KR20170104776A - Pharmaceutical composition for preventing or treating cancer comprising Punctaria latifolia extract - Google Patents
Pharmaceutical composition for preventing or treating cancer comprising Punctaria latifolia extract Download PDFInfo
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- KR20170104776A KR20170104776A KR1020160027598A KR20160027598A KR20170104776A KR 20170104776 A KR20170104776 A KR 20170104776A KR 1020160027598 A KR1020160027598 A KR 1020160027598A KR 20160027598 A KR20160027598 A KR 20160027598A KR 20170104776 A KR20170104776 A KR 20170104776A
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- 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
The present invention relates to a pharmaceutical composition for preventing or treating cancer, which comprises a brown algae extract, and provides a pharmaceutical composition for prevention or treatment of cancer, which comprises a broad spectrum astaxanthin extract.
The pharmaceutical composition of the present invention inhibits the growth of cancer cells and induces apoptosis, and thus can be usefully used for the prevention and treatment of cancer.
Description
The present invention relates to a pharmaceutical composition for preventing or treating cancer, which comprises a brown algae extract, and more particularly, to a pharmaceutical composition for preventing or treating cancer, which comprises a broad range of extracts exhibiting an effect of inhibiting growth by inducing apoptosis in cancer cells ≪ / RTI >
Cancer is one of the diseases threatening human life around the world, and cancer incidence and mortality are steadily increasing due to inherited causes such as domestic and Westernized diet and environment (Non-Patent Documents 1 and 2). Stomach cancer has a high incidence in Asia, and it occurs at high frequency in South America and Eastern Europe (Non-Patent Document 3).
Currently, there are surgery, chemotherapy, and radiation therapy for stomach cancer, but there is a high possibility of recurrence even after surgery, and it is difficult to expect a good prognosis due to low survival rate (Non-patent
Cancer (cancer) remains unclear and remains a refractory disease. Various treatments such as chemotherapy, radiotherapy and immunotherapy have been introduced to treat it. However, it has been known that cancer affects normal cells and causes serious side effects (Non-Patent Documents 8 and 9). In order to overcome this problem, development of anticancer drugs with low side effects and development of drugs that prevent the development of cancer have been actively conducted (Non-patent Documents 10 to 12).
For a long time, human beings have used natural resources obtained from the ocean and land as food ingredients, medicines, and health supplements (Non-patent Documents 13 and 14). In particular, brown algae, which is a marine resource, is most widely consumed in Asia, and is known as a natural resource rich in proteins and minerals and having various physiological activity functions. Such natural resources have been found to contain active ingredients that regulate physiological activities such as antioxidant and anti-cancer in vivo, and research on the development of natural resource anticancer drugs that act specifically on cancer cells has been actively conducted (see Non-patent Documents 15 to 18 ).
As a representative marine resource, seaweed belonging to brown algae, sea tangle and the like are known to have various physiological activities such as anticancer, anticoagulant, antibacterial, anti-inflammation and prevention of hypertension (Non-patent Documents 19 to 22). The principal components of brown algae are structurally similar polysaccharides such as cellulose, and viscous polysaccharides such as alginic acid, laminaran, and fucoidan. These components are recognized for their ability to regulate physiological activity, Is underway. In particular, fucoidan and laminaran are known to have excellent physiological activities such as anticancer and anticoagulant (Non-Patent Documents 23 and 24).
According to the existing (non-patent document 25) studies, many kinds of anticancer drugs are known to inhibit the development and progression of cancer by inducing apoptosis in cancer cells. Such apoptosis is involved in normal development and differentiation in the developmental stage of an individual, and eliminates abnormal cells and damaged cells in the cell prior to defense for the survival of the individual in DNA damage and virus infection (Non-Patent Document 26).
The Bcl-2 family, which is known to inhibit the development and progression of cancer through cell death, is distinguished as a pro-apoptotic protein and an anti-apoptotic protein (Non-Patent Document 27 ). Bax, Bid, and Bad proteins are known to exfoliate the mitochondrial outer wall and induce apoptosis. Anti-apoptotic proteins include Bcl-2, Bcl-xL, and A1, which preserve the outer wall of mitochondria and inhibit cell death (Non-patent Documents 28-30).
