KR102567621B1 - Composition for metastasis inhibition of cancer comprising Ishige okamurae extracts - Google Patents

Abstract

The present invention relates to a composition for inhibiting cancer metastasis and an anti-cancer auxiliary composition comprising an extract of shell ( Ishige okamurae ) as an active ingredient, and according to the present invention, the shell extract exhibits PD-L1 expression inhibitory activity in various cancer cells, Since it has migration and invasion inhibitory activity without affecting the proliferation of cancer cells, it can be usefully used for preventing, improving or treating cancer, particularly cancer metastasis.

Description

Composition for inhibiting metastasis of cancer comprising shell extract as an active ingredient {Composition for metastasis inhibition of cancer comprising Ishige okamurae extracts}

The present invention relates to a composition for inhibiting cancer metastasis and a composition for adjuvant anticancer treatment comprising shellfish extract as an active ingredient.

Cancer has a high mortality rate worldwide and is the second most common cause of death after cardiovascular disease in Western societies. In particular, lung cancer is increasing due to the aging of the population, the increase in the smoking population, and air pollution. Breast cancer and prostate cancer are continuously increasing.

Among them, malignant cancer usually develops in one organ (lung, liver, kidney, stomach, large intestine, rectum, etc.) and then spreads from the organ, which is the primary site, to other tissues. This is called metastasis. Metastasis is a phenomenon accompanying the progression of malignant cancer. As malignant cancer cells proliferate and cancer progresses, they acquire new genetic traits necessary for metastasis, infiltrate into blood vessels and lymph glands, circulate along blood and lymph, and settle in other tissues. After that, it proliferates.

The principles of treatment for metastasis of malignant cancer differ depending on the type of cancer and the site of metastasis. For some malignant cancers where local symptoms due to metastasis are severe or where surgical treatment for metastasis is known to improve the natural course of malignant cancer, local treatment policies such as curative surgery or radiation therapy can be considered for metastasis. In general, when metastasis occurs in malignant cancer, it is helpful to treat not only the metastasis site but also the cancer in the primary site through systemic treatment such as chemotherapy rather than local treatment. However, except for a very small number of cancers such as lymphoma, the possibility of a complete cure is very low for malignant cancers that have metastasized. The course of malignant cancer with metastasis varies, and the course is determined by the type of primary malignant cancer and the overall cancer progression rate. Complications may vary depending on which organ it has metastasized to. For example, in the case of brain metastasis, symptoms such as headache, decreased visual field, nausea, and vomiting may occur. In the case of bone metastases, bone pain may occur and pathological fractures may occur. Consciousness clouding may occur due to hypercalcemia accompanying bone metastases. Therefore, early detection of cancer through screening and genetic testing of primary cancer are ways to prevent an increase in mortality due to metastasis. On the other hand, it is known that recurrence and metastasis can be prevented by using adjuvant chemotherapy and radiation treatment after surgical treatment of some cancers, but these treatments affect normal cells and cause serious side effects. Therefore, there is a need for a safer, more effective alternative cancer treatment method, and recently, attention has been focused on pharmaceutical research and functional foods using natural resources such as plants and microorganisms with guaranteed stability.

Drugs developed for cancer treatment to date have many systemic side effects due to drug administration, and thus have many side effects compared to surgery or radiation therapy. Existing chemical treatments that are effective by directly attacking cancer cells also have very strong side effects, and innovative new drugs that can prevent metastasis to organs such as the lungs have not yet been developed.

On the other hand, programmed death receptor-ligand 1 (PD-L1) is known to play an important role in immune evasion of cancer cells. 1 to reduce T-cell receptor (TCR)-mediated proliferation and cytokine production. Therefore, PD-L1 may be an important target in conquering cancer.

Therefore, in order to prevent metastasis of malignant cancer, it is necessary to develop a natural product-derived cancer metastasis inhibitor that can suppress the expression of PD-L1 and does not cause side effects.

While studying natural products capable of inhibiting cancer metastasis, the inventors of the present invention found that an extract of a marine brown algae plant ( Ishige okamurae ) excellently inhibits PD-L1 expression of cancer cells and inhibits migration and invasion of cancer cells. The present invention was completed by confirming the effect.

