WO2009131263A1 - Composition for cancer chemoprevention comprising the extracts of cutleria cylindrica - Google Patents

Composition for cancer chemoprevention comprising the extracts of cutleria cylindrica Download PDF

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Publication number
WO2009131263A1
WO2009131263A1 PCT/KR2008/002362 KR2008002362W WO2009131263A1 WO 2009131263 A1 WO2009131263 A1 WO 2009131263A1 KR 2008002362 W KR2008002362 W KR 2008002362W WO 2009131263 A1 WO2009131263 A1 WO 2009131263A1
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Prior art keywords
cutleria
cylindrica
extract
cancer
composition
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PCT/KR2008/002362
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French (fr)
Inventor
Cheol-Ho Pan
Saet Byoul Lee
Min Cheol Kim
Byung Hun Um
Eun Ha Lee
Joo Young Lee
Chu Won Nho
Sang Hoon Jung
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Korea Institute Of Science And Technology
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Priority to PCT/KR2008/002362 priority Critical patent/WO2009131263A1/en
Publication of WO2009131263A1 publication Critical patent/WO2009131263A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/02—Algae
    • A61K36/03—Phaeophycota or phaeophyta (brown algae), e.g. Fucus
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • 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
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention relates to a composition for cancer chemoprevention comprising the extract of the seaweed Cutleria cylindrica, more particularly to a pharmaceutical or functional health food composition for cancer prevention comprising the extract obtained by extracting Cutleria cylindrica with ethanol, which activates quinone reductase, an anticarcinogenic enzyme, is without cell toxicity, and provides cancer chemoprevention effect by inducing activation of the phase II detoxifying enzyme system although not inducing activation of the phase I detoxifying enzyme system, as active ingredient.
  • cancer can be treated by surgery, radiation therapy, chemotherapy or other methods.
  • an early diagnosis accompanied by surgery, radiation therapy or chemotherapy is necessary.
  • the treatment becomes complicated and requires much more psychological and economic burden. Accordingly, along with the diagnosis method enabling early detection of cancer, the cancer chemoprevention is becoming an important field in recent cancer researches.
  • cancer chemoprevention is a new strategy in cancer research attempting to artificially suppressing, retarding or reversing carcinogenesis using relatively nontoxic chemicals, thereby preventing normal cells from converting to cancer cells. Toxicity should be non-existent or slight for a material to be a candidate for cancer chemoprevention. Further, easiness in synthesis or isolation from natural products is preferred. For these reasons, mainly compounds originated from plants are utilized except for some vitamin metabolites [Surh YJ, Nature Rev. Cancer, 3, 768-780, 2003].
  • Cancer develops through the stages of initiation, promotion, progression and metastasis.
  • Cancer chemoprevention mainly targets the initiation and promotion stages and is divided into two categories, depending on mechanism: blocking agents which prevent a carcinogen from reacting with an intracellular target or reaching the target; and suppressing agents which suppress the process of a cell exposed to a carcinogen forming a neoplasm (neoplasia) [Surh YJ, Nature Rev. Cancer, 3, 768-780, 2003].
  • Previously known blocking agents include: 1) diallyl sulfide, isothiocyanate, ellagic acid, and the like which inhibits the cytochrome P-450 enzyme, and 2) phenylethyl isothiocyanate, sulforaphane, oltipraz, and the like which induce the phase II detoxifying enzyme system.
  • Previously known suppressing agents include: 1) DFMO which inhibits the polyamine metabolism, 2) retinoids which promote the cell differentiation, 3) genistein which inhibits protein kinase C, and 4) EGCG which inhibits oxidative DNA damaging.
  • the blocking agents which control the activity of the detoxifying enzyme system may be categorized into monofunctional inducers and bifunctional inducers, depending on their functions.
  • Monofunctional inducers induce the activation of the phase II detoxifying enzyme system such as quinone reductase and glutathione S-transferase.
  • bifunctional inducers induce the activation of the cytochrome P-450-based phase I detoxifying enzyme system, as well as inducing that of the phase II detoxifying enzyme system induced by the monofunctional inducers.
  • the increased activity of the phase II detoxifying enzyme system aids in the prevention of chemical carcinogenesis through promoting the excretion of carcinogens or procar- cinogens out of the body.
  • phase I detoxifying enzyme system results in endowing with or increasing the carcinogenesis through metabolizing procarcinogens, besides the detoxification of carcinogens. Accordingly, with respect to cancer chemoprevention, monofunctional inducers are more effective than bifunctional inducers [Prochaska HJ and Talalay P, Cancer Res., 48, 4776-4782, 1988].
  • ARE antioxidant response element
  • XRE xenobiotic responsive element
  • the inventors of the present invention have searched for edible natural products having the effect of activating monofunctional inducers in order to develop cancer chemoprevention substances with no or slight toxicity to the human body. In doing so, they have found that the extract of Cutleria cylindrica activates quinone reductase, an anticarcinogenic enzyme, is without cell toxicity, and provides cancer chemoprevention effect by inducing activation of the phase II detoxifying enzyme system although not inducing activation of the phase I detoxifying enzyme system, and, thus, a composition comprising the same as active ingredient can be used as medicine or health functional food for cancer chemoprevention. Disclosure of Invention Technical Problem
  • the present invention has been made in view of the above problems, and an object of the present invention is to provide a composition for medicine or health functional food comprising the extract of Cutleria cylindrical, which has excellent cancer chemoprevention effect and is without toxicity to the human body, as active ingredient.
  • composition according to the present invention is characterized in comprising the extract of Cutleria cylindrica as active ingredient for treating or preventing cancer.
  • the extract of Cutleria cylindrica activates quinone reductase, an anticarcinogenic enzyme, is without cell toxicity, and provides cancer chemoprevention effect by inducing activation of the phase II detoxifying enzyme system although not inducing activation of the phase I detoxifying enzyme system, thereby inhibiting carcinogenesis of procarcinogens and promoting excretion of carcinogens or procarcinogens out of the body.
  • a composition comprising the same as active ingredient can be used as medicine or health functional food for cancer chemoprevention.