Recently, consumption of plants in marine and terrestrial species has been increasing, and studies on the search for functional substances such as anticancer, anti-obesity, antioxidant, and antibacterial using natural substances obtained from such plants have been actively conducted (Non-Patent Documents 31 and 32). As a natural resource that can be easily obtained from the ocean, brown algae such as seaweed, kelp, and tortoise are widely used as food ingredients and health supplement foods in daily life. Such brown algae have been reported to have anticancer, anti-inflammatory, antibacterial effects (Non-Patent Document 33). Korean Patent No. 10-1110063 (published December 16, 2010) discloses an anticancer composition comprising astaxanthin, and Korean Patent Publication No. 10-2015-0102752 (published on June 20, 2015) An anticancer composition containing galactofuko-oligosaccharide as an active ingredient has been disclosed.
However, since the composition of all brown algae is not proven yet, various studies are under way. Especially, deep - seaweed and broad - seaweed are similar to seaweed, but studies using it are poor. In this study, we investigated the effects of seaweed, vinegar, and broad vinegar extracts on brown algae AGS and breast cancer cells MDA-MB-231 and SK-BR-3.
The inventors of the present invention found out that a wide range of starch extract is useful for inhibiting the growth of cancer cells while studying the anticancer effect of brown algae.
Accordingly, it is an object of the present invention to provide a pharmaceutical composition for prevention or treatment of cancer, which comprises a broad spectrum astringent extract.
According to one aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating cancer, which comprises a broad astringent extract.
In one embodiment, the broad astringent extract may be extracted with a solvent selected from the group consisting of methanol, distilled water, ethanol, acetone, ethyl acetate, saturated n-butanol, chloroform, methylene chloride, water, The selected solvent may be an aqueous 80% ethanol solution.
In one embodiment, the broad astringent extract can induce auto-apoptosis of cancer cells.
In one embodiment, the cancer may be gastric or breast cancer.
According to one aspect of the present invention, there is provided a food composition comprising a broad astringent extract.
In one embodiment, the broad astringent extract may be extracted with a solvent selected from the group consisting of methanol, distilled water, ethanol, acetone, ethyl acetate, saturated n-butanol, chloroform, methylene chloride, water, The selected solvent may be an aqueous 80% ethanol solution.
It has been found by the present invention that a wide range of starch extract induces apoptosis and inhibits the growth of cancer cells. Accordingly, the pharmaceutical composition containing the broad range of the extract of the present invention can be usefully used for prevention and treatment of cancer.
Figure 1 (A) AGS, (B) MDA-MB-231 , and (C) SK-BR-3 cells (2 x 10 4 cells / ml ) seaweed for (Undaria pinnatifida, UP), seaweed iron (Petalonia binghamiae , PB) and Punctaria latifolia (PL) extracts. (Data are shown as the mean and standard deviation for the triple test. * P <0.05 was considered significant for the control group ).
FIG. 2 is a graph showing the frequency of (A) chromatin condensation and (B) cell killing after treatment of AGS, MDA-MB-231 and SK-BR-3 cells with a wide range of starch extract.
FIG. 3 shows the results of the effect of broad-spectrum extracts on Bcl-2 family expression in AGS, MDA-MB-231 and SK-BR-3 cells. (A) Antibodies (anti-Bax and anti- ) And (B) Bax / Bcl-2 values calculated from the ratio of Bax and Bcl-2 on the basis of [beta] -actin.
Fig. 4 shows Western blot results showing the effect of a wide range of starch extract on expression of PARP protein in AGS, MDA-MB-231 and SK-BR-3 cells.
As used herein, "apoptosis" means autologous cell death of a cell. It is a process that starts when the cell shrinks, and after that, a gap is formed between adjacent cells, and the DNA is regularly cleaved and fragmented to kill the cell, which is also called prospective cell death.
The present invention provides a pharmaceutical composition for preventing or treating cancer, which comprises a broad astringent extract.
In one embodiment of the invention, the broad astringent extract may be extracted with a solvent selected from the group consisting of methanol, distilled water, ethanol, acetone, ethyl acetate, saturated n-butanol, chloroform, methylene chloride, water, , And the selected solvent may be an aqueous 80% ethanol solution.