Accordingly, an object of the present invention is to provide a pharmaceutical composition for inhibiting cancer metastasis.

Another object of the present invention is to provide a food composition for preventing or improving cancer metastasis.

Another object of the present invention is to provide a pharmaceutical composition for adjuvant anti-cancer treatment.

Another object of the present invention is to provide a food composition for adjuvant anti-cancer treatment.

In order to achieve the above object, the present invention provides a pharmaceutical composition for inhibiting cancer metastasis comprising an extract of shellfish ( Ishige okamurae ) as an active ingredient.

In addition, in order to achieve the above another object, the present invention shell ( Ishige okamurae ) Provides a food composition for preventing or improving cancer metastasis comprising an extract as an active ingredient.

In addition, in order to achieve the above another object, the present invention shell ( Ishige okamurae ) Provides an anti-cancer auxiliary pharmaceutical composition comprising an extract as an active ingredient.

In addition, in order to achieve the above another object, the present invention shell ( Ishige okamurae ) Provides an anti-cancer supplement food composition comprising an extract as an active ingredient.

The present invention confirms the cancer metastasis inhibitory activity of the shell ( ishige okamurae ) extract among marine brown algae plants, and the shell extract shows PD-L1 expression inhibitory activity in various cancer cells, without affecting the proliferation of the cancer cells. Since it exhibits migration and invasion inhibitory activity, it can be usefully used as a composition for inhibiting cancer metastasis or a composition for adjuvant anticancer treatment.

In Figure 1, A is a diagram confirming the PD-L1 expression inhibitory effect of 40 types of marine brown algae plant extracts, and in FIG. C in Figure 1 is a diagram confirming the concentration-dependent effect of the shell ( ishige okamurae ) extract selected through the above.
In Figure 2, A is a diagram confirming the PD-L1 expression inhibitory effect of the shell extract in various cancers, B in Figure 2 is a diagram confirming the cancer cell migration inhibitory activity of the shell extract, and C in FIG. 2 is a shell extract It is a diagram confirming the cancer cell invasion inhibitory activity.
3 is a diagram confirming the effect of shell extract on cancer cell proliferation in various cancers.

Hereinafter, the present invention will be described in detail.

The present invention provides a pharmaceutical composition for inhibiting cancer metastasis comprising an extract of shellfish ( Ishige okamurae, I.okamurae ) as an active ingredient.

The inventors of the present invention completed the present invention by confirming that the plaque ( Ishige okamurae ) extract exhibits PD-L1 expression inhibitory effect as well as cancer cell migration and invasion inhibitory activity while searching for a natural product-derived material effective in inhibiting cancer metastasis did

The shell ( Ishige okamurae ) belongs to the shell family as brown algae. Distributed along the coasts of China, Japan, and Thailand. It has been reported that plaque has anti-inflammatory and anti-oxidant effects, especially anti-plasmin inhibitory effects. However, it has not been known that the plaque can suppress PD-L1 expression and cancer metastasis as in the present invention.

The shell extract may be extracted with any one solvent selected from the group consisting of C1 to C4 lower alcohol, water, and mixtures thereof, preferably with ethanol.

In addition, filtration, concentration and purification, drying, freezing, etc. may be optionally added for ease of handling, storage, etc. during the preparation of the shellfish extract of the present invention.

The filtration process may be performed by a known filtration method, but is not limited thereto, and for example, filtration using a filter net or microfilter, centrifugation, and separatory funnel may be used. The concentration process may be by a known concentration method, but is not limited thereto, and may be concentrated using, for example, precipitation concentration, evaporation concentration, vacuum concentration, ultrafiltration, reverse osmosis, and centrifugation.

The drying process may be by a known drying method, but is not limited thereto, and may be, for example, freeze drying, spray drying or hot air drying.

In particular, according to one embodiment of the present invention, the shellfish extract inhibits PD-L1 expression in various cancer types and exhibits migration and invasion inhibitory activity without affecting the proliferation of cancer cells. The pharmaceutical composition for inhibition can inhibit the migration of various cancer cells based on the above effect.

