KR20100134966A - Use in anti-cancer agent of 4'-o-glucose-luteolin - Google Patents

Abstract

PURPOSE: An agent for preventing or treating cancer containing flavonol derivative compound is suppress TNF-alpha(tumor necrosis factor alpha) and NF-kB(nuclear factor kappa B) activation. CONSTITUTION: A pharmaceutical composition for preventing or treating cancer contains 4'-O-glucose-luteolin of chemical formula 1 or pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition further contains one or more kinds of pharmaceutically acceptable carrier. A food composition contains the 4'-O-glucose-luteolin and pharmaceutically acceptable salt thereof as an active ingredient. The food composition is used in the form of beverage, bread, capsule or tablet.

Description

Use of 4'-O-glucose-luteolin as anticancer agent {USE IN ANTI-CANCER AGENT OF 4'-O-GLUCOSE-LUTEOLIN}

The present invention relates to a novel use of a flavonol-based compound as a cancer prevention or therapeutic agent, specifically 4'-O-glucose-luteolin (4'-O-glucose-luteolin) excellent in anticancer activity Or to novel uses for use as therapeutics.

Cells produce an appropriate amount of cells through growth and differentiation, and maintain a certain number of functions and functions by removing unnecessary cells through the process of apoptosis. In order to perform this function, there are cytokines (Cytokines) that express various cells in the cells. However, cytokines, through external stimuli or internal modifications, disrupt cell homeostasis by oversecreting or overexpressing enzymes, resulting in excessive cell proliferation and abnormal cell formation. Typically, one of the cytokines causing these signals is the cytokine tumor necrosis factor TNF-a (Tumor necrosis factor alpha, cachexin or cachectin).

Increasing TNF-a is a type of enzyme that maintains cell growth while maintaining a dual function of inducing apoptosis or interfering with apoptosis, depending on the receptors (R1 or R2) that are commonly transmitted. Induces increased expression of nuclear factor kappa B (NF-κB) (RE Kast, Inflammopharmacology, 14, 256-259, 2006).

Transcription factor NF-κB (nuclear factor Kappa B) is one of the most actively studied transcription factors since it was first discovered as a factor that binds to immunoglobulin κ-chain, and apoptosis It is involved in various cellular reactions, such as immune response and inflammatory response. NF-κB, composed of the p50 subunit family and the p65 subunit family, homo- or dimers, binds to its inhibitor, IκB, in the cytoplasm. IKK known as IκB kinase by various stimuli such as TNF-a, IL-1, lipopolysaccharide (LPS), adriamycin, free radical, and radiation The protein is activated and eventually IκB is phosphorylated to be released and released from IκB while NF-κB is activated and enters the nucleus to function as a transcription factor (PA Baeuerie and D. Baltimore, Cell 87, 13-20, 1996).

NF-κB expresses cyclooxygenase-2 (COX2), inducible nitric oxide synthase, and various cytokines such as TNF-a and E-selectin in inflammatory reactions. Not only is it an important transcription factor for the expression of adhesion molecules such as E-selectin), ICAM, VCAM, etc., but it also plays a role in regulating apoptosis signals through death receptors such as the TNF-a receptor family. (FH Epstein, New Engl J Med 336 (15), 1066-1071, 1997; T. Collins, MA Read et. Al., FASEB J9, 899-909, 1995). For example, it plays an important role in regulating expression of Mn-SOD, zinc finger protein (A20), inhibitor of apoptosis protein (IAP), which are known as proteins that inhibit apoptosis by mediating death receptors. (DJ Van Antwerp, SJ Martin, et. Al., Trends in Cell Biology 8, 107-111, 1998; C.-Y. Wang, MW Mayo et. Al., Science 281, 1680-1683, 1998). Even in cancer cells, treatment with TNF-a or adriamycin activates NF-κB and inhibits apoptosis induced by these drugs. Inhibiting the activation of NF-κB induced by these drugs causes apoptosis. Increased drug sensitivity (AA Beg and D. Baltimore, Science 274, 782-784, 1996; C.-Y. Wang, MW Mayo and AS Baldwin Jr., Science 274,784-789, 1996).

