Composition for preventing and treating a pancreatic cancer comprising extracts of Dioscorea tokora Makino

Abstract

The present invention relates to a composition for the prevention or treatment of pancreatic cancer comprising a *Bihae* extract as an active ingredient. It has been confirmed that the *Bihae* extract of the present invention effectively kills pancreatic cancer cell lines. Furthermore, it has been confirmed that it regulates the expression of factors related to apoptosis and induces mitochondrial-mediated apoptosis. Additionally, it has been confirmed that the *Bihae* extract specifically kills pancreatic cancer cell lines.

Description

Technology Field

[0001] The present invention relates to a composition for the prevention or treatment of pancreatic cancer comprising a pyrethrum extract as an active ingredient. Background Technology

[0002] Cancer has a high mortality rate globally and is the second most common cause of death in Western societies, after cardiovascular disease. In particular, lung cancer is on the rise due to population aging, an increase in smoking, and air pollution. Furthermore, colorectal, breast, and prostate cancers are on a continuous upward trend due to the Westernization of dietary habits leading to the generalization of high-fat diets, a rapid increase in environmental pollutants, and rising alcohol consumption. Under these circumstances, there is an urgent need to develop anticancer substances that can enable early prevention and treatment, thereby contributing to the improvement of human health, the enhancement of the quality of healthy life, and the advancement of global public health. To conquer cancer, innovative cancer research focusing on a deeper understanding of the fundamental mechanisms of DNA damage and repair, apoptosis, tumorigenesis, and molecular aspects of treatment is strongly required; this will ultimately serve as a breakthrough in cancer therapy.

[0003] According to statistics from the Ministry of Health and Welfare, pancreatic cancer ranked 8th among all cancers in 2017. It is known to have a poor prognosis due to the difficulty of early diagnosis and its tendency to metastasize to other organs. Furthermore, its 5-year survival rate is approximately 12%, which is significantly lower compared to gastric, colorectal, and breast cancers, which stand at 76.5%, 75%, and 93%, respectively. Currently, surgical, radiation, and chemotherapy methods are used to treat cancer. Among these, chemotherapy refers to the method of treating cancer using anticancer drugs. Today, about 60 different types of anticancer drugs are in use. However, since currently used anticancer drugs such as gemcitabine and radiation therapy can cause various side effects in the vascular, nervous, hematological, and skin systems, there is a need for new treatments that minimize these side effects and offer better therapeutic efficacy.

[0004] Meanwhile, cells in the body are eliminated through the process of apoptosis. However, cancer cells proliferate indefinitely due to continuous division. To eliminate these cancer cells, apoptosis must be induced. Poly-ADP-Ribose Polymerase (PARP) plays a role in repairing DNA when it is damaged. It ceases to function when apoptosis occurs. Consequently, the amount of PARP appears to decrease in cells undergoing apoptosis. Reactive oxygen species (ROS) are one of the factors that induce apoptosis in cancer cells. Staining with DCF-DA allows for the verification of the level of ROS generation, and an increase in ROS confirms an increase in cancer cell death.

[0005] Meanwhile, the rain is Tokoroma ( Dioscorea tokoroIt is the rhizome of *Makino*, also known as *Sanbihae* or *Baekji*. *Bihae* is used when urination is cloudy and unsatisfactory due to damp heat, accompanied by a sensation of heat and pain. It is used for joint pain, degenerative arthritis, rheumatoid arthritis, lower back pain, and knee pain, as well as for eczema, boils, and erysipelas. Pharmacological effects reported for *Bihae* include insecticidal, antifungal, and therapeutic effects on atherosclerosis.

[0006] Accordingly, the inventors confirmed that the comparative extract induces apoptosis in pancreatic cancer cells, thereby completing the present invention. The problem to be solved

[0007] The objective of the present invention is to compare ( Dioscorea tokoro The present invention provides a pharmaceutical composition for the prevention or treatment of pancreatic cancer comprising an extract of Makino as an active ingredient.

[0008] Another objective of the present invention is to compare ( Dioscorea tokoro The purpose is to provide an anticancer adjuvant for pancreatic cancer containing Makino extract as an active ingredient.