The cancer is characterized in that it is a cancer showing a PD-L1 expression positivity, and may preferably be any one or more selected from the group consisting of oral cancer, salivary gland cancer, breast cancer, and prostate cancer, but is not limited thereto.

The pharmaceutical composition of the present invention may be formulated and used in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories and sterile injection solutions according to conventional methods, respectively. . Carriers, excipients, and diluents that may be included in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, and cellulose. , methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. When formulated, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations contain at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, in the shell extract of the present invention. , gelatin, etc. are mixed and prepared. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral use include suspensions, solutions for oral use, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, aromatics, and preservatives may be included. . Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried formulations, and suppositories. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspensions. As a base for the suppository, witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerogeratin and the like may be used.

The dosage of the pharmaceutical composition of the present invention will vary depending on the age, sex, and weight of the subject to be treated, the specific disease or pathological condition to be treated, the severity of the disease or pathological condition, the route of administration, and the judgment of the prescriber. Determination of dosage based on these factors is within the level of those skilled in the art, and generally dosages range from 0.01 mg/kg/day to approximately 2000 mg/kg/day. A more preferred dosage is 0.1 mg/kg/day to 1000 mg/kg/day. Administration may be administered once a day, or may be administered in several divided doses. The dosage is not intended to limit the scope of the present invention in any way.

The pharmaceutical composition of the present invention can be administered to mammals such as rats, livestock, and humans through various routes. All modes of administration are contemplated, eg oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine intrathecal or intracerebrovascular injection.

In the present invention, the pharmaceutical composition for inhibiting cancer metastasis, in addition to the active ingredient, any compound or natural extract whose safety has already been verified and known to have anti-cancer activity or suppression of cancer metastasis for enhancement and reinforcement of cancer metastasis inhibition, additionally can include

In addition, the pharmaceutical composition of the present invention can be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers for the inhibition of cancer metastasis.

In addition, the present invention provides a pharmaceutical composition for adjuvant anti-cancer treatment comprising an extract of shell ( Ishige okamurae ) as an active ingredient.

As used herein, the term "for adjuvant anticancer treatment" refers to an effect of synergistically increasing the effect of anticancer treatment by preventing the possibility of cancer metastasis when applied in parallel with treatment with an anticancer agent.

Therefore, the composition for adjuvant anticancer treatment can be used as an adjunct to cancer treatment using known anticancer agents, and can be administered simultaneously or sequentially with anticancer agents as anticancer adjuvants.

In addition, the present invention provides a food composition for preventing or improving cancer metastasis comprising an extract of shellfish ( Ishige okamurae ) as an active ingredient.

In addition, the present invention provides a food composition for adjuvant anti-cancer treatment comprising the shell ( Ishige okamurae ) extract as an active ingredient.

The food composition according to the present invention includes all types of functional food, nutritional supplements, health food and food additives. Food compositions of this type can be prepared in various forms according to conventional methods known in the art.

For example, as a health food, the shellfish extract of the present invention may be granulated, encapsulated, and powdered to be ingested, or prepared in the form of tea, juice, and drink to be consumed. In addition, the shellfish extract of the present invention can be prepared in the form of a composition by mixing it with known substances or active ingredients known to have cancer metastasis inhibitory or anticancer effects.

In addition, functional foods include beverages (including alcoholic beverages), fruits and their processed foods (e.g., canned fruit, bottled food, jam, marmalade, etc.), fish, meat, and their processed foods (e.g., ham, sausage corned beef, etc.) , breads and noodles (e.g. udon, buckwheat noodles, ramen, spaghetti, macaroni, etc.), fruit juice, various drinks, cookies, taffy, dairy products (e.g. butter, cheese, etc.), edible vegetable oil, margarine, vegetable protein, retort It can be prepared by adding the shellfish extract of the present invention to food, frozen food, various seasonings (eg, soybean paste, soy sauce, sauce, etc.).