As such, NF-κB is activated in response to external pressure and plays a central role in the expression of inflammatory mediators. Although it is still controversial, NF-κB activation is involved in neuronal cell death and TNF-a It also plays an important role in the expression of proteins that function to inhibit the death of cancer cells induced by anticancer drugs. (E. Kopp and S. Ghosh, Science 265, 956-959, 1994; A. Ray, K. E. Prefontaine, Proc Natl Acad Sci U S A91, 752-756, 1994).

In general, NF-κB that is abnormally expressed in cancer cells is known to promote continuous cell differentiation when it is excessively present in the nucleus. Since the target molecules of NF-κB are the cyclin D1 and c-Myc promoters, which are involved in the continuous growth of cells, excessive cell division and production are induced, and the formation of abnormal cells or an increase in the absolute amount of cells promotes cancer cells. (Mol. Cell, Biol., 21, 8428-8436. 2001). In addition, NF-κB-induced expression of cyclooxygenase (COX) promotes the growth of cancer cells that have already occurred (N. D. Perkins, Biochmical Society Transaction, v. 32, part 6, 936-939, 2004). As a result, inhibitors of NF-κB that induce excessive growth of cells, such as expressing proteins involved in the continuous growth of cells and promoting the growth of cancer cells, inhibit the formation and progression of cancer cells. Can function as an anticancer agent.

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The present inventors, one of 4'- O of the flavonol derivatives - glucose - transferring the luteolin (4'-O-glucose-luteolin ) compounds which are modulated by TNF-a In order to investigate the efficacy as anti-cancer therapeutic factor NF-κB As a result of investigating the effect on the activation, it was confirmed that the activity of NF-κB is inhibited by the addition of flavonol derivatives to complete the present invention.

It is therefore an object of the present invention 4'- O - to provide a luteolin (4'-O-glucose-luteolin ) a new use of a compound-glucose.

The objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.

In order to achieve the above object, the present invention 4'- O - glucose - luteolin prevention or treatment of cancer, including (4'-O-glucose-luteolin ) , or a pharmaceutically acceptable salt thereof as an active ingredient It provides a pharmaceutical composition.

The invention also 4'- O - provides the NF-κB activation inhibitor containing luteolin (4'-O-glucose-luteolin ) as an active ingredient-glucose.

The invention also 4'- O - provides a food composition comprising a Luteolin (4'-O-glucose-luteolin ) as an active ingredient-glucose.

Hereinafter, the present invention will be described in detail.

The present invention is an anticancer agent that inhibits the activity of the transcription factor NF-κB (Neuclear factor kappa B) of 4'-O-glucose-luteolin, a flavonol derivative represented by the following formula (1): Provides use as

4′- O -glucose-luteolin of the present invention is a compound represented by Chemical Formula 1 as a flavonol derivative.

The compounds of formula (I) according to the invention can be prepared by extraction, separation from plants or by synthetic methods well known in the art. The inventors have described 4′- O -glucose-luteolin in C. Zidorn et al., Sci Pharm., 76, 743, 2008].

4′- O -glucose-luteolin of the present invention has an excellent antiproliferative effect due to its superior inhibitory activity against NF-κB, thereby inhibiting diseases related to cell proliferation such as cancer, inflammation, vascular stenosis and blood vessel formation. Or as a therapeutic composition. In particular, it can be used very effectively as an anticancer agent.

The present invention provides a pharmaceutical composition for preventing or treating cancer, comprising 4′- O -glucose-luteolin or a pharmaceutically acceptable salt thereof as an active ingredient.

As the pharmaceutically acceptable salt of the present invention, acid addition salts formed by free acid are useful. In this case, organic acids and inorganic acids may be used as the free acid, and hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, and the like may be used as the inorganic acid, and methane may be used as the organic acid. Methane sulfonic acid, p-toluen sulfonic acid, acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, propionic acid, citric acid, lactic acid, glycolic acid ), Gluconic acid, galacturon acid, glutamic acid, glutaric acid, glucuronic acid, glucuronic acid, aspartic acid, ascorbic acid (ascorbic acid), carbonic acid, vanillic acid, hydro Hydroiodic acid may be used.

In addition, bases can be used to make pharmaceutically acceptable metal salts. An alkali metal or alkaline earth metal salt is obtained by, for example, dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate. In this case, as the metal salt, it is particularly suitable to prepare sodium, potassium or calcium salt, and the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).