[0009] Another objective of the present invention is to compare ( Dioscorea tokoro The present invention provides a food composition for the prevention or improvement of pancreatic cancer, comprising Makino extract as an active ingredient. means of solving the problem

[0010] To achieve the above objective, the present invention ( Dioscorea tokoro A pharmaceutical composition for the prevention or treatment of pancreatic cancer is provided, comprising an extract of Makino as an active ingredient.

[0011] In addition, the present invention ( Dioscorea tokoro An anticancer adjuvant for pancreatic cancer is provided, containing Makino extract as an active ingredient.

[0012] In addition, the present invention ( Dioscorea tokoro A food composition for the prevention or improvement of pancreatic cancer is provided, comprising an extract of Makino as an active ingredient. Effects of the invention

[0013] It was confirmed that the extract of the *Bi* species of the present invention effectively kills pancreatic cancer cell lines. Furthermore, it was confirmed that it regulates the expression of factors related to apoptosis and induces mitochondrial-mediated apoptosis. Additionally, since it was confirmed that the *Bi* extract specifically kills pancreatic cancer cell lines, it can be usefully utilized in related industries. Brief explanation of the drawing

[0014] Figure 1 is a figure confirming the cell viability of pancreatic cancer cell lines PANC-1 and MIA PaCa 2 according to the treatment concentration of the comparative extract of the present invention. Figure 2 is a Western blot analysis of the expression of apoptosis-related proteins in pancreatic cancer cell lines PANC-1 and MIA PaCa 2 following treatment with the comparative extract of the present invention. Figure 3 is a figure quantifying the mitochondrial membrane permeability in pancreatic cancer cell lines PANC-1 and MIA PaCa 2 as the JC-1 ratio following treatment with the comparative extract of the present invention. Figure 4 is a figure confirming the cell viability of prostate cancer and lung cancer cell lines according to the treatment concentration of the comparative extract of the present invention. Specific details for implementing the invention

[0015] Embodiments of the present invention will be described in detail below with reference to the attached drawings. In the following description, detailed descriptions of technologies well known to those skilled in the art may be omitted. Furthermore, in describing the present invention, detailed descriptions of related known functions or configurations may be omitted if it is determined that such descriptions would unnecessarily obscure the essence of the present invention. Additionally, the terminology used in this specification is used to appropriately express preferred embodiments of the present invention, and may vary depending on the intent of the user or operator, or the conventions of the field to which the present invention belongs.

[0016] Therefore, the definitions of these terms should be based on the content throughout this specification. Throughout the specification, when a part is described as "comprising" a certain component, this means that, unless specifically stated otherwise, it does not exclude other components but may include additional components.

[0017] The present invention is compared ( Dioscorea tokoro A pharmaceutical composition for the prevention or treatment of pancreatic cancer is provided, comprising an extract of Makino as an active ingredient.

[0018] The term “prevention” as used in this invention refers to any act of suppressing the symptoms of a specific disease or delaying its progression through the administration of the composition of this invention.

[0019] The term “treatment” as used in this invention refers to any act of improving or beneficially altering the symptoms of a specific disease through the administration of the composition of this invention.

[0020] Pancreatic cancer can be classified into malignant pancreatic tumors (pancreatic ductal adenocarcinoma, neuroendocrine tumor), and cystic pancreatic tumors (mucinous cystic neoplasm, intraductal papillary mucinous neoplasm, solid pesudopapillary neoplasm).

[0021] There are various cell lines used to study pancreatic cancer, and currently, more than 11 cell lines, including PANC-1 and AsPC-1, are generally used. Each of these cell lines exhibits different phenotypes and genotypes, and accordingly, it is known that their characteristics regarding tumor growth, invasion, and metastasis, as well as chemotherapy and drug resistance, differ (Pancreas. 2010 May; 39(4): 425-435.)

[0022] The pharmaceutical composition of the present invention may additionally include an adjuvant in addition to the active ingredient. Any adjuvant known in the art may be used without limitation, but, for example, Freund's complete or incomplete adjuvant may be further included to increase the effect.

[0023] The pharmaceutical composition according to the present invention may be prepared in a form in which an active ingredient is incorporated into a pharmaceutically acceptable carrier. Here, the pharmaceutically acceptable carrier includes carriers, excipients, and diluents commonly used in the pharmaceutical field. Pharmaceutically acceptable carriers that can be used in the pharmaceutical composition of the present invention are not limited to these, but may include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil.