In one embodiment of the present invention, the broad astringent extract may induce auto-apoptosis of cancer cells.
In one embodiment of the invention, the cancer may be gastric or breast cancer.
In one embodiment of the invention, the pharmaceutical composition may further comprise at least one pharmaceutically acceptable carrier or additive. That is, the pharmaceutical composition of the present invention can be formulated in the form of oral, granule, tablet, capsule, suspension, emulsion, syrup, aerosol or the like oral preparation, external preparation, suppository and sterilized injection solution according to a conventional method . The pharmaceutically acceptable carrier may be selected from the group consisting of lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, Cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, and the like. It also includes diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, and the like. Solid form preparations for oral use include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose or lactose lactose, gelatin and the like, and may include lubricants such as magnesium stearate and talc. Oral liquid preparations include suspensions, solutions, emulsions, syrups, and the like, and may contain diluents such as water and liquid paraffin, wetting agents, sweetening agents, fragrances, preservatives and the like. Examples of the non-aqueous solution include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations and suppositories. Non-aqueous solvents and suspensions include vegetable oils such as propylene glycol, polyethylene glycol and olive oil, ethyl And injectable esters such as oleate. As a suppository base, witepsol, macrogol, tween, cacao butter, laurin, glycerogelatin and the like can be used.
The dosage of the broad astringent extract contained in the pharmaceutical composition of the present invention varies depending on the condition and the weight of the patient, the degree of disease, the drug form, the administration route and the period, but can be appropriately selected by those skilled in the art. For example, the broad astringent extract may be administered at a dose of 0.0001 to 1000 mg / kg, preferably 0.01 to 1000 mg / kg per day, and the administration may be administered once a day or several times a day. In addition, the pharmaceutical composition of the present invention may contain 0.001 to 50% by weight of a broad astringent extract based on the total weight of the composition.
In addition, the present invention provides a food composition comprising a broad flavor extract.
In one embodiment of the invention, the broad astringent extract may be extracted with a solvent selected from the group consisting of methanol, distilled water, ethanol, acetone, ethyl acetate, saturated n-butanol, chloroform, methylene chloride, water, , And the selected solvent may be an aqueous 80% ethanol solution.
Hereinafter, the present invention will be described in more detail through examples and test examples. However, the following examples and test examples are provided for illustrating the present invention, and the scope of the present invention is not limited thereto.
<Examples>
1. Cell lines and reagents
Gastric cancer cell AGS and breast cancer cells MDA-MB-231 and SK-RB-3 were distributed from KCLB (Korea Cell Line Bank, Seoul, Korea). 1% streptomycin / penicillin (BRL, Grand Island, NY, USA) was purchased from Welgene (Gyeonsan, Korea) and 5% fetal bovine serum Were purchased from Gibco. Typical reagents used in this study were purchased from Sigma Chemical Co. (St. Louis, Mo., USA). Antibodies (anti-rabbit IgG, anti-Bax, anti-Bcl-2, anti-β-actin and anti-PARP) were purchased from Cell signaling Technology (Danvers, MA, USA).
2. Preparation of brown algae extract
The extracts of Undaria pinnatifida (UP), Petalonia binghamiae (PB) and Punctaria latifolia (PL) were all collected from the Marine Brown Algae Resources Bank, Gwangju, Korea. . The collected samples were washed with flowing tap water to remove salts and foreign substances, and then dried completely through a dryer. The dried sample was ground finely and leached the active ingredient for one week with 80% ethyl alcohol, which was 20 times the weight of the dried sample. The leached samples were concentrated under reduced pressure at 45 ~ 50 ℃ using a rotary vacuum concentrator (EYELA N-1000, EYELA, Tokyo, Japan) and lyophilized using a freeze dryer to obtain the final extract. The obtained extract was stored in an ultra-low temperature freezer at -80 ° C.
3. Cell culture
AGS, MDA-MB-231 and SK-BR-3 cells were cultured in RPMI-1640 medium supplemented with 5% FBS and 1% streptomycin / penicillin in an incubator under the conditions of 37 ° C and 5% CO 2 . When the cells were filled with about 80% of the 175-cm 2 flask, the cells were washed with PBS (pH 7.4) and treated with trypsin-EDTA for subculture. The medium was replaced every 2-3 days.