  • FIG. 1 is a graph showing the effect of activating quinone reductase of the extract of
  • Fig. 2 is a graph showing the cell toxicity of the extract of Cutleria cylindrica according to the present invention
  • Fig. 3 is a graph showing the effect of the extract of Cutleria cylindrica according to the present invention on xenobiotic responsive element (XRE) (* 3-methylcolanthrene treated control group)
  • Fig. 4 is a graph showing the effect of the extract of Cutleria cylindrica according to the present invention on antioxidant response element (ARE).
  • XRE xenobiotic responsive element
  • the present invention provides an composition comprising the extract of
  • Cutleria cylindrica as active ingredient for treating or preventing cancer.
  • the composition according to the present invention has a use for cancer chemoprevention.
  • the extract of Cutleria cylindrica is an ethanol extract.
  • the extract of Cutleria cylindrica promotes the activity of quinone reductase.
  • the extract of Cutleria cylindrica induces the activation of the phase II detoxifying enzyme system.
  • the composition according to the present invention is a pharmaceutical composition for treating or preventing cancer.
  • the composition according to the present invention is a functional food composition for treating or preventing cancer.
  • cancer or "for treating or preventing cancer” is used in the broadest meaning, embracing prevention, treatment, alleviation, and amelioration of cancer.
  • cancer chemoprevention is the broadest meaning, including preventing one or more of initiation, promotion, progression and metastasis stages of cancer. In particular, it refers to the prevention of initiation and promotion of cancer.
  • it includes the prevention of cancer through the blocking mechanism of preventing a carcinogen from reacting with an intracellular target or reaching the target. Also, it includes the prevention of cancer through the suppressing mechanism of suppressing the process of a cell exposed to a carcinogen forming a neoplasm (neoplasia). Further, it includes the prevention of cancer through promoting the excretion of carcinogens or procarcinogens out of the body. It also includes the prevention of cancer through metabolizing procarcinogens.
  • the extract of Cutleria cylindrica includes any one obtained by extraction from the natural product Cutleria cylindrica, without restriction.
  • Cutleria cylindrica is immersed in water or organic solvent and an active ingredient may be extracted therefrom through such means as sedimentation, stirring, pressurizing, heating, and the like.
  • a lyophilization product obtained by lyophilizing the liquid extract is included.
  • a powder obtained by triturating the lyophilization product is included.
  • any extract obtained by any means to extract the active ingredient is included, and one processed after the extraction, including lyophilization, is also included.
  • an extract obtained by the traditionally transcended methods such as heating in a water bath or extraction at room temperature, or the methods described in the Oriental medical books or textbooks.
  • an extract obtained by the Stass-Otto method which is specialized for isolation of specific active compounds, or a fractional extract obtained through column chromatography or other methods is included.
  • the present invention provides an extract of Cutleria cylindrica for cancer chemo- prevention.
  • the Cutleria cylindrica used in the present invention is not particularly limited, but may be harvested, grown or purchased one.
  • the solvent for extraction is ethanol.
  • the extract of Cutleria cylindrica may be prepared by washing Cutleria cylindrica with water to remove impurities and salts, drying and extracting the same, concentrating the resultant filtrate under reduced pressure, and drying the same.
  • the present invention further provides a pharmaceutical or health functional food composition for cancer chemoprevention comprising the extract of Cutleria cylindrica as active ingredient.
  • the pharmaceutical composition according to the present invention may further comprise an adequate vehicle, excipient or diluent commonly used in the preparation of a pharmaceutical composition.
  • the pharmaceutical composition according to the present invention may be administered in the form of a pharmaceutically acceptable salt, either alone or in combination with other pharmaceutically active compound(s).
  • the pharmaceutically acceptable salt is not particularly limited. Examples include hydrochloride, sulfate, nitrate, phosphate, hydrofluoride, hydrobromide, formate, acetate, tartarate, lactate, citrate, fumarate, maleate, succinate, methanesulfonate, benzenesulfonate, toluene- sulfonate, naphthalenesulfonate, etc.
  • the pharmaceutical composition according to the present invention may be prepared into any pharmaceutical preparation forms including oral administration forms such as powder, granule, tablet, capsule, suspension, emulsion, syrup, aerosol, etc.; external application forms such as ointment, cream, etc.; suppository; sterilized solution for injection; and the like, according to a method known to those skilled in the art.
  • oral administration forms such as powder, granule, tablet, capsule, suspension, emulsion, syrup, aerosol, etc.
  • external application forms such as ointment, cream, etc.
  • suppository sterilized solution for injection; and the like, according to a method known to those skilled in the art.
  • a preferred dosage of the extract of Cutleria cylindrica may be determined adequately by those skilled in the related art, depending on the subject's age, sex, body weight, symptoms, severity of disease, preparation form, administration route and period of administration. To attain an intended effect, it is preferred to administer the extract of Cutleria cylindrica of the present invention at a dose of 0.001 to 1000 mg/kg per day, either once a day or several times a day. The administration dose may be increased or decreased depending on age, sex, body weight, severity of disease, administration route, and the like. Hence, the administration dose by no means limits the scope of the present invention.
  • composition according to the present invention may be administered to mammals, including rat, mouse, livestock, human, etc., through various administration routes including parenteral and oral administrations.
  • Various modes of administration may be expected, including oral administration and rectal, intravenous, intramuscular, subcutaneous, intrauterine or intracerebroventricular injection.
  • composition according to the present invention can be administered safely over a long period of time for preventive purpose, since it is without severe toxicity or side reactions.
  • the composition according to the present invention may comprise 0.001 to 99.9 weight% of the extract of Cutleria cylindrica as active ingredient, based on the total weight of the composition.
  • the intended effect is attained when the content is at least 0.001 weight%, and it is difficult to attain a content greater than 99.9 weight% due to the presence of impurities or the like.
  • a binder such as gum arabic, cornstarch, microcrystalline cellulose or gelatin
  • an excipient such as dicalcium phosphate or lactose
  • a disintegrant such as alginic acid, cornstarch or potato starch
  • a surfactant such as magnesium stearate
  • a sweetener such as sucrose or saccharin
  • a flavor such as peppermint, methyl salicylate or fruit flavor
  • a liquid vehicle such as polyethylene glycol or fatty oil may be further added.
  • the present invention provides a health functional food composition
  • a health functional food composition comprising the extract of Cutleria cylindrica and a sitologically acceptable food additive.