[0024] 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, and aerosols, external formulations, suppositories, or sterile injectable solutions, each according to conventional methods.

[0025] When formulating, the product may be prepared using diluents or excipients such as commonly used fillers, volume expanders, binders, wetting agents, disintegrants, and surfactants. Solid dosage forms for oral administration include tablets, pills, powders, granules, and capsules, and such solid dosage forms may be prepared by mixing at least one excipient, such as starch, calcium carbonate, sucrose, lactose, gelatin, etc., with the active ingredient. In addition, lubricants such as magnesium stearate and talc may also be used in addition to simple excipients. Liquid dosage forms for oral administration include suspensions, liquid formulations, emulsions, and syrups, and may contain various excipients, such as wetting agents, sweeteners, flavoring agents, and preservatives, in addition to commonly used diluents such as water and liquid paraffin. Preparations for parenteral administration include sterile aqueous solutions, water-insoluble solvents, suspensions, emulsions, lyophilized preparations, and suppositories. Water-insoluble solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Bases for suppositories may include Witepsol, Tween 61, cocoa paste, laurin paste, glycerogelatin, etc.

[0026] The pharmaceutical composition according to the present invention may be administered to an individual by various routes. Any mode of administration may be anticipated, for example, by oral, intravenous, intramuscular, subcutaneous, or intraperitoneal injection.

[0027] The dosage of the pharmaceutical composition according to the present invention is selected by taking into consideration the age, weight, gender, physical condition, etc. of the individual. It is obvious that the concentration of the active ingredient included in the pharmaceutical composition can be selected in various ways depending on the subject, and preferably, it is included in the pharmaceutical composition at a concentration of 0.01 to 5,000 μg / ml. If the concentration is less than 0.01 μg / ml, pharmaceutical activity may not appear, and if it exceeds 5,000 μg / ml, it may exhibit toxicity to the human body.

[0028] According to one embodiment of the present invention, the above-mentioned extract may be extracted with a solvent selected from the group consisting of water, C1 to C4 lower alcohols, lower alcohol aqueous solutions, ethyl acetate, hexane, and chloroform, preferably an aqueous ethanol solution, but is not limited thereto.

[0029] According to one embodiment of the present invention, the above-mentioned extract may induce apoptosis in pancreatic cancer cells.

[0030] According to one embodiment of the present invention, inducing apoptosis may be increasing the expression of C-Caspase-3 or C-PARP, and decreasing the expression of pro-PARP.

[0031] According to one embodiment of the present invention, the above-mentioned comparative extract may increase mitochondrial membrane permeability, and increasing mitochondrial membrane permeability may increase mitochondrial-mediated cell death.

[0033] In addition, the present invention ( Dioscorea tokoro An anticancer adjuvant for pancreatic cancer is provided, containing Makino extract as an active ingredient.

[0034] The "anticancer adjuvant" of the present invention is a preparation capable of improving, enhancing, or increasing the anticancer effect of an anticancer drug. It may be a preparation that does not exhibit anticancer activity on its own but can improve, enhance, or increase the anticancer effect of said anticancer drug when used together with said anticancer drug. Additionally, it may be a preparation capable of improving, enhancing, or increasing the anticancer effect of said anticancer drug when a preparation exhibiting concentration-dependent anticancer activity is used together with said anticancer drug at a level where it does not exhibit anticancer activity on its own.

[0035] The route of administration of the anticancer adjuvant may be any general route as long as it can reach the target tissue. Depending on the purpose, the anticancer adjuvant of the present invention may be administered intraperitoneally, intravenously, intramuscularly, subcutaneously, intradermally, orally, intranasally, intrapulmonaryly, or rectally, but is not limited thereto. Additionally, the anticancer adjuvant may be administered by any device capable of delivering the active substance to the target cells.

[0037] In addition, the present invention ( Dioscorea tokoro A food composition for the prevention or improvement of pancreatic cancer is provided, comprising an extract of Makino as an active ingredient.

[0038] As used in the present invention, the term “improvement” refers to any action that at least reduces parameters related to the condition being treated, such as the degree of symptoms.

