An anticancer agent icaritin induces sustained activation of the extracellular signal-regulated kinase (ERK) pathway and inhibits growth of breast cancer cells

Department of Medical Microbiology and Immunology, Creighton University Medical School, 2500 California Plaza, Omaha, NE 68178, USA.
European journal of pharmacology (Impact Factor: 2.53). 03/2011; 658(2-3):114-22. DOI: 10.1016/j.ejphar.2011.02.005
Source: PubMed


Icaritin, a prenylflavonoid derivative from Epimedium Genus, regulates many cellular processes. However, the function and the underlying mechanisms of icaritin in breast cancer cell growth have not been well established. Here, we report that icaritin strongly inhibited the growth of breast cancer MDA-MB-453 and MCF7 cells. At concentrations of 2-3 μM, icaritin induced cell cycle arrest at the G(2)/M phase accompanied by a down-regulation of the expression levels of the G(2)/M regulatory proteins such as cyclinB, cdc2 and cdc25C. Icaritin at concentrations of 4-5 μM, however, induced apoptotic cell death characterized by the accumulation of the annexin V- and propidium iodide-positive cells, cleavage of poly ADP-ribose polymerase (PARP) and down-regulation of the Bcl-2 expression. In addition, icaritin also induced a sustained phosphorylation of extracellular signal-regulated kinase (ERK) in these breast cancer cells. U0126, a specific ERK activation inhibitor, abrogated icaritin-induced G2/M cell cycle arrest and cell apoptosis. Icaritin more potently inhibited growth of the breast cancer stem/progenitor cells compared to anti-estrogen tamoxifen. Our results indicate that icaritin is a potent growth inhibitor for breast cancer cells and provide a rationale for preclinical and clinical evaluations of icaritin for breast cancer therapy.