  • the food composition according to the present invention may be, for example, various foods including chewing gum, caramel, candies, ice cakes, confectionery, etc., drinks including soft drinks, mineral water, alcoholic drinks, etc., or health functional foods including vitamins, minerals, etc..
  • the extract of Cutleria cylindrica may be comprised in an amount of 0.001 to 99.9 weight% based on the total weight of the food. In case of a drink, it may be comprised in an amount of 0.001 to 0.1 g, more preferably 0.05 to 0.1 g, based on 100 mL of the drink.
  • the drink comprising the extract of Cutleria cylindrica according to the present invention may further comprise other ingredients, in addition to the extract of Cutleria cylindrica as essential ingredient, without restriction.
  • other ingredients in addition to the extract of Cutleria cylindrica as essential ingredient, without restriction.
  • various flavors or natural carbohydrates may be added as in common drinks.
  • the health functional food composition according to the present invention may further comprise various nutrients, vitamins, minerals (electrolytes), synthetic or natural flavors, coloring agents and thickeners (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH modifiers, stabilizers, antiseptics, glycerin, alcohols, carbonating agents used in soft drinks, and the like.
  • the health functional food composition according to the present invention may comprise a pulp used to prepare natural fruit juices, fruit juice drinks, or vegetable drinks. These ingredients may be used alone or in combination. Although the addition amount of these additives is not so important, it is common to select a range of 0 to 20 parts by weight, based on 100 parts by weight of composition of the present invention.
  • the inventors of the present invention have performed experiments on the hepatoma cell line (Hepalclc7) of white rats, in order to evaluate the effect of inducing the activation of quinone reductase of the extract of Cutleria cylindrica. As a result, it was confirmed that the extract of Cutleria cylindrica according to the present invention improved the activity of quinone reductase by 2 times and 2.7 times as compared to the non-treated control group, at concentrations of 50 and 100 ⁇ g/mL, respectively.
  • the extract of Cutleria cylindrica according to the present invention is with no or slight cell toxicity, the IC 50 or the half maximal inhibitory concentration being 705 ⁇ g/mL.
  • the inventors of the present invention have also performed experiments on the human hepatoma cell line (HepG2), in order to evaluate the effect of activating the phase I and phase II detoxifying enzyme systems of the extract of Cutleria cylindrica.
  • HepG2 human hepatoma cell line
  • Cutleria cylindrica collected at Geumjin, Gangneung-si, Gangwon-do, Korea was washed with water to remove impurities and salts. After drying and cutting to a proper size, 20 g of Cutleria cylindrica and 500 mL of aqueous ethanol solution were added to an extractor. An extract was obtained following reflux condensation and filtration. The extraction process was repeated for 4 times. Subsequently, after concentration under reduced pressure followed by removal of the solvent, 880 mg of an ethanol extract was obtained.
  • Test Example 1 Evaluation of effect of inducing activation of quinone reductase of
  • the Cutleria cylindrica extract prepared in Example 1 was treated at concentrations of 25, 50 and 100 ⁇ g/mL, and culturing was carried out further for 24 hours under the condition of 5% CO 2 and 37 0 C. Then, after washing the cells with PBS (phosphate buffered saline) solution, the cell membrane was solubilized with 80 ⁇ L of solution containing 0.08% digitonin and 2 mM EDTA and a protein solution was obtained.
  • PBS phosphate buffered saline
  • reaction solution A 49 mL of 25 mM Tris buffer, 34 mg of BSA, 0.34 mL of 1.5% Tween-20 solution, 0.34 mL of coenzyme solution, 100 units of glucose-6-phosphate dehydrogenase, 15 mg MTT, 50 ⁇ L of 50 mM menadione
  • concentration of protein was measured at 595 nm using Bradford solution.
  • the coenzyme solution consisted of 150 rnM glucose-6-phosphate, 4.5 rnM NADP and 0.75 rnM FAD, and MTT is an abbreviation for 3-(4,5-dimethylthiazo-2-yl)-2,5-diphenyltetrazolium bromide.
  • Activity of quinone reductase was calculated by the following Equation 1.
  • A nmol MTT/min (rate of increase of absorbance at 610 nm in the cells treated with the extract of Cutleria cylindrica);
  • Test Example 2 Measurement of cell toxicity of Cutleria cylindrica extract
  • the Cutleria cylindrica extract prepared in Example 1 was treated at 5 different concentrations ranging from 12.5 to 200 ⁇ g/mL, and culturing was carried out further for 24 hours under the condition of 5% CO 2 and 37 0 C. Then, after treating with 10 ⁇ L of Cell Counting Kit (CCK- 8, Dojindo Laboratories) for 3 hours, absorbance was measured at 450 nm using a microplate reader. The cell proliferation ratio was calculated as the percentage of the absorbance of the cells treated with the Cutleria cylindrica extract prepared in Example 1 as compared to the absorbance of non-treated cells.
  • Example 1 is with no or slight cell toxicity, the IC 50 or the half maximal inhibitory concentration being 705 ⁇ g/mL.
  • Test Example 3 Evaluation of effect on XRE of Cutleria cylindrica extract
  • XRE reporter gene assay was carried out for the human hepatoma cell line (HepG2), in order to evaluate the effect on XRE, which induces the activation of phase I and phase II detoxifying enzyme systems, of the extract of Cutleria cylindrica according to the present invention.
  • HepG2 human hepatoma cell line
  • FBS fetal bovine serum
  • CAT chloramphenicol acetyl transferase
  • the expression ratio of the CAT protein was calculated as the percentage of the level of expression of the cells treated with the Cutleria cylindrica extract as compared to that of non-treated cells.
  • 3-MC 3-methylcolanthrene, Sigma, which is a carcinogen known to increase the activity of XRE, was used as positive control.
  • Example 1 has no concentration-dependent effect on XRE, which induces the activation of phase I and phase II detoxifying enzyme systems.
  • Test Example 4 Evaluation of effect on ARE of Cutleria cylindrica extract
  • ARE reporter gene assay was carried out for the human hepatoma cell line (HepG2), in order to evaluate the effect on XRE, which induces the activation of phase II detoxifying enzyme system, of the extract of Cutleria cylindrica according to the present invention.
