KR20140134818A - Composition for Inhibiting Metastasis or Invasion of Cancer Comprising Extracts of Cirsium japonicum var. ussuriense As Active Ingredient - Google Patents
Composition for Inhibiting Metastasis or Invasion of Cancer Comprising Extracts of Cirsium japonicum var. ussuriense As Active Ingredient Download PDFInfo
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- KR20140134818A KR20140134818A KR20130054529A KR20130054529A KR20140134818A KR 20140134818 A KR20140134818 A KR 20140134818A KR 20130054529 A KR20130054529 A KR 20130054529A KR 20130054529 A KR20130054529 A KR 20130054529A KR 20140134818 A KR20140134818 A KR 20140134818A
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- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
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- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/308—Foods, ingredients or supplements having a functional effect on health having an effect on cancer prevention
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Abstract
Description
The present invention relates to a composition for inhibiting metastasis or invasion of cancer comprising an extract of thistle as an active ingredient.
Metastasis refers to a condition in which a primary tumor cell migrates from its original site of origin to another site at a remote location and continues to proliferate in the transplanted site, eventually leading to death in most cancer patients . In order for the metastasis to progress, the metastatic process must undergo a connected, sequential step that the tumor cells undergo, and the metastatic cells undergo invasion and obstruction, survival in the circulation process, remote distant capillary system, And proliferation. ≪ / RTI > In addition, basement membrane and extracellular matrix (ECM) must be degraded in order for invasion and metastasis of malignant tumor cells to occur. The degradation of ECM is initiated by proteolytic enzymes secreted by different types of cells involved in tumor cell infiltration, and the expression or activity of all known types of proteolytic enzymes is associated with malignancy and invasiveness of tumor cells. Of these enzymes, matrix metalloproteinases (MMPs), which can degrade most components of the ECM, play an important role in tumor cell invasion and metastasis. MMPs are proteases, and the basic mechanisms of protein degradation regulate the behavior of various cells in relation to tumor biology. Most MMPs are produced in the form of zymogen (pro-MMP), which requires activation for catalytic activity. These include cancer cell growth, differentiation, apoptosis, migration, and invasion, and modulation of tumor angiogenesis and immune surveillance. MMPs constitute a zinc-dependent endopeptidase family consisting of numerous analogs derived from 21 or more human MMPs and other species [4, 5]. Among the previously reported human MMPs, Gelatinase A (72 kDa type VI collagenase, MMP-2) and Gelatinase B (92 kDa type VI collagenase, MMP 9) are capable of degrading type IV collagen and fibronectin, Is known to be closely related to invasion and metastasis of tumor cells.
It has been reported that the mitogen-activated protein kinase (MAPK) pathway plays a major role in tumor development and invasion, and that inhibition of MAPK signaling reduces tumor invasion. MAPKs are known to be involved in the regulation of proteolytic enzymes that degrade the basement membrane. In metastatic cells, it has been reported that ERK1 / 2 activity is further increased when compared to non-metastatic cancer cells.
ERK1 / 2 phosphorylation modulates the expression of MMP-2 and MMP-9 through the activation of transcription factors including AP-1 (activating protein-1). These proteolytic enzymes mediate tumor invasion and metastasis, suggesting that the MAPK signaling pathway plays an important role in the regulation of cancer cell metastasis processes such as proteolytic enzyme-induction, cell migration and apoptosis. Some natural products known as anticancer agents are known to be highly effective in inhibiting tumor metastasis and invasion. For example, various flavonoids contained in edible plants exhibit anti-metastasis and anti-infiltration effects by inhibiting MMP-9 and MMP-2 enzyme activity.
Numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to better understand the state of the art to which the present invention pertains and the content of the present invention.
The present inventors have made efforts to develop a substance capable of inhibiting cancer metastasis and invasion from natural products. As a result, the present inventors have completed the present invention by experimentally confirming that Cirsium japonicum var. Ussuriense extract can inhibit metastasis and invasion of cancer cells.