4. Statistical analysis
All experimental results were expressed using mean and standard deviation, and t-test analysis was performed after one-way ANOVA. P <0.05 compared with the control group was statistically significant.
<Test Example>
1. Identification of cancer cell growth inhibitory effect by extract
Seaweed has been reported to have antioxidant, anti-inflammatory and anti-cancer effects. These results suggest that the same sweet potato starch and broad starch potato may have potent anti-cancer effects. Therefore, MTT analysis was performed to determine whether brown algae extracts affected the growth of AGS, MDA-MB-231, and SK-BR-3 cells.
AGS, MDA-MB-231 and SK-BR-3 cells were seeded in 96 well plates at 2 x 10 4 cells / ml and cultured for 24 hours. Then seaweed (UP), seaweed iron (PB), a wide seaweed iron (PL) the extract of 0, 50, 100 and after treatment with 200 μg / ml concentration of, 37 ℃, 5% CO that the second condition is maintained And incubated in an incubator for 24 hours.
Then, 40 μl of 2 mg / ml MTT [3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide] solution (5 mg / ml, Sigma Chemical Co) And then cultured in an incubator for one and a half hours. After removing the MTT solution, the absorbance was measured by adding 100 μl of dimethylsulfoxide (DMSO, Sigma Chemical Co) to each well. Absorbance was measured at 595 nm with an ELISA-reader (Bio-Rad Lab-oratories Inc. Hercules, Calif., USA).
As a result, significant inhibitory effects of cancer cells on AGS and MDA-MB-231 cells at concentrations of 50 μg / ml or more were confirmed for all the extracts (FIGS. 1A and 1B). In SK-BR-3 cells, inhibition of cancer cell growth was observed when the broad-spectrum extract was at a concentration of 100 μg / ml or more and at a concentration of 200 μg / ml of the seaweed and the seaweed extract (FIG. The growth inhibition rates of AGS, MDA-MB-231 and SK-BR-3 cells were 43.53%, 39.95%, 14.52%, and 53.35%, respectively, in the waxy extract and 200 μg / 49.06% and 22.37%, respectively, and the broad range of sweet potato extracts were 80.56%, 50.42% and 55.2%, respectively.
From these results, it was confirmed that the seaweed, vinegar, and broad vinegar extract inhibited the growth of cancer cells in a dose - dependent manner, and that the broad vinegar extract showed a significant inhibitory effect on cancer cell growth as compared with other extracts. This shows the possibility that seaweed and broad seaweed have more effective anti-cancer effect than seaweed.
2. Identification of the induction of cancer cell death by the broad-spectrum extract
In order to visualize the effects of broad-spectrum extracts, which showed the most effective inhibitory effect on cancer cells at the same concentration, on cell nuclear changes in AGS, MDA-MB-231 and SK-BR-3 cells, DAPI staining that specifically reacted to the DNA sequence was performed (Fig. 2).
After incubation with AGS, MDA-MB-231 and SK-BR-3 cells in 175-cm 2 flasks, the cells were divided into 1 × 10 5 cells / ml in 60 mm dishes at 80-90% in an incubator maintained at a CO 2 condition were cultured for 24 hours. The medium was then discarded and the broad-spectrum extracts were treated at 0, 50, 100 and 200 μg / ml, cultured in an incubator for 24 h, carefully washed with PBS, and then washed with 4% paraformaldehyde solution Was added and fixed for 15 minutes. After washing again with PBS, 2 ml of DAPI staining solution diluted 10-fold with PBS was treated. (Zeiss fluorescence microscope, Thornwood, NY, USA) in a dark room.
As a result, typical apoptosis forms including apoptotic bodies and chromatin condensation were observed most frequently in each cancer cell treated with 200 μg / ml of wide-ranging starfish (FIG. 2A) As a result of counting each cell killer, it was confirmed that it was statistically increased at 200 μg / ml (FIG. 2B). The number of apoptotic cells was measured by means of an optical microscope in five independent samples and the mean was calculated as the mean ± standard deviation.