  • HepG2 human hepatoma cell line
  • DMEM/10% FBS solution was mixed with hepatoma culture medium. After adjusting to a cell concentration of lxl0 5 cells/mL, the cells were transferred to a 48-well plate, 500 ⁇ L per each well, and cultured under the condition of 5% CO 2 and 37 0 C.
  • a vector in which an ARE- containing promoter and a CAT protein expressing gene were inserted was transformed using Fugene ⁇ (Roche Biochemicals).
  • the Cutleria cylindrica extract prepared in Example 1 was treated at concentrations of 1, 10 and 100 ⁇ g/mL, and culturing was carried out for 24 hours under the condition of 5% CO 2 and 37 0 C.
  • the expression of the CAT protein was measured using CAT- ELISA Kit (Roche Biochemicals).
  • the expression ratio of the CAT protein was calculated as the percentage of the level of expression of the cells treated with the Cutleria cylindrica extract as compared to that of non-treated cells.

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Abstract

Provided is a composition for cancer chemoprevention comprising the extract of the seaweed Cutleria cylindrica. Specifically, the composition for cancer chemoprevention according to the present invention comprising the extract obtained by extracting Cutleria cylindrica with ethanol, which activates quinone reductase, an anticarcinogenic enzyme, is without cell toxicity, and provides cancer chemoprevention effect by inducing activation of the phase II detoxifying enzyme system although not inducing activation of the phase I detoxifying enzyme system, as active ingredient can be useful as medicine or health functional food for cancer prevention.

Description

Description
COMPOSITION FOR CANCER CHEMOPREVENTION COMPRISING THE EXTRACTS OF CUTLERIA CYLINDRICA
Technical Field
[1] The present invention relates to a composition for cancer chemoprevention comprising the extract of the seaweed Cutleria cylindrica, more particularly to a pharmaceutical or functional health food composition for cancer prevention comprising the extract obtained by extracting Cutleria cylindrica with ethanol, which activates quinone reductase, an anticarcinogenic enzyme, is without cell toxicity, and provides cancer chemoprevention effect by inducing activation of the phase II detoxifying enzyme system although not inducing activation of the phase I detoxifying enzyme system, as active ingredient. Background Art
[2] Although researches on cancers have been carried out extensively for over 30 years, the incidence rate of cancer is still increasing because of environmental pollution, wrong diet habits, and the like. Worldwide, about 10 million people are diagnosed as cancer each year, and the World Health Organization (WHO) regards cancer as one of leading causes of death. Cancer is the disease of the elderly people 70% or more of new clinical cases are diagnosed in those who are 60 years or older. In aging societies, the increase of the incidence of cancer is an inevitable phenomenon. According to the Ministry of Health & Welfare, every year, approximately 100,000 patients are diagnosed as cancer in Korea.
[3] In general, cancer can be treated by surgery, radiation therapy, chemotherapy or other methods. To ensure treatment of cancer, an early diagnosis accompanied by surgery, radiation therapy or chemotherapy is necessary. In case of retarded diagnosis or metastasis, the treatment becomes complicated and requires much more psychological and economic burden. Accordingly, along with the diagnosis method enabling early detection of cancer, the cancer chemoprevention is becoming an important field in recent cancer researches.
[4] Whereas the previous chemotherapy is associated with severe toxicity and side reactions, affecting not only cancer cells but also normal cell, cancer chemoprevention is a new strategy in cancer research attempting to artificially suppressing, retarding or reversing carcinogenesis using relatively nontoxic chemicals, thereby preventing normal cells from converting to cancer cells. Toxicity should be non-existent or slight for a material to be a candidate for cancer chemoprevention. Further, easiness in synthesis or isolation from natural products is preferred. For these reasons, mainly compounds originated from plants are utilized except for some vitamin metabolites [Surh YJ, Nature Rev. Cancer, 3, 768-780, 2003].
[5] Cancer develops through the stages of initiation, promotion, progression and metastasis. Cancer chemoprevention mainly targets the initiation and promotion stages and is divided into two categories, depending on mechanism: blocking agents which prevent a carcinogen from reacting with an intracellular target or reaching the target; and suppressing agents which suppress the process of a cell exposed to a carcinogen forming a neoplasm (neoplasia) [Surh YJ, Nature Rev. Cancer, 3, 768-780, 2003]. Previously known blocking agents include: 1) diallyl sulfide, isothiocyanate, ellagic acid, and the like which inhibits the cytochrome P-450 enzyme, and 2) phenylethyl isothiocyanate, sulforaphane, oltipraz, and the like which induce the phase II detoxifying enzyme system. Previously known suppressing agents include: 1) DFMO which inhibits the polyamine metabolism, 2) retinoids which promote the cell differentiation, 3) genistein which inhibits protein kinase C, and 4) EGCG which inhibits oxidative DNA damaging.
[6] The blocking agents which control the activity of the detoxifying enzyme system may be categorized into monofunctional inducers and bifunctional inducers, depending on their functions. Monofunctional inducers induce the activation of the phase II detoxifying enzyme system such as quinone reductase and glutathione S-transferase. In contrast, bifunctional inducers induce the activation of the cytochrome P-450-based phase I detoxifying enzyme system, as well as inducing that of the phase II detoxifying enzyme system induced by the monofunctional inducers. In general, it is known that the increased activity of the phase II detoxifying enzyme system aids in the prevention of chemical carcinogenesis through promoting the excretion of carcinogens or procar- cinogens out of the body. However, it is known that the increased activity of the phase I detoxifying enzyme system results in endowing with or increasing the carcinogenesis through metabolizing procarcinogens, besides the detoxification of carcinogens. Accordingly, with respect to cancer chemoprevention, monofunctional inducers are more effective than bifunctional inducers [Prochaska HJ and Talalay P, Cancer Res., 48, 4776-4782, 1988].