Accordingly, an object of the present invention is to provide a composition for inhibiting metastasis and invasion of cancer, which comprises a thistle extract as an active ingredient.
Another object of the present invention is to provide 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one derived from thistle extract, 4-one) as an active ingredient. The present invention also provides a composition for inhibiting cancer metastasis or invasion.
The objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.
According to one aspect of the present invention, there is provided a composition for inhibiting metastasis and invasion of cancer comprising an extract of Cirsium japonicum var. Ussuriense as an active ingredient.
The present inventors have made efforts to develop a substance capable of inhibiting cancer metastasis and invasion from natural products. As a result, it was experimentally confirmed that the extract of Cirsium japonicum var. Ussuriense inhibited the metastasis and invasion of cancer cells.
The composition of the present invention increases the expression of p53 , p21 and Ei24 . Ei24 is a DNA damaging response gene related to cell growth inhibition and cellular apoptosis . Expression of Ei24 gene is directly regulated by p53, and when overexpressed, it inhibits cell growth and induces apoptosis.
As demonstrated in the following specific example of the present invention, the composition of the present invention inhibits the motility of cancer cells and inhibits the infiltration ability of cancer cells.
The cancer to be metastasized or infiltrated in the present invention is not particularly limited, and examples thereof include breast cancer, lung cancer, gastric cancer, liver cancer, blood cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or ocular melanoma, Endometrial cancer, endometrial cancer, small intestine cancer, endocrine cancer, thyroid cancer, pituitary cancer, kidney cancer, soft tissue tumor, urethral cancer, prostate cancer, bronchial cancer or bone marrow cancer.
According to another aspect of the present invention, there is provided a method for producing 5,7-dihydroxy-2- (4-methoxyphenyl) chromen- 4-methoxyphenyl) chromen-4-one as an active ingredient.
The composition of the present invention may be provided in the form of a pharmaceutical composition for inhibiting metastasis or invasion of cancer.
The pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier in addition to thistle extract as an active ingredient. The pharmaceutically acceptable carriers to be contained in the pharmaceutical composition of the present invention are those conventionally used in the present invention and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, But are not limited to, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrups, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. It is not.
The pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. in addition to the above components. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington ' s Pharmaceutical Sciences (19th ed., 1995).
The appropriate dosage of the pharmaceutical composition of the present invention may vary depending on factors such as the formulation method, administration method, age, body weight, sex, pathological condition, food, administration time, administration route, excretion rate, . On the other hand, the oral dosage amount of the pharmaceutical composition of the present invention is preferably 0.001-1000 mg / kg (body weight) per day.
The pharmaceutical composition of the present invention can be administered orally or parenterally, and when administered parenterally, it can be administered by local application to the skin, intravenous injection, subcutaneous injection, muscle injection, intraperitoneal injection, transdermal administration, .
The concentration of 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one, an active ingredient contained in the composition of the present invention, is determined in consideration of the purpose of treatment, And is not limited to a specific range of concentrations.
The pharmaceutical composition of the present invention may be formulated into a unit dose form by formulating it using a pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by a person having ordinary skill in the art to which the present invention belongs. Or by intrusion into a multi-dose container. The formulations may be in the form of solutions, suspensions or emulsions in oils or aqueous media, or in the form of excipients, powders, granules, tablets or capsules, and may additionally contain dispersing or stabilizing agents.
The composition of the present invention may be provided in the form of a food composition for inhibiting cancer metastasis or invasion.
The functional food composition of the present invention includes components that are ordinarily added during the manufacture of food, and includes, for example, proteins, carbohydrates, fats, nutrients, and seasonings. For example, when it is made of a drink, a flavoring agent or a natural carbohydrate may be included as an additional ingredient in addition to thistle extract as an active ingredient. For example, natural carbohydrates include monosaccharides (e.g., glucose, fructose, etc.); Disaccharides (e.g., maltose, sucrose, etc.); oligosaccharide; Polysaccharides (e.g., dextrin, cyclodextrin and the like); And sugar alcohols (e.g., xylitol, sorbitol, erythritol, etc.). Natural flavoring agents (e.g., tau martin, stevia extract, etc.) and synthetic flavoring agents (e.g., saccharin, aspartame, etc.) may be used as flavorings.