[0039] In addition to containing the active ingredient of the present invention, the food composition of the present invention may contain various flavoring agents or natural carbohydrates, etc., as additional ingredients, as in conventional food compositions.

[0040] Examples of the natural carbohydrates described above include monosaccharides, e.g., glucose, fructose, etc.; disaccharides, e.g., maltose, sucrose, etc.; polysaccharides, e.g., dextrin, cyclodextrin, etc., and conventional sugars, and sugar alcohols such as xylitol, sorbitol, erythritol, etc. The flavoring agents described above may advantageously use natural flavoring agents (taumatin), stevia extracts (e.g., rebaudioside A, glycyrrhizin, etc.), and synthetic flavoring agents (saccharin, aspartame, etc.). The food composition of the present invention may be formulated in the same manner as the pharmaceutical composition described above and used as a functional food or added to various foods. Foods to which the composition of the present invention may be added include, for example, beverages, meat, chocolate, food products, confectionery, pizza, ramen, other noodles, chewing gum, candy, ice cream, alcoholic beverages, vitamin complexes, and health supplements.

[0041] In addition, the above food composition may contain, in addition to the extract which is an active ingredient, various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. Furthermore, the food composition of the present invention may contain fruit pulp for the production of natural fruit juice, fruit juice beverages, and vegetable beverages.

[0042] The functional food composition of the present invention may be manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, etc., for the purpose of preventing or treating pancreatic cancer. In the present invention, the term "health functional food composition" refers to a food manufactured and processed using raw materials or ingredients having functional properties useful to the human body pursuant to Article 6727 of the Act on Health Functional Foods, and means consuming it for the purpose of obtaining effects useful for health uses, such as regulating nutrients or physiological actions regarding the structure and function of the human body. The health functional food of the present invention may include conventional food additives, and unless otherwise stipulated, suitability as a food additive is determined according to the specifications and standards for the relevant item in accordance with the general provisions and general test methods of the Food Additives Codex approved by the Ministry of Food and Drug Safety. Items listed in the aforementioned "Food Additives Codex" include, for example, chemical synthetic compounds such as ketones, glycine, calcium citrate, nicotinic acid, and cinnamic acid; Examples include natural additives such as persimmon pigment, licorice extract, crystalline cellulose, sorghum pigment, and guar gum; and mixed preparations such as L-sodium glutamate preparations, alkaline additives for noodles, preservative preparations, and tar dye preparations. For example, a health functional food in tablet form may be produced by granulating a mixture of the active ingredient of the present invention with an excipient, a binder, a disintegrant, and other additives using a conventional method, and then adding a lubricant or the like and compression molding, or by directly compression molding the said mixture. In addition, the health functional food in tablet form may contain a binder or the like as needed. Among health functional foods in capsule form, hard capsules may be manufactured by filling a conventional hard capsule with a mixture of the active ingredient of the present invention mixed with additives such as excipients, and soft capsules may be manufactured by filling a capsule base such as gelatin with a mixture of the active ingredient of the present invention mixed with additives such as excipients. The above soft capsule may contain plasticizers such as glycerin or sorbitol, coloring agents, preservatives, etc., as needed.A health functional food in the form of a pill can be prepared by molding a mixture of the active ingredient of the present invention, excipients, binders, disintegrants, etc., using a previously known method, and if necessary, it can be coated with sucrose or other coating agents, or the surface can be coated with a substance such as starch or talc. A health functional food in the form of a granule can be prepared by making a mixture of the active ingredient of the present invention, excipients, binders, disintegrants, etc., into a granular form using a previously known method, and may contain flavoring agents, stimulating agents, etc., if necessary.

[0044] The present invention will be explained in more detail below through examples. These examples are merely for the purpose of explaining the present invention more specifically, and it will be obvious to those skilled in the art that the scope of the present invention is not limited to these examples.

[0046] <Preparation Example 1> Preparation of Bihae Extract

[0047] Comparison of the present invention ( Dioscorea tokoro To confirm the anticancer effect of the Makino extract against pancreatic cancer, a Bihae extract was prepared. Specifically, 3 L of 25% ethanol was added to 600 g of Bihae so that the flask containing the Bihae was completely submerged, and extraction was carried out for 72 hours. The ethanol was evaporated using an evaporator to leave only the pure Bihae extract components. Subsequently, the extract was freeze-dried to obtain the Bihae extract. The yield of the Bihae extract obtained in this way was 13.073%.