[7] It is reported that two regulatory elements antioxidant response element (ARE) and xenobiotic responsive element (XRE) are involved in the genetic regulation of the detoxifying enzyme system with regard to cancer chemoprevention [Okey AB et al. , Toxicol. Lett., 70, 1-22]. ARE can be utilized to evaluate the effect of monofunctional inducers because it regulates the activation of the phase II detoxifying enzyme system. XRE is known to regulate the activation of both the phase I and phase II detoxifying enzyme systems and, therefore, can be utilized to evaluate the effect of bifunctional inducers. [8] Cutleria cylindrica is a green-brown seaweed. When young, it is 30-50 cm tall and has brown hair, 2-3 mm thick, stretching radially, branching widely and thinning toward the tip. When fully grown, the hair is lost, and the inside becomes hollow. The male and female gametangia are grouped to form irregular, spherical bumps, which are distributed over the stalk. It is found on the rock in a calm, intertidal zone, and is often seen in tidepools in spring. It is distributed mainly in Japan. In Korea, it is distributed in Daejin, Samcheok, Hupo, Giseong, Busan and Odong-do [Kang JW, Illustrated Encyclopedia of Flora & Fauna of Korea, Samhwa Publishing, 1968].
[9] The inventors of the present invention have searched for edible natural products having the effect of activating monofunctional inducers in order to develop cancer chemoprevention substances with no or slight toxicity to the human body. In doing so, they have found that the extract of Cutleria cylindrica activates quinone reductase, an anticarcinogenic enzyme, is without cell toxicity, and provides cancer chemoprevention effect by inducing activation of the phase II detoxifying enzyme system although not inducing activation of the phase I detoxifying enzyme system, and, thus, a composition comprising the same as active ingredient can be used as medicine or health functional food for cancer chemoprevention. Disclosure of Invention Technical Problem
[10] Therefore, the present invention has been made in view of the above problems, and an object of the present invention is to provide a composition for medicine or health functional food comprising the extract of Cutleria cylindrical, which has excellent cancer chemoprevention effect and is without toxicity to the human body, as active ingredient. Technical Solution
[11] The composition according to the present invention is characterized in comprising the extract of Cutleria cylindrica as active ingredient for treating or preventing cancer.
Advantageous Effects
[12] The extract of Cutleria cylindrica according to the present invention activates quinone reductase, an anticarcinogenic enzyme, is without cell toxicity, and provides cancer chemoprevention effect by inducing activation of the phase II detoxifying enzyme system although not inducing activation of the phase I detoxifying enzyme system, thereby inhibiting carcinogenesis of procarcinogens and promoting excretion of carcinogens or procarcinogens out of the body. Thus, a composition comprising the same as active ingredient can be used as medicine or health functional food for cancer chemoprevention. Brief Description of Drawings [13] The above and other objects, features and other advantages of the present invention will be more clearly understood from the following detailed description taken in conjunction with the accompanying drawings, in which: [14] Fig. 1 is a graph showing the effect of activating quinone reductase of the extract of
Cutleria cylindrica according to the present invention; [15] Fig. 2 is a graph showing the cell toxicity of the extract of Cutleria cylindrica according to the present invention; [16] Fig. 3 is a graph showing the effect of the extract of Cutleria cylindrica according to the present invention on xenobiotic responsive element (XRE) (* 3-methylcolanthrene treated control group); and [17] Fig. 4 is a graph showing the effect of the extract of Cutleria cylindrica according to the present invention on antioxidant response element (ARE).
Best Mode for Carrying out the Invention [18] In an aspect, the present invention provides an composition comprising the extract of
Cutleria cylindrica as active ingredient for treating or preventing cancer. [19] In a preferred embodiment, the composition according to the present invention has a use for cancer chemoprevention. [20] In another preferred embodiment, the extract of Cutleria cylindrica is an ethanol extract. [21] In still another embodiment, the extract of Cutleria cylindrica promotes the activity of quinone reductase. [22] In yet another embodiment, the extract of Cutleria cylindrica induces the activation of the phase II detoxifying enzyme system. [23] In still yet another embodiment, the composition according to the present invention is a pharmaceutical composition for treating or preventing cancer. [24] In a still further embodiment, the composition according to the present invention is a functional food composition for treating or preventing cancer.
Mode for the Invention
[25] Hereinafter, the present invention is described in further detail.
[26] In this description, the term "anticancer" or "for treating or preventing cancer" is used in the broadest meaning, embracing prevention, treatment, alleviation, and amelioration of cancer. [27] As used herein, "cancer chemoprevention" is the broadest meaning, including preventing one or more of initiation, promotion, progression and metastasis stages of cancer. In particular, it refers to the prevention of initiation and promotion of cancer.
Further, it includes the prevention of cancer through the blocking mechanism of preventing a carcinogen from reacting with an intracellular target or reaching the target. Also, it includes the prevention of cancer through the suppressing mechanism of suppressing the process of a cell exposed to a carcinogen forming a neoplasm (neoplasia). Further, it includes the prevention of cancer through promoting the excretion of carcinogens or procarcinogens out of the body. It also includes the prevention of cancer through metabolizing procarcinogens.
[28] As used herein, "the extract of Cutleria cylindrica" includes any one obtained by extraction from the natural product Cutleria cylindrica, without restriction. For example, Cutleria cylindrica is immersed in water or organic solvent and an active ingredient may be extracted therefrom through such means as sedimentation, stirring, pressurizing, heating, and the like. Further, a lyophilization product obtained by lyophilizing the liquid extract is included. In addition, a powder obtained by triturating the lyophilization product is included. Besides, any extract obtained by any means to extract the active ingredient is included, and one processed after the extraction, including lyophilization, is also included. Further, an extract obtained by the traditionally transcended methods, such as heating in a water bath or extraction at room temperature, or the methods described in the Oriental medical books or textbooks. Further, an extract obtained by the Stass-Otto method, which is specialized for isolation of specific active compounds, or a fractional extract obtained through column chromatography or other methods is included.
[29] The present invention provides an extract of Cutleria cylindrica for cancer chemo- prevention.
[30] The Cutleria cylindrica used in the present invention is not particularly limited, but may be harvested, grown or purchased one. The solvent for extraction is ethanol. The extract of Cutleria cylindrica may be prepared by washing Cutleria cylindrica with water to remove impurities and salts, drying and extracting the same, concentrating the resultant filtrate under reduced pressure, and drying the same.
[31] The present invention further provides a pharmaceutical or health functional food composition for cancer chemoprevention comprising the extract of Cutleria cylindrica as active ingredient.