The features and advantages of the present invention are summarized as follows:
(i) The present invention relates to a composition for suppressing cancer metastasis or invasion, comprising a thistle extract as an active ingredient.
( Ii ) The composition of the present invention has anti-metastasis and anti-infiltration effects on cancer cells by increasing the expression of Ei24 , p53 and p21 which are involved in the metastasis or invasion of cancer cells.
(Iii) The composition of the present invention can be developed as a pharmaceutical composition or a functional food composition for inhibiting cancer metastasis or invasion.
1 is a schematic diagram of a method for screening an Ei24 activator.
Fig. 2 is a graph showing screening results of a plant extract that activates Ei24- GFP fluorescence.
FIG. 3 shows the result of screening of a plant extract that activates Ei24- GFP in MDA-MB-231 cells.
FIG. 4 shows the result of screening of a plant extract that activates Ei24- GFP in an Ei24- GFP expressing cell line. One plant extract that activates Ei24- GFP from five plant extracts was selected. NP066-053 is a Cirsium japonicum var. Ussuriense extract.
Figure 5 shows the chemical formula of a compound derived from thistle extract.
(a) 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one, (b) 5,7-dihydroxy-2- (4-methoxyphenyl).
6 is a photograph showing fluorescence intensity of Ei24- GFP expressing cell line.
FIG. 7 shows the results of confirming the inhibitory effect of the
FIG. 8 shows the results of measurement of changes in the breeding ability of the human breast cancer cell line MDA-MB-231 by the
FIG. 9 shows the results of Western blotting of changes in Ei24 expression level according to the treatment with the
10 is a result of immunostaining MDA-MB-231 cells treated with the
FIG. 11 shows the results of measurement of changes in p53 expression level according to the treatment with the
FIG. 12 shows the results of measurement of the change in p21 expression level according to the treatment with the
FIG. 13 shows the result of measuring the cell cycle change of MDA-MB-231 according to the treatment with the
FIG. 14 shows the results of measurement of changes in MDA-MB-231 cell infiltration according to the treatment with the
FIG. 15 shows the results of measurement of changes in cell activity of MDA-MB-231 according to the treatment with the
16 shows the results of measurement of tumor volume and weight change according to the treatment of
CTRL: Control group, ACA: 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one.
FIG. 17 shows the results of evaluating the state of lung cancer metastasis according to the treatment with the
CTRL: Control group, ACA: 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one.
18 is a schematic diagram showing the signal transduction pathway of the
Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .
Example
Materials and methods
Experimental material
The
Cell culture
Cell lines expressing MDA-MB-231 (human breast cancer cell line), HepG2 (human liver cancer cell line), HEK-293 (human embryonic kidney cell line) and Ei24- GFP were cultured in DMEM medium containing 10% FBS and 1% antibiotic. All cell lines were cultured in a humidified 5% CO 2 incubator at 37 ° C.
Cell growth and viability assessment
MDA-MB-231 cells were plated in 96-well plates and cultured for 24 hours, then treated with various concentrations of compound for 72 hours. Cell growth was measured by MTT (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyl tetrazolium bromide, Sigma-Aldrich, USA) colorimetric assay and viability was assessed by trypan blue staining 18). MDA-
Western blot analysis
The cell lysate was loaded onto 10% SDS (sodium dodecyl sulfate-polyacrylamide) gel, electrophoresed and then transferred to PVDF membrane (polyvinylidene fluoride membranes, Millipore, USA). Membranes were blocked and primary antibodies (anti-Ei24, anti-p53, anti-p21 and anti-tubulin antibodies) were treated overnight at 4 ° C. Immunolabeling was detected according to the manufacturer's instructions using an ECL (enhanced chemiluminescence) kit (GE Healthcare, UK). The bands on the membranes shown through immunoassay detection were observed using Universal Hood III (Bio-Rad Laboratories, Inc, USA).