[0049] <Example 1> Confirmation of cytotoxicity of the extract against pancreatic cancer cell lines

[0050] The cytotoxicity of the comparative extract of the present invention against pancreatic cancer was confirmed. Specifically, pancreatic cancer cell lines PANC-1 and MIA PaCa 2 (Korean Cell Line Bank, Seoul, Republic of Korea) were used, and DMEM medium containing 10% inactivated fetal bovine serum and 1% penicillin-streptomycin was used as the culture medium. 100 μl of PANC-1 and MIA PaCa 2 cell lines were placed in a 96-well plate at a volume of 1.3 × 10⁶ 4 After dispensing each sample to achieve the required cell concentration, the cells were cultured in a 5% CO2 incubator (MCO-15AC, Sanyo, Osaka, Japan) at 37°C. After removing the medium from the cultured cells, 100 μl of the extract of the *Hibiscus* from Preparation Example 1 was added at concentrations of 0, 6.25, 12.5, 25, 50, 100, and 200 μg / ml, respectively, and the cells were cultured for an additional 24 hours. Subsequently, 10 μl of EZ-Cytox reagent (DoGen) was added to the cultured cells and reacted for 1 hour. After the reaction was completed, the absorbance was measured at a wavelength of 450 nm using a microplate reader (BKMPR-1101) to confirm cell viability.

[0052] As a result, as shown in Figure 1, it was confirmed that the comparative extract of the present invention killed pancreatic cancer cell lines PANC-1 and MIA PaCa 2 in a concentration-dependent manner, thereby confirming cytotoxicity against cancer cell lines.

[0054] <Example 2> Confirmation of the apoptosis-inducing effect of the yam extract

[0055] It was confirmed whether the extract of the *Bai* of the present invention regulates the expression of factors related to apoptosis. C-Caspase-3 is activated when Pro-Caspase-9 is activated. The activated Pro-Caspase-3 is cleaved to become the activated C-Caspase-3, which acts as an apoptosis factor and activates PARP. PARP is then cleaved to become C-PARP, which transmits signals to induce apoptosis, thereby causing cell death. Specifically, PANC-1 and MIA PaCa 2 cell lines were treated with the *Bai* extract at concentrations of 25 and 50 μg / ml, respectively, and cultured for 24 hours under conditions of 5% CO2 at 37°C. Subsequently, the cells were harvested, washed with PBS, and then lysed with CETI Lysis Buffer with Inhibitor (TransLab, Korea). The cells were then incubated at -4°C for 30 minutes. Subsequently, the cell lysate was centrifuged at 13,000 rpm for 10 minutes to remove cell membrane components, and the protein was quantified using the RC DC™ Protein Assay Kit II (protein assay kit) (Bio-rad, USA) to ensure that the same amount of protein was contained in each sample (treatment groups of 25 and 50 μg / ml of phytoextract). Then, a 5× loading die was placed in the protein sample and heated at 100°C for 5 minutes to denature the protein. The sample was then loaded onto a 12% SDS-PAGE gel and electrophoresis was performed at 90V for 120 minutes, and the proteins separated on the gel were transferred to a membrane at 280mA for 2 hours. After that, the membrane was blocked with a TBST (tris buffered saline, pH 7.5) solution containing 5% skim milk at room temperature for 1 hour, then washed three times with TBST, diluted the primary antibody to a ratio of 1:1000, and reacted with the blocked membrane overnight at 4°C.After the reaction was completed, the membrane was washed three times with TBST. Then, horseradish peroxidase-conjugated anti-rabbit IgG and anti-mouse IgG were diluted 1:10,000 and reacted with the membrane at room temperature for 1 hour, followed by washing three times with TBST. The washed membrane was reacted with a chemiluminescent reagent for 1 minute, and protein bands were visualized using a chemiluminescent western blot imaging device (Corebiosystem, Korea).

[0057] As a result, as shown in Figure 2, it was confirmed that the extract of the Korean pancreatic cancer induces apoptosis in pancreatic cancer cell lines by increasing the expression of C-Caspase-3 and C-PARP and decreasing pro-PARP in a concentration-dependent manner in PANC-1 and MIA PaCa 2 cell lines.