Pharmaceutically acceptable salts of the invention include salts of acidic or basic groups which may be present in the compounds of the invention, unless otherwise noted. For example, pharmaceutically acceptable salts include sodium, calcium, and potassium salts of the hydroxy group, and other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfate, and hydrogen sulfate. sulfate, phosphate, hydrogen sulfate, dihydrogen sulfate, acetate, succinate, citrate, tartrate, lactate ), Methanesulfonate (mesylate, methane sulfonate) and p -toluenesulfonate (tosylate, p- toluen sulfonate) salts, and can be prepared through a method or a manufacturing process of salts known in the art.

The 4′- O -glucose-luteolin or a pharmaceutically acceptable salt thereof can be appropriately adjusted depending on the purpose of use, and there is no particular limitation. The pharmaceutical composition of the present invention may be administered to a patient by a general oral or parenteral administration method, and may be in any form in a solid or liquid form.

"Cancer", a disease to be improved, prevented or treated by the compositions of the present invention, is an aggressive property in which cells divide and grow, ignoring normal growth limits, and an invasive property that penetrates surrounding tissues. And diseases caused by cells having metastatic properties that spread to other parts of the body. In the present specification, the cancer is also used in the same sense as a malignant tumor, and includes, but is not limited to, solid tumors and blood born tumors.

The term cancer refers to the bladder, bone or blood, brain, breast, cervix, chest, colon, endrometrium, esophagus, eyes, head, kidney, small intestine, kidney, thyroid, parathyroid gland, endocrine tissue, bone marrow, liver, Refers to diseases of skin tissue, organs, blood and blood vessels, including but not limited to, cancers of the lymph nodes, lungs, mouth, throat, ovaries, pancreas, prostate, rectum, stomach, testes, throat, anus and uterus. Certain cancers include advanced malignancy, amyloidosis, neuroblastoma, meningiomas, pericarcinoma, multiple brain metastase, glioblastoma multiforms, glioblastoma, brain stem glioma stem glioma, poor prognosis malignant brain tumor, malignant glioma, recurrent malignant glioma, anaplastic astrocytoma, anaplastic astrocytoma Anaplastic oligodendroglioma, neuroendocrine tumor, adenocarcinoma, Dukes C & D colorectal cancer, unresectable rectal colon cancer, metastatic hepatocellular carcinoma, Kaposi's sarcoma, acute karotype Myelogenous leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, diffuse giant B-cell Diffuse large B-Cell lymphoma, low grade follicular lymphoma, malignant melanoma, malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, Celiac carcinoma, papillary serous carcinoma, gynecologic sarcoma, soft tissue sarcoma, scelroderma, subcutaneous vasculitis, langerhans cell histiocytosis, smooth muscle sarcoma, Fibrodysplasia ossificans progressive, hormonal unresponsive prostate cancer, surgically high-risk soft tissue sarcoma, unrescectable hepatocellular carcinoma that is difficult to remove surgically, and Waldenstrom macro Globulinemia, exposed myeloma, painless myeloma, cervical cancer, androgen-independent prostate cancer, androgen-dependent stage IV non-metastasis Prostate cancer, hormone-insensitive prostate cancer, chemotherapeutic-nonsensitized prostate cancer, papillary gland carcinoma, follicular gonocarcinoma, medullary goiter carcinoma, and leiomyoma leiomyoma), including but not limited to head and neck cancer.

As used herein, the term "prevention" means to inhibit the occurrence of a disease or condition in an animal that has not been diagnosed as having a disease or condition but is prone to such disease or condition. As used herein, the term "treatment" refers to (1) inhibition of the development of a disease or condition; (2) alleviation of the disease or disorder; And (3) elimination of the disease or condition.

The compositions of the present invention can be administered before, simultaneously or after an anticancer agent for the prevention or treatment of cancer. It is administered in a therapeutically effective amount upon administration for clinical purposes. The term “therapeutically effective amout” means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective amount for a particular patient is age, sex, weight, health condition. , Time of administration, route of administration, rate of excretion, drug mixture and severity of disease.

In addition, the pharmaceutical compositions of the present invention may further comprise one or more pharmaceutically acceptable liquid or solid carriers. It may also be prepared using diluents or excipients, such as fillers, extenders, binders, wetting agents, disintegrants, lubricants, surfactants that are commonly used, but is not limited thereto.