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Available from: Xintian Zhang, Dec 02, 2014
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    • "Icaritin is a hydrolytic product of icariin that is extracted from Epimedium brevicornum, which is a traditional Chinese medicine (TCM). Icaritin has showed significant antitumor activities with minor side effects in various neoplasms, such as inducing apoptosis in human endometrial cancer Hec1A cells [2], leading to cell growth inhibition, G1 arrest, and apoptosis of prostate cancer PC-3 cells [3], resulting in cell cycle arrest at the G2/M phase, apoptotic cell death [4] and enhancing radio sensitivity [5] in breast cancer cells, inhibiting growth [6], and reversing multidrug resistance [7] of hepatoma HepG2 cells. For hematopoietic neoplasms, Li and his team demonstrated the antitumor effect of icaritin in acute myeloid leukemia cells [8], and we reported that icaritin showed potent antileukemia activity on chronic myeloid leukemia in vitro and in vivo [9]. "
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    ABSTRACT: Icaritin (ICT), a hydrolytic product of icariin from Epimedium genus, exhibits antitumor activities in several human solid-tumor and myeloid leukemia cells with extensive influence on various cell signal molecules, such as MAPKs being involved in cell proliferation and Bcl-2 participating in cell apoptosis. However, the effect of icaritin on Burkitt Lymphoma has not been elucidated. In the present study, we first screened the potential effect of icaritin on Burkitt lymphoma Raji and P3HR-1 cell lines and found that icaritin showed cytotoxicity in both cell lines. We further found that icaritin could significantly inhibit Raji cells proliferation with S-phase arrest of cell cycle and induced cell apoptosis accompanied by activation of caspase-8 and caspase-9 and cleavage of PARP. We also observed that icaritin was able to decrease Bcl-2 levels, thus shifting the Bcl-2/Bax ratio, and it could obviously reduce c-Myc, a specific molecular target in Burkitt lymphoma. Our findings demonstrated that icaritin showed cytotoxicity, inhibited cell growth, caused S arrest, and induced apoptosis in Burkitt lymphoma cells and provided a rationale for the further evaluation of icaritin for Burkitt lymphoma therapy.
    Full-text · Article · May 2014 · BioMed Research International
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    • "Icaritin has many pharmacological and biological activities, such as suppression of osteoclast differentiation [33], stimulation of neuronal differentiation [34], [35], and promotion of cardiac differentiation of mouse embryonic stem cells [36]. Icaritin was recently demonstrated to induce apoptosis in human endometrial cancer cells [37], and potently inhibited growth of the breast cancer stem/progenitor cells via inhibition of ERK signaling [38]. In hematological malignancy, Icaritin showed potent anti-leukemia activity in chronic myeloid leukemia in vitro and in vivo by regulating MAPK, AKT and JAK2/STAT3 signaling pathways [39]. "
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    ABSTRACT: Signal transducer and activator of transcription-3 (STAT3) is critical for cancer progression by regulating tumor cell survival, proliferation, and angiogenesis. Herein, we investigated the regulation of STAT3 activation and the therapeutic effects of Icaritin, a prenyl flavonoid derivative from Epimedium Genus, in renal cell carcinoma (RCC). Icaritin showed significant anti-tumor activity in the human and mouse RCC cell lines, 786-O and Renca, respectively. Icaritin inhibited both constitutive and IL-6-induced phospho-STAT3 (STAT3(Y705)) and reduced the level of STAT3-regulated proteins Bcl-xL, Mcl-1, Survivin, and CyclinD1 in a dose-dependent manner. Icaritin also inhibited activation of Janus-activated kinase-2 (JAK2), while it showed minimal effects on the activation of other key signaling pathways, including AKT and MAPK. Expression of the constitutively active form of STAT3 blocked Icaritin-induced apoptosis, while siRNA directed against STAT3 potentiated apoptosis. Finally, Icaritin significantly blunted RCC tumor growth in vivo, reduced STAT3 activation, and inhibited Bcl-xL and Cyclin E, as well as VEGF expression in tumors, which was associated with reduced tumor angiogenesis. Overall, these results suggest that Icaritin strongly inhibits STAT3 activation and is a potentially effective therapeutic option for the treatment of renal cell carcinoma.
    Full-text · Article · Dec 2013 · PLoS ONE
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    • "Several other herbal supplements might have beneficial effects as well. For example, icariin, a prenyl flavonoid derivative from Epimedium Genus has been shown to induce cell cycle arrest in breast cancer cells [19] and also has estrogenic effects [20]. Red clover has been shown to possess antioxidant and antiinflammatory activities, as well as inhibit angiogenesis and displaying anti-cancer properties [21]. "
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    ABSTRACT: Gynecological cancers are among the most common in women and are directly related to a variety of hormonal factors. One potential risk factor associated with developing a gynecological malignancy is the ratio of two hormone metabolites, 2-Hydroxyestrone (2-HE) and 16alpha-Hydroxyestrone (16alpha-HE). A number of botanical constituents such as indoles, flavonoids, and resveratrol have been shown to have a favorable effect on the metabolic pathways that affect this ratio. The present study was designed to evaluate if a multi-nutrient supplement containing targeted botanical constituents would affect the 2-HE/16 alpha-HE ratio in middle-aged women. A retrospective analysis was performed on 76 female patients (mean age 54 years) who received 2-HE/16 alpha-HE ratio assessments at two separate time points. The ratio assessment was part of standard care for women who presented with risk indicators associated with a high proliferative state. All patients who completed pre and post assessments were included. Sixty-five of the patients received a multi-nutrient supplement, Lucentia Peak(R), during the study period. Eleven patients chose not to take the supplement, but did receive ratio assessments at similar time points as the treatment group, allowing for between group comparisons. Paired t-tests were used to compare the changes in the 2-HE and 16alpha-HE measures as well as their ratio, both within groups and between groups. The results demonstrated a significant increase in the 2-HE/16alpha-HE ratio in the treated group (pre 0.38 to post 0.57, p<0.0001), and was significantly different (p=0.02) compared to the change in the control group (pre 0.65 to post 0.64). This change appears to be mediated primarily by an increase in the 2-HE level. Individually, 54 patients given Lucentia Peak(R) had increased ratios while 11 patients had a decrease. In the control group, 3 patients had an increase in their ratio and 8 patients had a decrease. The results demonstrated that women receiving the Lucentia Peak(R) multi-nutrient supplement had significant increases in their 2-HE:16alpha-HE ratio, which appears to be mediated primarily by increasing the 2-HE levels. These results suggest further research on phytonutrients that might positively affect estrogen metabolism is warranted.
    Full-text · Article · Oct 2013 · Journal of Translational Medicine
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