[0059] <Example 3> Confirmation of Mitochondrial Membrane Permeability of Bihae Extract in Pancreatic Cancer Cell Lines

[0060] It was confirmed whether the extract of the *Bi* of the present invention alters mitochondrial membrane permeability in pancreatic cancer cell lines. JC-1 dye is a lipophilic cation dye that penetrates the mitochondrial membrane well; it exhibits green fluorescence when existing as a monomer and red fluorescence when it is a J-aggregate. That is, when the cell is alive, it penetrates the mitochondrial membrane well and turns red, but when apoptosis occurs, a problem with MMPs causes it to exist as a monomer in the cytoplasm, appearing green. Mitochondrial membrane potential was confirmed following treatment with the *Bi* extract using the JC-1 assay.

[0062] As a result, as shown in Figure 3, when the extract was applied to pancreatic cancer cell lines PANC-1 and MIA PaCa 2, it was confirmed that the mitochondrial membrane permeability significantly increased and the JC-1 ratio decreased, confirming that the extract induces mitochondrial-mediated cancer cell death.

[0064] <Example 4> Confirmation of Pancreatic Cancer-Specific Apoptosis by Biae Extract

[0065] It was confirmed whether the comparative extract of the present invention specifically kills pancreatic cancer cell lines. Specifically, cell viability was confirmed by measuring cytotoxicity in the same manner as in Example 1 in the pancreatic cancer cell lines PANC-1 and MIA PaCa 2 of Example 1, the prostate cancer cell line PC 3, and the lung cancer cell line H1299.

[0067] As a result, as shown in Figures 1 and 4, the extract of the *Bi* plant kills two types of pancreatic cancer cell lines in a concentration-dependent manner. It was confirmed that all cells in the PANC-1 cell line were killed at a concentration of 200 μg / ml and all cells in the MIA PaCa 2 cell line were killed at a concentration of 400 μg / ml. However, in the PC3 prostate cancer cell line, no cell death was observed even at a concentration that killed both types of pancreatic cancer cell lines, confirming that prostate cancer cell lines are not affected by the cell death induced by the *Bi* plant extract. Furthermore, in the H1299 lung cancer cell line, it was confirmed that the cell viability was over 50% even at a concentration that killed both types of pancreatic cancer cell lines, confirming that lung cancer cell lines resist the cell death induced by the *Bi* plant extract, thus confirming that the *Bi* plant extract of the present invention exhibits specific toxicity to pancreatic cancer cell lines.

[0069] Therefore, it was confirmed that the extract of the *Bi* species of the present invention effectively kills pancreatic cancer cell lines. Furthermore, it was confirmed that it regulates the expression of factors related to apoptosis and induces mitochondrial-mediated apoptosis. Additionally, it was confirmed that the *Bi* extract specifically kills pancreatic cancer cell lines.

Claims

Claim 1 Compared to Dioscorea tokoro A pharmaceutical composition for the prevention or treatment of pancreatic cancer comprising an ethanol extract of Makino as an active ingredient. Claim 2 delete Claim 3 A composition according to claim 1, wherein the above comparative extract induces apoptosis in pancreatic cancer cells. Claim 4 A composition according to claim 3, wherein the one inducing the cell death is increasing the expression of C-Caspase-3 or C-PARP. Claim 5 A composition according to claim 3, wherein the one inducing the cell death is a reduction in the expression of pro PARP. Claim 6 A composition according to claim 1, wherein the above comparative extract increases mitochondrial membrane permeability. Claim 7 A composition according to claim 6, wherein increasing the mitochondrial membrane permeability increases mitochondrial-mediated apoptosis. Claim 8 A composition according to claim 1, wherein the pancreatic cancer is a carcinoma selected from the group consisting of malignant pancreatic tumors (pancreatic ductal adenocarcinoma) and cystic pancreatic tumors (intraductal papillary mucinous neoplasm). Claim 9 Compared to Dioscorea tokoro An anticancer adjuvant for pancreatic cancer containing Makino ethanol extract as an active ingredient. Claim 10 Compared to Dioscorea tokoro A food composition for the prevention or improvement of pancreatic cancer, comprising an ethanol extract of Makino as an active ingredient.

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