 The solid form preparations may be tablets, pills, powders, granules, capsules, pellets, granules or powders, and such solid preparations may be prepared by adding a carrier, excipients and / or diluents to the compound. The carrier, excipient and / or diluent may include lactose, sucrose, dextrose, mannitol, malitol, malitol, sorbitol, xylitol, and erythritol. (erithritol), starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, polyvinyl pyrrolidone polyvinyl pyrrolidone, magnesium stearate, and mineral oil.

The formulations in liquid form may be solutions, suspensions or emulsions, and may include various excipients, for example wetting agents, sweeteners, fragrances, preservatives, etc., in addition to the commonly used simple diluents, water and liquid paraffin. Aqueous suspensions suitable for oral use may be prepared by dispersing the finely divided active component in a viscous material such as natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose and known suspending agents. Can be.

Examples of fillers that may be used in the pharmaceutical compositions and dosage forms disclosed herein include talc, calcium carbonate (eg, granules or powders), microcrystalline cellulose, powder cellulose, dexrate, kaolin, mannitol, silicic acid, sorbitol , Starch, pre-gelatin ring starch, and mixtures thereof. The binder or filler of the pharmaceutical composition of the present invention is generally present in about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.

Disintegrants that can be used in the pharmaceutical compositions and dosage forms disclosed herein are intended to disintegrate when the tablet is exposed to an aqueous environment. Tablets containing too much disintegrant may disintegrate during storage, while tablets containing too little do not disintegrate at the desired rate under the desired conditions. A sufficient amount of disintegrant, therefore not too much or too little, should not be used to form the solid oral dosage form of the invention so as not to be bad for controlling the release of the active ingredient. The amount of disintegrants used varies depending on the type of formulation, and can be readily determined by one of ordinary skill in the art. Typical pharmaceutical compositions contain from about 0.5 to about 15 weight percent of disintegrant, preferably from about 1 to about 5 weight percent of disintegrant. The disintegrants that can be used in the pharmaceutical compositions and dosage forms of the present invention are agar. Agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, poracryline potassium, sodium starch glycolenmit, potato or tapioca starch, other starch, pre-gelatinized starch, other starch, clay , Other algins, other celluloses, gums, and mixtures thereof.

Glidants that can be used in the pharmaceutical compositions and dosage forms of the present invention include calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, Sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, Agar, and mixtures thereof, including but not limited to. Additional lubricants are, for example, siloid silica (AEROSIL200, manufactured by WR Grace Co., Baltimore, MD), coagulated aerosol of synthetic silica, manufactured by Degussa Co., Plano, TX, CAB- O-SIL (pyrogenic silicon dioxide product, Cabot Co., Boston, Mass.), And mixtures thereof. If used, glidants are generally used in amounts up to about 1 weight percent of the pharmaceutical composition or dosage form in which they are contained.

The pharmaceutical composition of the present invention may be administered orally or parenterally, and when administered parenterally, may be administered by intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, or the like. It is preferable that the route of administration of the pharmaceutical composition of the present invention is determined according to the type of the disease to be applied.

Examples of the parenteral administration include injections, drops, sap, ointments, sprays, suspensions, emulsions, suppositories, and the like. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations and suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate may be used. As a base of suppositories, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin, and the like may be used.

The pharmaceutical compositions of the present invention are administered in combination with therapies that have conventionally been used to treat, prevent or treat cancer. Examples of such conventional therapies include, but are not limited to, surgery, chemotherapy, radiation therapy, hormone therapy, biological therapy and immunotherapy.

In addition, the pharmaceutical composition of the present invention can be effective in the prevention or treatment of cancer by using in combination with other anticancer agents. Other anticancer agents that can be administered in combination with the pharmaceutical compositions of the present invention are as follows.