The preferable content of the shellfish extract of the present invention in the food composition of the present invention is not limited thereto, but may be, for example, 0.01 to 80% by weight of the final food, preferably 0.01 to 80% by weight of the final food. 50% by weight.

In addition, in order to use the shellfish extract of the present invention in the form of a food additive, it can be prepared and used in the form of a powder or concentrate.

The contents of the present invention described above are equally applied to each other unless contradictory to each other, and implementation by adding appropriate changes by a person skilled in the art is also included in the scope of the present invention.

Hereinafter, the present invention will be described in detail through examples, but the scope of the present invention is not limited only to the following examples.

Example 1. Cancer cell culture

Oral squamous cell line (HN22, HSC-2, HSC-3) as a type of oral cancer cell, mucoepidermoid cell line (YD-15M), breast cancer cell line (MDA-MB-231) and prostate cancer cell line as a type of salivary gland cancer cell (DU145) was used in the experiments. The HN22 cell line was provided by Dankook University, the HSC-2 and HSC-3 cell lines were provided by Hokkaido University, and the YD-15M cell line was purchased directly from Korea Cell Line Bank. In addition, the MDA-MB-231 cell line was purchased from ATCC (American Type Culture Collection), and the DU145 cell line was purchased from Korea Research Institute of Bioscience and Biotechnology. HN22, HSC-2, HSC-3, and MDA-MB-231 cell lines were cultured in Dulbecco's Modified Eagle Medium/Nutrient Mixture F-12 (1:1) medium, and YD-15M and DU145 cell lines were cultured in Rosewell Park Memorial Institute 1640 medium. cultured on. 1% penicillin/streptomycin and 10% FBS (Fetal Bovine Serum) were added to each medium used in the experiment, and culture conditions of 5% CO ₂ and 37° C. were maintained using a cell incubator.

Example 2. Preparation of marine brown algae plant extract

In order to derive a natural extract having an inhibitory effect on PD-L1 expression in cancer cells, the brown algae plants shown in Table 1 below were distributed from a marine brown algae plant resource deposit and preservation institution.

After washing and drying the brown algae used in the experiment, they were ground with a mixer and powdered. After extracting with 80% ethanol, it was concentrated and lyophilized.

Example 3. Confirmation of PD-L1 expression inhibitory effect of marine brown algae plant extract

Oral squamous cancer cells (HN22 cells) were treated with 40 marine brown algae plant extracts obtained in Example 2, and then the decrease in PD-L1 expression was evaluated.

HN22 cells were dispensed in a 6-well plate at 2 ml each under the condition of 1.2 × 10 ⁵ cells / ml, and when a cell density of 50% was formed, 20 μg / ml of 40 marine brown algae plant extracts and 0.2% DMSO (as a control) dimethyl sulfoxide) for 24 hours. Afterwards, the amount of specific protein was confirmed by Western blot. First, the HN22 cell line treated with DMSO (dimethyl sulfoxide) and 40 marine brown algae plant extracts was washed twice with PBS, treated with 0.5 ml of 0.5% trypsin, and reacted for 10 minutes in a cell incubator for cell attachment suppressed. 2 ml of PBS (phosphate buffer saline) was added to each well to collect floating cells, and the cells were separated from the supernatant through a centrifuge. After adding 70 μl of RIPA buffer (Radioimmunoprecipitation assay buffer), proteins were extracted using a vortex and centrifugal separator. The protein concentration was measured through BCA protein assay (Bicinchoninic Acid Protein Assay) quantification method. The same protein (30 μg) of each sample was separated according to molecular weight using SDS polyacrylamide gel electrophoresis with a current of 100 V for 2 hours and 10 minutes. Proteins separated on the SDS polyacrylamide gel were adsorbed onto a polyvinylidene fluoride membrane (PVDF). In order to reduce the non-specific binding of the antibody, the PVDF membrane adsorbed with the protein was immersed in 5% skim milk and reacted at room temperature for 1 hour, and then PD-L1 (Cell Signaling Technology, # 13684) and β- Actin (β-actin (Santa Cruz Biotechnology, sc-47778)) antibody was diluted in TBS-T buffer in an appropriate amount (PD-L1: 1:2000; β-actin: 1:3000) and reacted at 4°C for one day. . After that, after reacting with a secondary antibody to which horseradish peroxidase is bound to the host of the primary antibody, Western Blotting Luminol Reagent (sc-2048) and X-ray film (X-ray film) ray film) was used to detect fluorescence.