[32] The pharmaceutical composition according to the present invention may further comprise an adequate vehicle, excipient or diluent commonly used in the preparation of a pharmaceutical composition.
[33] The pharmaceutical composition according to the present invention may be administered in the form of a pharmaceutically acceptable salt, either alone or in combination with other pharmaceutically active compound(s). The pharmaceutically acceptable salt is not particularly limited. Examples include hydrochloride, sulfate, nitrate, phosphate, hydrofluoride, hydrobromide, formate, acetate, tartarate, lactate, citrate, fumarate, maleate, succinate, methanesulfonate, benzenesulfonate, toluene- sulfonate, naphthalenesulfonate, etc.
[34] The pharmaceutical composition according to the present invention may be prepared into any pharmaceutical preparation forms including oral administration forms such as powder, granule, tablet, capsule, suspension, emulsion, syrup, aerosol, etc.; external application forms such as ointment, cream, etc.; suppository; sterilized solution for injection; and the like, according to a method known to those skilled in the art.
[35] With regard to the composition according to the present invention, a preferred dosage of the extract of Cutleria cylindrica may be determined adequately by those skilled in the related art, depending on the subject's age, sex, body weight, symptoms, severity of disease, preparation form, administration route and period of administration. To attain an intended effect, it is preferred to administer the extract of Cutleria cylindrica of the present invention at a dose of 0.001 to 1000 mg/kg per day, either once a day or several times a day. The administration dose may be increased or decreased depending on age, sex, body weight, severity of disease, administration route, and the like. Hence, the administration dose by no means limits the scope of the present invention.
[36] The composition according to the present invention may be administered to mammals, including rat, mouse, livestock, human, etc., through various administration routes including parenteral and oral administrations. Various modes of administration may be expected, including oral administration and rectal, intravenous, intramuscular, subcutaneous, intrauterine or intracerebroventricular injection.
[37] Meanwhile, the composition according to the present invention can be administered safely over a long period of time for preventive purpose, since it is without severe toxicity or side reactions.
[38] The composition according to the present invention may comprise 0.001 to 99.9 weight% of the extract of Cutleria cylindrica as active ingredient, based on the total weight of the composition. The intended effect is attained when the content is at least 0.001 weight%, and it is difficult to attain a content greater than 99.9 weight% due to the presence of impurities or the like.
[39] When preparing the extract of Cutleria cylindrica into tablet, capsule, chewable tablet, granule, powder, liquid solution, suspension, dispersion, emulsion, syrup, etc. for oral administration, a binder such as gum arabic, cornstarch, microcrystalline cellulose or gelatin, an excipient such as dicalcium phosphate or lactose, a disintegrant such as alginic acid, cornstarch or potato starch, a surfactant such as magnesium stearate, a sweetener such as sucrose or saccharin, and a flavor such as peppermint, methyl salicylate or fruit flavor may be included. In case the administration form is capsule, a liquid vehicle such as polyethylene glycol or fatty oil may be further added.
[40] Further, the present invention provides a health functional food composition comprising the extract of Cutleria cylindrica and a sitologically acceptable food additive. The food composition according to the present invention may be, for example, various foods including chewing gum, caramel, candies, ice cakes, confectionery, etc., drinks including soft drinks, mineral water, alcoholic drinks, etc., or health functional foods including vitamins, minerals, etc..
[41] The extract of Cutleria cylindrica may be comprised in an amount of 0.001 to 99.9 weight% based on the total weight of the food. In case of a drink, it may be comprised in an amount of 0.001 to 0.1 g, more preferably 0.05 to 0.1 g, based on 100 mL of the drink.
[42] The drink comprising the extract of Cutleria cylindrica according to the present invention may further comprise other ingredients, in addition to the extract of Cutleria cylindrica as essential ingredient, without restriction. For example, various flavors or natural carbohydrates may be added as in common drinks.
[43] In addition, the health functional food composition according to the present invention may further comprise various nutrients, vitamins, minerals (electrolytes), synthetic or natural flavors, coloring agents and thickeners (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH modifiers, stabilizers, antiseptics, glycerin, alcohols, carbonating agents used in soft drinks, and the like. Besides, the health functional food composition according to the present invention may comprise a pulp used to prepare natural fruit juices, fruit juice drinks, or vegetable drinks. These ingredients may be used alone or in combination. Although the addition amount of these additives is not so important, it is common to select a range of 0 to 20 parts by weight, based on 100 parts by weight of composition of the present invention.
[44] The inventors of the present invention have performed experiments on the hepatoma cell line (Hepalclc7) of white rats, in order to evaluate the effect of inducing the activation of quinone reductase of the extract of Cutleria cylindrica. As a result, it was confirmed that the extract of Cutleria cylindrica according to the present invention improved the activity of quinone reductase by 2 times and 2.7 times as compared to the non-treated control group, at concentrations of 50 and 100 μg/mL, respectively.
[45] Further, it was confirmed that the extract of Cutleria cylindrica according to the present invention is with no or slight cell toxicity, the IC50 or the half maximal inhibitory concentration being 705 μg/mL.
[46] The inventors of the present invention have also performed experiments on the human hepatoma cell line (HepG2), in order to evaluate the effect of activating the phase I and phase II detoxifying enzyme systems of the extract of Cutleria cylindrica. As a result, it was confirmed that the extract of Cutleria cylindrica according to the present invention had no effect on the activity of XRE, which induces activation of both the phase I and phase II detoxifying enzyme systems, but had a concentration- dependent effect on the activity of ARE, which induces activation of the phase II detoxifying enzyme system, at concentrations of 1, 10 and 100 βg/mL. This shows that the extract of Cutleria cylindrica according to the present invention provides an effective cancer chemoprevention effect through selectively improving the activity of the phase II detoxifying enzyme system.
[47]
[48] Hereinafter, the present invention is described in further detail through examples.
[49] However, the following examples are intended to be illustrative of the present invention, and they do not limit the scope of the present invention.
[50]
[51] Example 1 : Preparation of Cutleria cylindrica extract
[52] Cutleria cylindrica collected at Geumjin, Gangneung-si, Gangwon-do, Korea was washed with water to remove impurities and salts. After drying and cutting to a proper size, 20 g of Cutleria cylindrica and 500 mL of aqueous ethanol solution were added to an extractor. An extract was obtained following reflux condensation and filtration. The extraction process was repeated for 4 times. Subsequently, after concentration under reduced pressure followed by removal of the solvent, 880 mg of an ethanol extract was obtained.