Wound-healing assay
For cell motility evaluation, MDA-MB-231 cells were seeded into 6-well plates at 3x10 5 cells / mL and cultured on plates until 80-90% filling. After the medium was removed, a portion of the cell monolayer was scraped with a sterile micropipette tip to create a gap of constant width. Cell debris was then washed with PBS (1X) and cells were treated with 5, 7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one at a concentration of 1, 5, 10 [mu] M. The cell state was photographed 24 hours later using an Olympus IX70 microscope (Olympus America, Inc., USA) at a magnification of 100x.
In vivo experiments on
MMTV-PyMT transgenic mice were used to investigate the effect of the
Statistical analysis
Results were expressed as mean ± standard deviation. Student's T test was used to assess statistical differences between the control and experimental groups. A p-value less than 0.05 was considered statistically significant.
Experiment result
Screening of compounds derived from natural products
Cell-based screening was performed to find low molecular compounds that activate the Ei24 gene from plants (Fig. 1), and it was confirmed that 9700 plant extracts induced Ei24- GFP fluorescence activity (Fig. 2). First, 50 plant extracts were selected (FIG. 3) and finally 5 candidate materials were selected and re-tested at various doses (FIG. 4). It was finally confirmed that the
Increased Ei24-GFP fluorescence activity by thistle extract and 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one
When treated with thistle crude extract, Ei24 -GFP fluorescence activity was increased in Ei24 -GFP MDA-MB-231 cells. It was determined whether 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one would be a major active ingredient in thistle extract and whether Ei24- GFP fluorescence was increased. As shown in FIG. 6, the 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one increased Ei24- GFP fluorescence activity in a dose-dependent manner. These results indicate that the 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one is a novel natural material-derived low molecular weight compound that induces Ei24- GFP fluorescence activity.
The effect of 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one on MDA-MB-231, HepG2 and HEK-293 cell proliferation was evaluated (FIG. The cancer cells were treated with various concentrations of 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one for 3 days and cell growth was measured by MTT colorimetric assay. (IC 50 , 34 μM), HepG2 (IC 50 , 50 μM), HEK-293 (IC 50 , 50 μM), and 5,7-dihydroxy- , 100 [mu] M) cells (Fig. 7). These results indicate that the 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one is more effective in inhibiting the growth of MDA-MB-231 cells than HepG2 and HEK-293 cells do. Treatment of MDA-MB-231, HepG2, and HEK-293 cells with 1-50 μM of 5,7-dihydroxy-2- (4-methoxyphenyl) chromen- Method, the 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one decreased cell viability in a dose-dependent manner (0-10 mu M) (Fig. 8).
Western blot was performed using an anti-Ei24 antibody to confirm that 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one increases the expression of the Ei24 gene. (0-24 hours) of 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one at concentrations of 1, 5 and 10 μM resulted in Ei24 gene expression of 5, Dependent on the concentration of 7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one and the treatment time (FIG. 9). In addition, the immunostaining fluorescence intensity of the anti-Ei24 antibody increased depending on the dose of 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one (FIG. 10).
Increased expression of p53 and p21 by the
The Ei24 gene is directly regulated by p53 and (10) the 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one increases Ei24 gene expression. In order to confirm whether 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one increases the expression of p53 , Western blotting was performed using anti-p53 antibody. 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one (10 [mu] M) increased expression of p53 in dependence of treatment time (0-24 hours) (Fig.
At 12 hours after treatment with 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one, the expression level of p53 was three times higher than that of the control group. Expression of p21 was also dependent on the treatment capacity (1, 5, 10 [mu] M) and treatment time (0-24 hours) of 5,7-dihydroxy-2- (4-methoxyphenyl) (Fig. 12).
MDA-MB-231 cell cycle arrest by
The effect of 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one on cell cycle progression of MDA-MB-231 is shown in FIG. When treated with 1
Compound MDA-MB-231 cell infiltration and motility inhibition by 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-
Cells were stimulated with serum to pass MDA-MB-231 cells through Matrigel. Compared with the control group, treatment with 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one inhibited dose-dependent invasiveness. Treatment of 10 μM of 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one resulted in 26% of infiltrated MDA-MB-231 cells (FIG. 14).