Examples of anticancer agents that can be administered in combination with a composition of the present invention include acivicin; Aclarubicin; Acodazole hydrochloride; acodazole hydrochloride; Acronine; Adozelesin; Aldesleukin; Altretamine; aambomycin; amethantroneacetate; Amsacrine; Anastrozole; Anthracyycin; Asparaginase; Asperlin; Azacyitidine; Azetepa; Azotomycin; Batimastat; Benzodepa; Bicalutamide; Bisantrene hydrochloride; Bisnafide dimesylate; Baselesin; Bleomycin sulfate; Brequinar sodium; Bropirimine; Busulfan; Cactinomycin; Calussterone; Caracemide; Carbetimer; Carboplatin; Carmustine; Carubicin hydrochloride; Carzelesin; Cedefingol; Celecoxib (COX-2 inhibitor); Chlorambucil; Sirolemycin; Cisplatin; Cladribine; Crisnatol mesylate; Cyclophosphamide; Cytarabine; Dacarbazine; Dactinomycin; Daunorubicin hydrochloride; Decitabine; Dexormaplatin; Dezaguanine; Dezaguanine mesylate; Diaziquone; Docetaxel; Doxorubicin; Doxorubicin hydrochloride; Drroloxifene; Drroloxifene citrate; Dromostanolone propionate; Duazomycin; Edatrexate; Eflornithine hydrochloride; Elsamitrucin; Enloplatin; Enpromate; Epipropidine; Epirubicin hydrochloride; Erbulozole; Esorubicin hydrochloride; Estramustine; Estramustine phosphate sodium; Etanidazole; Etoposide; Etoposide phosphate; Etoprine; fadrozole hydrochloride; Fazarabine; Fenretinide; Floxuridine; Fludarabine phosphate; Fluorouracil; Flurocitabine; Fosquidone; Postriecin sodium (fostriecin sodium); Gemcitabine; Gemcitabine hydrochloride; Hydroxyurea; Idarubicin hydrochloride; Ifosfamide; Ilmofosine; Iproplatin; Irinotecan; Irinotecan hydrochloride; Lanreotide acetate; Letrozole; Leuprolide acetate; Liarozole hydrochloride; Rometrexol sodium; Lomustine; Losoxantrone hydrochloride; Masoprocol; Maytansine; Mechlorethamine hydrochloride; Megestrol acetate; Melengestrol acetate; Melphalan; Menogaril; Mecaptopurine; Methotrexate; Methotrexate sodium; Metoprine; Meturedepa; Mitindomide; Mitocarcin; Mitocromin; Mitogillin; Mitomalcin; Mitomycin; Mitosper; Mitotane; Mitoxantrone hydrochloride; Mycophenolic acid; Nocodazole; Nogalamycin; ormaplatin; Oxisuran; Paclitaxel; Pegaspargase; Peliomycin; Pentamustine; Peplomycin sulfate; Perfosfamide; Pipobroman; Piposulfan; Pyroxantrone hydrochloride; Plicamycin; Plomestane; Porfimer sodium; Porfiromycin; Prednimustine; Procarbazine hydrochloride; Puromycin; Puromycin hydrochloride; Pyrazofurin; Riboprine; Safining; Safingol hydrochloride; Semustine; Simtrazene; Spafosatesodium; Spasomycin; Spirogermanium hydrochloride; Spiromustine; Spiroplatin; Streptonigrin; Streptozocin; Sulofenur; Talisomycin; Tecogalalan sodium; Taxotere; Tegafur; Teloxantrone hydrochloride; Temoporfin; Teniposide; Teroxirone; Testolactone; Thiamiprine; Thioguanine; Thiotepa; Tiazofurin; Tirapazamine; Toremifene citrate; Trestolone acetate; Trisiribine phosphate; Trimetrexate; Trimetrexate glucuronate; Triptorelin; Tubulozolehydrochloride; Uracil mustard; Uredepa; Vapreotide; Verteporfin; Vinblastine sulfate; Vincristine sulfate; Vindesine; Vindesine sulfate; Vinepidine sulfate; Vinlycinate sulfate; Vinleurosine sulfate; Vinorelbine tartrate; Vinrosidine sulfate; Vinzolidine sulfate; bororozole; Zeniplatin; Zinostatin; And zorubicin hydrochloride.