[53]
[54] Test Example 1 : Evaluation of effect of inducing activation of quinone reductase of
Cutleria cylindrica extract
[55] Experiments were performed on the hepatoma cell line (Hepalclc7) of white rats, in order to evaluate the effect of inducing the activation of quinone reductase of the extract of Cutleria cylindrica according to the present invention. First, a-MEM (minimum essential medium)/10% FBS (fetal bovine serum) solution was mixed with hepatoma culture medium. After adjusting to a cell concentration of lxl05cells/mL, the cells were transferred to a 96- well plate, 100 μL per each well, and cultured for 24 hours under the condition of 5% CO2 and 370C. After the cells were stabilized, the Cutleria cylindrica extract prepared in Example 1 was treated at concentrations of 25, 50 and 100 μg/mL, and culturing was carried out further for 24 hours under the condition of 5% CO2 and 370C. Then, after washing the cells with PBS (phosphate buffered saline) solution, the cell membrane was solubilized with 80 μL of solution containing 0.08% digitonin and 2 mM EDTA and a protein solution was obtained. 50 μL of the protein solution was mixed with 200 ul of reaction solution A (49 mL of 25 mM Tris buffer, 34 mg of BSA, 0.34 mL of 1.5% Tween-20 solution, 0.34 mL of coenzyme solution, 100 units of glucose-6-phosphate dehydrogenase, 15 mg MTT, 50 μL of 50 mM menadione) and increase of absorbance was measured at 610 nm using a microplate reader. The concentration of protein was measured at 595 nm using Bradford solution. In the reaction solution A, the coenzyme solution consisted of 150 rnM glucose-6-phosphate, 4.5 rnM NADP and 0.75 rnM FAD, and MTT is an abbreviation for 3-(4,5-dimethylthiazo-2-yl)-2,5-diphenyltetrazolium bromide. Activity of quinone reductase was calculated by the following Equation 1.
[56] [Equation 1]
[57] Activity of quinone reductase = A / B
[58] where
[59] A = nmol MTT/min (rate of increase of absorbance at 610 nm in the cells treated with the extract of Cutleria cylindrica); and
[60] B = mg protein (total amount of protein in the cells treated with the extract of
Cutleria cylindrica).
[61] As seen in Fig. 1, it was confirmed that the extract of Cutleria cylindrica according to the present invention increased the activity of quinone reductase by 2 times and 2.7 times as compared to the non-treated control group, at concentrations of 50 and 100 μg/mL, respectively.
[62]
[63] Test Example 2: Measurement of cell toxicity of Cutleria cylindrica extract
[64] Experiments were performed on the hepatoma cell line (Hepalclc7) of white rats, in order to measure the cell toxicity of the extract of Cutleria cylindrica according to the present invention. First, a-MEM/10% FBS solution was mixed with hepatoma culture medium. After adjusting to a cell concentration of 5xl04cells/mL, the cells were transferred to a 96- well plate, 100 μL per each well, and cultured for 24 hours under the condition of 5% CO2 and 370C. After the cells were stabilized, the Cutleria cylindrica extract prepared in Example 1 was treated at 5 different concentrations ranging from 12.5 to 200 μg/mL, and culturing was carried out further for 24 hours under the condition of 5% CO2 and 370C. Then, after treating with 10 μL of Cell Counting Kit (CCK- 8, Dojindo Laboratories) for 3 hours, absorbance was measured at 450 nm using a microplate reader. The cell proliferation ratio was calculated as the percentage of the absorbance of the cells treated with the Cutleria cylindrica extract prepared in Example 1 as compared to the absorbance of non-treated cells.
[65] As seen in Fig. 2, it was confirmed that the extract of Cutleria cylindrica prepared in
Example 1 is with no or slight cell toxicity, the IC50 or the half maximal inhibitory concentration being 705 μg/mL.
[66]
[67] Test Example 3: Evaluation of effect on XRE of Cutleria cylindrica extract
[68] XRE reporter gene assay was carried out for the human hepatoma cell line (HepG2), in order to evaluate the effect on XRE, which induces the activation of phase I and phase II detoxifying enzyme systems, of the extract of Cutleria cylindrica according to the present invention. First, DMEM (Dulbeco's minimum essential medium)/10% FBS solution was mixed with hepatoma culture medium. After adjusting to a cell concentration of lxl05cells/mL, the cells were transferred to a 48-well plate, 500 μL per each well, and cultured under the condition of 5% CO2 and 370C. After the cells were stabilized, a vector in which an XRE-containing promoter and a chloramphenicol acetyl transferase (CAT) protein expressing gene were inserted was transformed using Fugeneβ (Roche Biochemicals). After the cells were stabilized, the Cutleria cylindrica extract prepared in Example 1 was treated at concentrations of 1, 10 and 100 μg/mL, and culturing was carried out for 24 hours under the condition of 5% CO2 and 370C. Then, the expression of the CAT protein was measured using CAT-ELISA Kit (Roche Biochemicals). The expression ratio of the CAT protein was calculated as the percentage of the level of expression of the cells treated with the Cutleria cylindrica extract as compared to that of non-treated cells. 3-MC (3-methylcolanthrene, Sigma), which is a carcinogen known to increase the activity of XRE, was used as positive control.
[69] As seen in Fig. 3, it was confirmed that the extract of Cutleria cylindrica prepared in
Example 1 has no concentration-dependent effect on XRE, which induces the activation of phase I and phase II detoxifying enzyme systems.