In addition, a wound healing assay was performed to evaluate the activity change of MDA-MB-231 cells according to 5,7-dihydroxy-2- (4-methoxyphenyl) chromen- Respectively. As a result, 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one suppressed the activity and migration rate of cells. When the 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one was treated with 10 μM, cell activity was inhibited to 44.5% (FIG.
To investigate the effect of 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one on the metastasis, MMTV-PyMT mouse control (n = 5) and 5,7- (N = 6) were prepared and dissected at 15 weeks of age to determine the body weight, tumor volume, and tumor weight (FIG. 16). The tumor volume in the 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one treated group was small as compared with the control group and the tumor weight was light compared with the control group. However, the phenotype of the transgenic mice was not significantly different between the control group and the 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one treated group. Tumor development was observed in 10 mammary glands in both the control and 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one treated groups and these results suggest that 5,7-dihydroxy- - (4-methoxyphenyl) chromen-4-one has non-toxic activity in tumor growth. However, the numbers of pulmonary metastases were different in the control and 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one treated groups. The spread of the tumor on the lung surface was significantly inhibited in the 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one treated group (Fig. 17). In conclusion, 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one is more effective at inhibiting cancer metastasis than tumor growth inhibition.
Argument
The present invention demonstrates that thistle extract activates Ei24- GFP fluorescence and Ei24 gene expression. At the molecular level, apoptosis mechanisms are very complex and involve a variety of genes and proteins. Ei24 gene Ei24 mechanism of cell death in the mechanism as a strong cancer inhibitor is important for understanding the function of the gene Ei24. The present inventors have confirmed that 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one inhibits cancer metastasis activity in vitro. In addition, the in vivo test showed that 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one was effective in inhibiting metastasis from breast cancer to lung cancer in the MMTV-PyMT transgenic mouse model Respectively.
conclusion
Using a cell-based screening assay, 9,700 plant extracts were screened and plant extracts were obtained to activate Ei24- GFP fluorescence and Ei24 gene expression. Among the extracts screened, 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one, a low molecular weight substance obtained from thistle extract, showed the highest Ei24- GFP fluorescence and Ei24 gene activation activation effect Respectively. In addition, the inventors evaluated the effect of 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one on Ei24 expression levels by analyzing immunostained images using confocal microscopy. MDA-MB-231 cells were more sensitive to inhibition of cell proliferation by 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one compared to HepG2 and HEK-293 cells. The cell viability of MDA-MB-231 decreased dependent on the treatment concentration of 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one. The 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one increased the expression of p21 , a target gene for cancer suppressor genes p53 and p53 . Furthermore, the 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one caused the cell cycle to stop in the sub-GO group. Through wound healing assays and cell invasion assays, it was confirmed that 5,7-dihydroxy-2- (4-methoxyphenyl) chromen-4-one inhibits cancer metastasis activity in a dose-dependent manner.
references
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While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.
Claims (8)
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| KR20220003917A (en) * | 2020-07-02 | 2022-01-11 | 경희대학교 산학협력단 | Pharmaceutical composition for preventing or treating cancers comprising the gold nanoparticle of Crisiumjaponicum |
| KR20230036569A (en) * | 2021-09-06 | 2023-03-15 | 충남대학교산학협력단 | Composition for preventing, improving or treating prostate disease comprising extract of Cirsium japonicum De Candole as effective component |
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| KR20220003917A (en) * | 2020-07-02 | 2022-01-11 | 경희대학교 산학협력단 | Pharmaceutical composition for preventing or treating cancers comprising the gold nanoparticle of Crisiumjaponicum |
| KR20230036569A (en) * | 2021-09-06 | 2023-03-15 | 충남대학교산학협력단 | Composition for preventing, improving or treating prostate disease comprising extract of Cirsium japonicum De Candole as effective component |
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