Other anticancer drugs include 20-epi-1, 25dihydroxyvitamin D3; 5-ethynyluracil; Abiraterone; Aclarubicin; Acylfulvene; Adecypenol; Adozelesin; Aldesleukin; ALL-TK antagonists; Altretamine; Ambamustine; amidox; Amifostine; Aminolevulinic acid; Amrubicin; Amsacrine; Anagrelide; Anastrozole; Andrographolide; Angiogenesis inhibitors; Antagonist D; Antagonist G; Antarlix; Anti-dorsalizing morphogenetic protein-1; Antiandrogen, prostatic carcinoma; Antiestrogens; Antineoplaston; Antisense oligonucleotides; Aphidicolin glycinate; Apoptosis gene modulators; Apoptosis regulators; Apurinic acid; Ara-CDP-DL-PTBA; Arginine deaminase; Asulacrine; Atamestane; Attrimustine; Axinastatin 1; Axitastatin 2 (axinastatin2); Axinastatin 3; Azasettron; Azatoxins; Azatyrosine; baccatin III derivatives; Balanol; Batimastat; BCR / ABL antagonists; benzochlorins; Benzoylstaurosporine; Beta lactamderivatives; Beta-alethine; Betaclamycin B; Betulinic acid; bFGF inhibitors; Bicalutamide; Bisantrene; Bisaziridinylspermine; Bisnafide; Bisratene A; Bizelesin; Breflate; Bropirimine; Budotitane; Butionine sulfoximine; Calcipotriol; Calphostin C; Camptothecinderivatives; Capecitabine; Carboxamide-amino-triazole; Carboxyaminotriazole; CaRestM3; CARN 700; Cartilage derived inhibitors; Carzelesin; Casein kinase inhibitors (ICOS); Castanospermine; Cecropin B; Cetrorelix; Chlorlns; Chloroquinoxaline sulfonamide; Cicaprost; Cis-porphyrin; Cladribine; Clomifeneanalogues; Clotrimazole; Collismycin A; Collismycin B; combretastatin A4; Combretastatin analogue; Conagenin; Crambescidin 816; Crisnatol; Cryptophycin 8; Cryptophycin A derivatives; Curacin A; Cyclopentanthraquinones; Cycloplatam; Cypemycin; Cytarabine ocfosfate; Cytolytic factors; Cytostatin; Dacliximab; Decitabine; Dehydrodidemnin B; Deslorelin; Dexamethasone; Dexifosfamide; Dexrazoxane; Dexverapamil; Diaziquone; Didemnin B; Didox; Diethylnorspermine; Dihydro-5-azacytidine; Dihydrotaxol; Dioxamycin; Diphenyl spiromustine; Docetaxel; Docosanol; Dorasetron; Doxifluridine; Doxorubicin; Drroloxifene; Dronabinol; Duocarmycin SA; Ebselen; Ecomustine; Edelfosine; Edrocolomab; Eflornithine; Elmene; Emitefur; Epirubicine; Episteride; Estramustine analogue; Estrogen antagonists; Etanidazole; Etoposide phosphate; Exemestane; Fadrozole; Fazarabine; Fenretinide; filgrastim; Finasteride; Flavopyridol; Flezelastine; Fluasterone; Fluorodaunorunicinhydrochloride; Forfenimex; Formestane; Postrescine; Gadolinium texaphyrin; Gallium nitrate; Galocitabine; Ganirelix; Gelatinase inhibitors; Gemcitabine; Glutathione inhibitors; Hepsulgam; Heregulin; Hexamethylene bisacetamide; Hypericin; Ibandronic acid; Idarubicin; Idoxifene; Idramantone; Ilmofosine; Ilomastat; Imatinib (eg, Gleevec®), imiquimod; Immunostimulatory peptides; Insulin-likegrowth factor-1 receptor inhibitors; Interferon antagonists; Interferon; Interleukin; Iobenguane; Iododoxorubicin; Ipomeanol; Iroplact; Irsogladine; Isobengazole; Isohomohalicondrin B; Itasetron