As a result, as shown in A in FIG. 1, No. 3 ( agarum clathratum , TC 9124), No. 17 ( codium fragile , TC 15429), No. 26 ( gracilaria vermiculophylla , TC7763), No. 29 It was confirmed that the extracts of ( Derbesia rhizophora , TC9099) and No. 34 (Pae, ishige okamurae , TC9238) effectively reduced PD-L1 expression.

Based on the above confirmation, the PD-L1 expression inhibitory activity of each extract was re-examined by treating oral squamous cancer cells (HN22 cells) with the selected four marine brown algae plant extracts. As a result, as shown in B in FIG. 1, it was confirmed that among the four extracts, the shellfish extract most effectively reduced the expression of PD-L1 in cancer cells. In addition, the shell extract was treated at a concentration of 0, 10, 20 or 40 μg/ml to confirm the inhibitory activity of PD-L1 expression according to the concentration. As a result, as shown in C in FIG. 1, it was confirmed that the shellfish extract showed a concentration-dependent inhibitory effect on the expression of PD-L1.

Example 4. Confirmation of the effect of shell extract on various types of cancer

Based on the effect of the shell extract confirmed in Example 3, the PD-L1 expression inhibitory effect of the shell extract was confirmed in various cancer types including oral squamous cancer cells.

To this end, oral squamous cancer cell lines (HN22, HSC-2, HSC-3 cells), mucoepidermoid cell line (YD-15M), breast cancer cell line (MDA-MB-231) and prostate cancer cell line (DU145) were treated with 40 μg/ml After treating the shell extract of 24 hours, PD-L1 expression was confirmed in the same manner as in Example 3. As a result, as shown in A in FIG. 2, the shell extract showed PD-L1 inhibitory activity in all of HN22, HSC-2, HSC-3, YD-15M, MDA-MB-231 and DU145 cells.

Meanwhile, recent studies have reported that cancer cells acquire cancer characteristics, including metastasis and growth, through increased expression of PD-L1. Therefore, in order to confirm that the PD-L1 expression inhibitory effect of the plaque extract regulates the metastatic ability of cancer cells, the migration ability of cancer cells through wound-healing assay and trans-well invasion assay ( Trans-well invasion assay) was used to confirm invasion ability.

The wound healing assay was performed as follows. After washing HN22, HSC-2, HSC-3, YD-15M, MDA-MB-231 and DU145 cells, in which PD-L1 expression was suppressed by the plaque extract, with PBS, cells attached using 0.5% trypsin. was removed and the supernatant was removed by centrifugation. After the obtained cells were suspended using the culture medium, the number of cells was measured. A 6-well plate was used to carry out the experiment, and the cells were diluted in the range of 2 - 4 x 10 ⁵ cells / ml according to the size and differentiation cycle of each cell line, dispensed by 2 ml, and cultured in a cell culture medium. When the cell density reached about 90% after about 18 hours, cell growth was inhibited by treatment with a serum-free culture medium diluted with 10 μg/ml mitomycin C for 4 hours. Then, the center of the well covered with cells was scraped at equal intervals using a 10 μl pipette tip. In order to prevent the cells that had fallen off from attaching to the plate again, they were washed three times with PBS, and treated with 40 μg/ml of plaque extract or a cell culture solution diluted with 0.2% DMSO as a control at 3 to 4 hour intervals. Cell migration was confirmed. The gap at the time of treatment and the time when the gap narrowed were photographed using a microscope, and the degree of recovery analysis was expressed through the difference between the width of the gap at the start and the gap at the end through Image J software.

