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: 2.59). 03/2011; 658(2-3):114-22. DOI:10.1016/j.ejphar.2011.02.005
Source: PubMed

ABSTRACT 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.

0 0
  • [show abstract] [hide abstract]
    ABSTRACT: Icaritin, a hydrolytic product of icaritin, is isolated from the traditional Chinese medicinal herb epimedium. Icaritin inhibits the proliferation of several tumor cell lines, but its effect on acute myeloid leukemia (AML) and underlying mechanisms remain to be identified. In the present study, we demonstrated that icaritin inhibits the proliferation of human AML cell lines NB4, HL60, and U937, in a dose- and time-dependent manner. Importantly, icaritin showed anti-leukemia activity on bone marrow mononuclear cells from 15 newly diagnosed AML patients. Flow cytometry analyses indicated that icaritin induces AML cells apoptosis. Icaritin induced activation of caspase-9, -3, -7 and the cleavage of PARP as measured by Western blotting. Icaritin downregulates p-ERK and p-AKT and inhibits the expression of c-myc. These results suggest that icaritin is a promising candidate drug for the treatment of AML. The underlying mechanisms of icaritin anti-AML activity are associated with inhibition of the MAPK/ERK and PI3K/AKT signals and downregulation of c-myc.
    International journal of hematology 04/2013; · 1.17 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Icaritin, an intestinal metabolite of prenylflavonoids from Herba Epimedii, has been known to regulate many cellular processes. The purpose of this study was to investigate the protective effects of icaritin on inflammation in lipopolysaccharide (LPS) stimulated mouse peritoneal macrophages in vitro and zymosan induced peritonitis model in vivo. The release of Nitric oxide (NO) was measured by a Griess reagent system. The phagocytosis, the expression of CD69, the production of inflammatory cytokines and the leukocytes numbers were determined by flow cytometry. The Ca(2+) influx was recorded by confocal microscopy. The phosphorylation of p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) was determined by Western blot. The results showed that icaritin significantly inhibited the NO, IL-6, IL-10 TNF-α, and MCP-1 production both in vitro and in vivo. Icaritin efficiently diminished the uptake of nonopsonized pHrodo™-labeled Escherichia coli bacteria on the LPS-stimulated macrophages. In addition, icaritin significantly inhibited the expression of CD69 on CD11b(+) macrophages. Icaritin pretreatment significantly inhibited the elevation of intracellular Ca(2+) induced by LPS. Furthermore, icaritin markedly decreased phospho-p38 and JNK protein expression in LPS-stimulated mouse peritoneal macrophages. In vivo study, it was also observed that icaritin prolonged survival of peritonitis mice, and inhibited massive leukocyte influx into the peritoneal cavity. These results suggest that icaritin possesses significant anti-inflammatory effects that may be mediated through the regulation of inflammatory cytokines and phosphorylation of p38 and JNK.
    International immunopharmacology 04/2013; · 2.21 Impact Factor
  • Source
    [show abstract] [hide abstract]
    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.
    Journal of Translational Medicine 10/2013; 11(1):252. · 3.46 Impact Factor


Available from

Yuming Guo