(itasetron); Jasplakinolide; Kahalalide F; Lamellarin-N triacetate; Lanreotide; Leinamycin; Lenograstim; lentinan sulfate; Leptolstatin; Letrozole; Leukemia inhibiting factor; Leukocyte alpha interferon; Leuprolide + estrogen + progesterone; Leuprorelin; Levamisole; Liarozole; Linear polyamine analogues; Lipophilic disaccharide peptide; Lipophilic platinum compounds; Lissoclinamide 7; Lobaplatin; Lombricine; Lometrexol; Ronidamine; Losoxantrone; Loxoribine; Lutotecan; Lutetium texaphyrin; Lysofylline; Lytic peptides; Maytansine; Mannostatin A; marimastat; Masoprocol; Maspin; Matrilysininhibitors; Matrix metalloproteinase inhibitors; Menogaril; Merbarone; Meterelin; Methioninase; Metoclopramide; MIF inhibitors; Mifepristone; Miltfosine; Mirimostim; Mitoguazone; Mitoractol; Mitomycin analogues; Mitonafide; Mitotoxin fibroblast growth factor-saporin; Mitoxantrone; Mofarotene; Molgramostim; Erbitux, human chorionic gonadotrophin; Monophosphoryl lipid A + myobacterium cell wall sk; Mopidamol; Mustard anticancer agent; Mycaperoxide B; Mycobacterial cell wall extract; Myriaporone; N-acetyldinaline; N-substituted benzamides; Nafarelin; Nagrestip; Naloxone + pentazocine; Napavin; Naphterpin; Nartograstim; Nedaplatin; Nemorubicin; Neridronic acid; Nilutamide; Nisamycin; Nitric oxide modulators; Nitroxide antioxidants; Nitrullyn; Oblimersen (Genasense); Benzylguanine; Octreotide; Okicenone; Oligonucleotides; Onapristone; Ondansetron; Ondansetron; Oracin; Oral cytokine inducers; Omaplatin; Osaterone; Oxaliplatin; Oxaunomycin; Paclitaxel; Paclitaxel analogs (paclitaxel analogues); Paclitaxel derivatives; Palauamine; Palmitolyrxin (palmitoylrhizoxin); Pamidronic acid; Panaxytriol; Panomifene; Parabactin; Pazelliptine; Pegaspargase; Peldesine; Pentosan polysulfate sodium; Pentostatin; Pentrozole; Perflubron; Perfosfamide; Perillyl alcohol; Phenazinomycin; Phenyl acetate; Phosphataseinhibitors; Picibanil; Pilocarpine hydrochloride; Pyrarubicin; Pyritrexim; Placetin A; Placetin B; Plasminogen activator inhibitors; Platinum complexes; Platinum compounds; Platinum-triamine complex; Porfimer sodium; Fort

Porfiromycin; Prednisone; Propyl bis-acridone; Prostaglandin J2; Proteasome inhibitors; Protein A-based immune modulator; Protein kinase C inhibitors; Protein kinase C inhibitors, leosided phosphorylase inhibitors; purpurins; Pyrazoloacridine; Pyridoxylated hemoglobin polyoxyethylene conjugate; Raf antagonists; raltitrexed; Lamosetron; Las farnesyl protein transferase inhibitors; Lath inhibitors; Lars-GAP inhibitors; Retelliftin dimethylated; rhenium Re 186 etidronate; Rhizoxin; Ribozyme; RII retinamide; Lohitukine; Romurtide; Roquinimex; Rubiginone B1; Luboksil; Safingol; Sinetopin; SarCNU; Sarcopitol A; Sargramostim; Sdi 1 mimetics; Semustine; Senescence derived inhibitor 1; Sensory oligonucleotides; Signal transduction inhibitors; Sizofiran; Small aliphatic acid; Sodium borocaptate; Sodium phenylacetate; Solberol; Somatomedin binding protein; Sonermin; Sparfosic acid; Spicamycin D; Spiromustine; Splenopentin; Spongestatin 1; Squalene; Stipiamide; Stromelysin inhibitors; Sulfinosine; Superactive vasoactive intestinal peptide antagonists; Suradista; Suramin; Swainsonine; Tallimustine; Tamoxifen methiodide; Tauromustine; Tazarotene; Tecogalalan sodium; Tegafur; Tellurapyrylium; Telomerase inhibitors; Temoporfin; Teniposide; Tetrachlorodecaoxide; Tetrazomine; Thaliblastine; Thiocoraline; thrombopoietin; Thrombopoietin mimetic; Thymalfasin; thymopoietin receptor agonist; Thymotrinan; Thyroid stimulating hormone; Tin ethyl etiopurpurin; Tirapazamine; Titanocene bichloride; Topsentin; Toremifene; Translation inhibitors; Tretinoin; Triacetyluridine; Trisiribine; Trimetrexate; Triptorelin; tropisetron; Turosteride; Tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; Ubenimex; Urogenitalsinus-derived growth inhibitory factor; Urokinase receptor antagonists; Vapreotide; Variolin B; Veraresol; Veramine; Verdins; Verteporfin; Vinorelbine; Vinxaltine; Vitamins; Bororozole; Zanoterone; Zeniplatin; Zilascorb; And zinostatinstimalamer.