This is a consequence of the fragmentation of the DNA fragment in the nucleosome, which is closely related to the induction of apoptosis. As a result, it is considered that 200 μg / ml of broad-spectrum extracts induce apoptosis in AGS, MDA-MB-231 and SK-BR-3 cells.
3. Confirmation of Bcl-2 family protein expression inhibition effect of broad-spectrum extract
Bcl-2 family proteins are proteins that regulate mitochondrial membrane permeability and play an important role in regulating the pathway of apoptosis through mitochondria (Non-Patent Document 34). Bcl-2 family has typical factors regulating apoptosis induction. Among them, Bax is a pro-apoptotic protein and is related to induction of apoptosis. Bcl-2, another representative factor, It is an anti-apoptotic protein that inhibits the induction of apoptosis.
Western blotting was performed to determine the expression pattern of the transformed protein when a broad vinegar extract induced apoptosis. In a 175-cm 2 flask in which AGS, MDA-MB-231 and SK-BR-3 cells were cultured at 1 × 10 6 cells / ml, a culture medium containing 0 and 200 μg / Lt; / RTI > Cells were harvested by treatment with trypsin-EDTA and then centrifuged (1,200 rpm, 5 min, 4 ° C). Cell lysis buffer (Invitrogen, Carlsbad, Calif., USA) was added and incubated at 4 ° C for 20 min. After 20 minutes, centrifugation was carried out at 13000 rpm for 5 minutes, and the supernatant was taken and used as a cell lysate.
The protein concentration of the cell lysate was measured using a protein assay (Bradford assay). The cell lysate was separated by 12% SDS-PAGE (sodium dodecyl sulfate polyacrylamide gel electrophoresis) and transferred to a nitrocellulose membrane (Bio-Rad Laboratories, Hercules, CA, USA). The membrane was blocked with 5% skim milk-TBST (20 mM Tris.HCl, pH 7.5, 150 mM NaCl, 0.1% Tween 20) for 2 hours and the amount of protein to be measured 1: 1000], anti-Bcl-2 [1: 1000], anti-β-actin [1: 10000], anti-PARP [ Danvers, MA, USA) and incubated overnight at 4 ° C. Then, secondary antibody (anti-rabbit IgG) was added and reacted for 2 hours. The density of each band was measured using an imaging program (Image J Launcher [provided by NCBI]).
Western blot analysis was performed to determine the changes of Bax and Bcl-2 proteins, which are the mechanisms of induction of apoptosis in AGS, MDA-MB-231 and SK-BR-3 cells at 0 and 200 μg / ml of broad-spectrum extracts Respectively. The expression of Bax, an apoptotic protein, was increased in AGS, MDA-MB-231 and SK-BR-3 cells when compared with a wide range of 0 and 200 μg / ml, It was confirmed that the expression of Bcl-2 protein was decreased (FIG. 3A).
The ratio of Bax / Bcl-2 is used as a clinical indicator in cancer patients. AGS, MDA-MB-231 and SK-BR-3 cells were treated with 200 μg / ml of vinegar. As a result, it was confirmed that the relative Bax / Bcl-2 ratio to β-actin was significantly increased by treatment with a broad-spectrum extract (FIG. 3B).
These results showed that the inhibitory effect of the broad-spectrum extract on cancer cell growth on AGS, MDA-MB-231 and SK-BR-3 cells was related to the Bcl-2 family protein, an apoptotic mechanism.
PARP (Poly ADP-ribose polymerase) is a protein that repairs damaged DNA. When the apoptosis is induced, normal DNA repair process is inhibited due to loss of PARP (Non-Patent Document 35). The expression of PARP was analyzed by western blotting. The results were as follows. The broad-spectrum extracts were treated with 200 μg / ml of AGE, MDA-MB-231 and SK-BR- (Fig. 4). The increase of PARP (cleaved-PARP) in AGS, MDA-MB-231 and SK-BR-3 cells was observed.
These PARP seg- ments increased the activity of AGS, MDA-MB-231, and SK-BR-3 cells, which is similar to that induced by DAPI staining.
Claims (8)
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| JP5391536B2 (en) * | 2007-08-29 | 2014-01-15 | 株式会社カネカ | Seaweed-derived product material enriched with physiologically active substances, production method thereof, and seaweed-derived product |
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