Infiltration assay was performed through a transwell as follows. On top of the 8.0 μm PET Falcon transwell, 100 μl of a mixture of a matrigel matrix and a serum-free culture medium at a ratio of 1:15 was put and coated. After putting it on a 24-well plate and storing it in a cell culture medium for 8 hours, the residue except for the coated Matrigel matrix was removed. After adding the serum-free culture medium to the upper part of the transwell and to the 24-well, it was rehydrated in a cell incubator for 2 hours. After obtaining cancer cell lines through trypsin and centrifugation, cell numbers were measured using an appropriate amount of serum-free culture medium. Depending on the invasion ability of each cell, 1.5 x 10 ⁵ to 3 x 10 ⁵ cells/well were added to the top of the transwell, and 750 μl of the culture medium containing 10% FBS was added to the bottom to form chemotaxis. Finally, the culture medium containing the cells on the top of the transwell was treated with 40 μg/ml shell extract or a cell culture medium diluted with 0.2% DMSO as a control. After culturing in a cell incubator for 24 hours, the cells penetrating the matrix and infiltrating were stained using crystal violet. Then, the effect of invasion was verified by checking the difference in the number of infiltrating cells in the experimental groups treated with DMSO and shell extract through a microscope.

As a result, as shown in B in FIG. 2, in the case of the experimental group treated with shell extract, it was confirmed that the migratory ability of all cancer cells was significantly suppressed. In addition, as shown in C in FIG. 2, it was confirmed that the invasion ability of cancer cells was also significantly inhibited by the treatment of the shellfish extract.

Example 5. Confirmation of the effect of plaque extract on cancer cell proliferation

In order to confirm whether the plaque extract has an effect on cancer cell proliferation, a cell proliferation assay was performed.

Cell growth assay was performed as follows. Cells were cultured in a 96-well cell culture plate in the range of 8000 to 12000 cells/well depending on the size and differentiation cycle of each cell line, and an appropriate amount of cells was included in 200 μl of cell culture medium per well. When confirmed under a microscope to form a confluency of 50%, the culture solution in which the shell extract was diluted was added in the same amount as the cell culture medium, and diluted with shell extract at 80 μg/ml considering the increased dilution factor. Based on the extract treatment time, the amount of cells at 0 and 24 hours of cells treated with and without 40 μg/ml of shell extract was measured. MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H, a type of Tetrazolium Reduction Assays that measure living cells -tetrazolium) analysis was performed. After adding 20 μl of MTS reagent to the well to be measured, it was wrapped with foil so as not to react to light, and reacted for 1 hour or 2 hours depending on the cell type in a cell incubator. Then, the absorbance was analyzed, and the change in cell proliferation rate was measured in proportion to the amount of cells and the absorbance value.

As a result, as shown in FIG. 3, no change in proliferation was found in most cancer cell lines when the shell extract was treated for 24 hours. In prostate cancer cells, a 10% decrease in proliferation rate was shown, but it was confirmed that the effect was insignificant compared to the previous metastasis or invasion inhibition.

Overall, the present invention confirms the cancer metastasis inhibitory activity of the shell ( ishige okamurae ) extract among marine brown algae plants. And since it exhibits migration and invasion inhibitory activity without affecting the proliferation of cancer cells, it can be usefully used as a composition for inhibiting cancer metastasis in cancer treatment.

Claims (8)

A pharmaceutical composition for suppressing PD-L1-positive cancer metastasis, comprising an ethanol extract of Ishige okamurae as an active ingredient.
delete According to claim 1,
The pharmaceutical composition for inhibiting cancer metastasis, characterized in that the composition inhibits migration by inhibiting PD-L1 expression of cancer cells.
delete According to claim 1,
The cancer is a pharmaceutical composition for inhibiting cancer metastasis, characterized in that at least one selected from the group consisting of oral cancer, salivary gland cancer, breast cancer and prostate cancer.
A food composition for preventing or improving PD-L1-positive cancer metastasis, comprising an ethanol extract of Ishige okamurae as an active ingredient.
Plaque ( Ishige okamurae ) A pharmaceutical composition for adjuvant anti-cancer treatment of PD-L1 positive cancer comprising an ethanol extract as an active ingredient.
A food composition for adjuvant anti-cancer treatment of PD-L1-positive cancer, comprising an ethanol extract of Ishige okamurae as an active ingredient.