference of EGFR similarly induced cellular senescence of glioblastoma cells. Furthermore, the cellular senescence induced by berberine could be rescued by introduction of a constitutive active MKK. Berberine also potently inhibited the growth of tumor xenografts, which was accompanied by downregulation of EGFR and induction of senescence. Our findings thus revealed a new route by which berberine exerts its anticancer activity. Because EGFR is commonly upregulated in glioblastoma, the demonstration of effective inhibition of EGFR by berberine points to the possibility of using berberine in the treatment of patients with glioblastoma.

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Antitumor effect of novel berberine derivatives in breast cancer cells

Pierpaoli

Arcamone²,

Buzzetti³

et al. 2013

BioFactors

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Breast cancer is the most common malignancy and the most common cause of cancer death in elderly women. Chemoprevention with dietary compounds and their synthetic analogs has emerged as an attractive strategy to prevent carcinogenic progression to invasive cancer. In this study, we investigated the efficacy of some new synthetic derivatives of berberine, a phytochemical isolated from Barberry and other plants, to induce growth arrest of HER-2/neu overexpressing SK-BR-3 breast cancer cells. Supplementation with berberine or with the synthetic derivatives NAX012, NAX013, NAX014, and NAX035 exerted a dose- and time-dependent inhibition of SK-BR-3 cell viability, with a greater effectiveness of NAX012 and NAX014 compounds with respect to berberine. This cytotoxic effect was related to an increased number of apoptotic cells that reached 71.6% and 68.4% after 72 h treatment with 50 µM of NAX012 and NAX014, respectively, compared with 44.2% of berberine. Real-time PCR analyses showed that berberine, NAX012 and NAX014 compounds increased the expression of some cell-cycle checkpoint molecules involved in cell senescence such as p53, p21(WAF1) , p16(INK4a) , and PAI-1, already after 24 h of 50 µM treatments. Furthermore, berberine, NAX012 and NAX014, all reduced both HER-2/neu expression and phosphorylation on tumor cells, the NAX014 compound showing the higher effectiveness. These results provide novel information on the mechanisms involved in the anticancer effects of berberine and demonstrate the greater effectiveness of NAX012 and NAX014 analogs in inducing apoptosis and cellular senescence in HER-2/neu overexpressing tumor cell lines.

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Berberine induces autophagic cell death and mitochondrial apoptosis in liver cancer cells: The cellular mechanism

Cited by 262 publications

References 47 publications

Berberine induces cell death in human hepatoma cells in vitro by downregulating CD147

Berberine induces cell death in human hepatoma cells in vitro by downregulating CD147

Berberine Induces Senescence of Human Glioblastoma Cells by Downregulating the EGFR–MEK–ERK Signaling Pathway

Antitumor effect of novel berberine derivatives in breast cancer cells

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