[70]
[71] Test Example 4: Evaluation of effect on ARE of Cutleria cylindrica extract
[72] ARE reporter gene assay was carried out for the human hepatoma cell line (HepG2), in order to evaluate the effect on XRE, which induces the activation of phase II detoxifying enzyme system, of the extract of Cutleria cylindrica according to the present invention. First, DMEM/10% FBS solution was mixed with hepatoma culture medium. After adjusting to a cell concentration of lxl05cells/mL, the cells were transferred to a 48-well plate, 500 μL per each well, and cultured under the condition of 5% CO2 and 370C. After the cells were stabilized, a vector in which an ARE- containing promoter and a CAT protein expressing gene were inserted was transformed using Fugeneβ (Roche Biochemicals). After the cells were stabilized, the Cutleria cylindrica extract prepared in Example 1 was treated at concentrations of 1, 10 and 100 μg/mL, and culturing was carried out for 24 hours under the condition of 5% CO2 and 370C. Then, the expression of the CAT protein was measured using CAT- ELISA Kit (Roche Biochemicals). The expression ratio of the CAT protein was calculated as the percentage of the level of expression of the cells treated with the Cutleria cylindrica extract as compared to that of non-treated cells.
[73] As seen in Fig. 4, it was confirmed that the activity of ARE increases in a concentration-dependent manner, as the concentration of the extract of Cutleria cylindrica increases. [74] As seen in Test Example 3 and 4, it was confirmed that the extract of Cutleria cylindrica according to the present invention provides an effective cancer chemo- prevention effect through selectively improving the activity of the phase II detoxifying enzyme system.
[75]
[76] Description on preparation examples according to preferred embodiments of the present invention is given hereinbelow. However, the following preparation examples are for illustrative purpose only, and they do not limit the present invention.
[77]
[78] Preparation Example 1 : Preparation of tablet
[79] Cutleria cylindrica extract prepared in Example 1 100 mg
[80] Cornstarch 68 mg
[81] Lactose 90 mg
[82] Microcrystalline cellulose 40 mg
[83] Magnesium stearate 2 mg
[84] According to common tablet making process, the above-listed ingredients were mixed homogeneously, agitated and granulated. After drying, tablets containing 100 mg of the Cutleria cylindrica extract per each tablet as active ingredient were prepared using a tablet making machine.
[85]
[86] Preparation Example 2: Preparation of capsule
[87] Cutleria cylindrica extract prepared in Example 1 100 mg
[88] Cornstarch 68 mg
[89] Lactose 90 mg
[90] Microcrystalline cellulose 40 mg
[91] Magnesium stearate 2 mg
[92] According to common capsule making process, the above-listed ingredients were mixed homogeneously and filled in a gelatin capsule of a proper size, such that 100 mg of the Cutleria cylindrica extract was contained in each capsule.
[93]
[94] Preparation Example 3: Preparation of chewable tablet
[95] Cutleria cylindrica extract prepared in Example 1 100 mg
[96] Frost sugar syrup 240 mg
[97] Fragrance 2 mg
[98] Cornstarch 60 mg
[99] Mannitol 100 mg
[100] Magnesium stearate 20 mg
[101] Purified water adequate [102] According to common chewable tablet making process, the above-listed ingredients were mixed in water, dissolved by heating, cooled, and prepared into chewable tablets with wanted shape using a molder, such that 100 mg of the Cutleria cylindrica extract was contained in each chewable capsule.
[103]
[104] Preparation Example 4: Preparation of candy
[105] Cutleria cylindrica extract prepared in Example 1 100 mg
[106] Frost sugar syrup 640 mg
[107] Fragrance 2 mg
[108] Starch syrup 230 mg
[109] 50% tartaric acid 20 mg
[110] Purified water adequate
[111] Frost sugar syrup was completely dissolved in a small amount of water. After heating to 11O0C, the Cutleria cylindrica extract dissolved in water and starch syrup were added, and the temperature was increased to 1450C. After stopping heating, fragrance and tartaric acid were added. After cooling to 75 to 8O0C, candies containing the Cutleria cylindrica extract were prepared using a molding roller.
[112]
[113] Preparation Example 5: Preparation of drink
[114] Cutleria cylindrica extract prepared in Example 1 100 mg
[115] Concentrated fruit juice 2 g
[116] Sucrose 12 g
[117] Sodium citrate 100 mg
[118] Fragrance 70 mg
[119] Water adequate
[120] According to common drink making process, the above-listed ingredients were mixed in water, dissolved by heating, cooled, and filled in a receptacle, such that 100 mg of the Cutleria cylindrica extract was contained in 200 mL of a drink.
[121]
[122] Although the preferred embodiments of the present invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that various modifications, additions and substitutions are possible, without departing from the scope and spirit of the invention as disclosed in the accompanying drawings.

Claims

Claims
[1] A composition comprising the extract of Cutleria cylindrica as active ingredient for treating or preventing cancer.
[2] The composition as defined in claim 1, which has a use for cancer chemo- prevention.
[3] The composition as defined in claim 1 or 2, wherein the extract of Cutleria cylindrica is an ethanol extract.
[4] The composition as defined in claim 1 or 2, wherein the extract of Cutleria cylindrica promotes the activity of quinone reductase.
[5] The composition as defined in claim 1 or 2, wherein the extract of Cutleria cylindrica induces the activation of the phase II detoxifying enzyme system.
[6] The composition as defined in claim 1 or 2, which is a pharmaceutical composition.
[7] The composition as defined in claim 1 or 2, which is a functional food composition.
PCT/KR2008/002362 2008-04-25 2008-04-25 Composition for cancer chemoprevention comprising the extracts of cutleria cylindrica WO2009131263A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10158156A (en) * 1996-03-22 1998-06-16 Nippon Suisan Kaisha Ltd Antitumor agent
KR20040033984A (en) * 2002-10-16 2004-04-28 이상국 Composition comprising the extract of Hordeum vulgare having inductive activity of Quinone reductase
KR20050006533A (en) * 2003-07-09 2005-01-17 이재화 Method obtaining extracts having anti-cancer effect and immune enhancing activity from marine algae
JP2007269767A (en) * 2006-03-30 2007-10-18 Ventuno:Kk Method for heated and pressurized extraction of algae

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10158156A (en) * 1996-03-22 1998-06-16 Nippon Suisan Kaisha Ltd Antitumor agent
KR20040033984A (en) * 2002-10-16 2004-04-28 이상국 Composition comprising the extract of Hordeum vulgare having inductive activity of Quinone reductase
KR20050006533A (en) * 2003-07-09 2005-01-17 이재화 Method obtaining extracts having anti-cancer effect and immune enhancing activity from marine algae
JP2007269767A (en) * 2006-03-30 2007-10-18 Ventuno:Kk Method for heated and pressurized extraction of algae

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