However, the 4'- O -glucose-luteolin-containing preparation according to the present invention for the purpose of anticancer effect is not limited to those described above, and any agent useful for the treatment or prevention of cancer may be included.

The present invention also provides an NF-κB activity inhibitor comprising 4'-0-glucose-luteolin as an active ingredient.

The NF-κB activity inhibitor may be used as an inhibitor of NF-κB activity for the prevention or treatment of cancer. In addition, the antiproliferative effect of the cells as well as cancer can be excellently used for the prevention or treatment of diseases related to cell proliferation, such as inflammatory diseases, vascular stenosis and blood vessel production.

Since 4′-O-glucose-luteolin inhibits NF-κB activity induced by cell death inhibitory factor or tumor necrosis factor, NF-κB activity inhibitor may be useful for the prevention or treatment of cancer.

In addition, the inflammatory disease may include a disease caused by inflammation, sepsis and neuronal cell death.

In addition, the present invention provides a food composition comprising 4'-O-glucose-luteolin as an active ingredient.

The food composition of the present invention includes all forms such as functional food, nutritinal supplement, health food and food additives. Food compositions of this type may be added as such or used with other foods or food ingredients, and may be used in various ways according to conventional methods known in the art.

For example, functional foods include meat, sausages, breads, chocolates, candy, snacks, confectionery, pizza, ramen and other dairy products including noodles, gums, ice creams, various soups, beverages, teas, drinks, alcoholic beverages, It can be prepared by adding 4'-O-glucose-luteolin or a pharmaceutically acceptable salt thereof to a vitamin complex or the like.

The beverage composition may contain various flavors or natural carbohydrates, etc. as additional ingredients, as in general beverages. The above-mentioned natural carbohydrates include monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose and polysaccharides such as dextrin and cyclodextrin. sugar alcohols such as polysaccharide, xylitol, sorbitol, and erythritol. As the sweetener, natural sweeteners such as taumatin and stevia extracts, or synthetic sweeteners such as saccharin and aspartame may be used.

In addition, the health food can be ingested by granulating, encapsulating and powdering the 4'-O-glucose-luteolin of the present invention. It can also be prepared in the form of a composition by mixing with the 4'-O-glucose-luteolin of the present invention and known active ingredients known to have anticancer effects.

In addition to the above, the food composition of the present invention includes various nutrients, vitamins, electrolytes, flavors, coloring agents, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols. And carbonation agents used in carbonated beverages. In addition, the composition of the present invention may contain a flesh for preparing natural fruit juice, fruit juice beverage or vegetable beverage. These components can be used independently or in combination.

Given the ease of access to food, the food composition of the present invention is very useful for the prevention or treatment of cancer.

Flavonol derivatives according to the present invention, more specifically 4'-O-glucose-luteolin (4'-O-glucose-luteolin) has the function of inhibiting the transcriptional activity of NF-κB.

Therefore, the present invention can be effectively used for the development of pharmaceutical compositions for preventing or treating cancer, inhibitors of transcriptional activity of NF-κB, and food compositions.

Hereinafter, the present invention will be described in more detail with reference to Examples.

It is to be understood by those skilled in the art that these examples are for illustrative purposes only and that the scope of the present invention is not construed as being limited by these examples.

Example 1 NF-κB Activity Assay

In the present invention, in order to observe the effect of inhibiting the transcription factor NF-κB activity by 4′- O -glucose-luteolin, when NF-κB is activated, luciferase gene expression is increased to increase luciferase enzyme activity. Luciferase reporter assay (luciferase reporter assay) was used.

As a reporter, a reporter using luciferase was purchased from Clontech Laboratory, USA, using a pNF-kB-luc reporter plasmid with four repeated NF-kB binding site sequences (GGGAATTTCC). It was.

Using the analyzed results, fusion of 0.5 μg of reporter plasmid (pNF-κB-Luc) containing NF-κB binding sequence into human breast cancer cell line MDA-MB-231 (ATCC, American Type Culture Collection, USA) was performed. After transfection with (fuGENE6, Transfection reagent), 48 hours later, the group treated with 10 ng / mL TNF-a alone in the cell culture was used as a control, and the TNF at 10 ng / mL was used as a control. Inhibition of TNF-a activity by 4′- O -glucose-luteolin in the group treated with -a and 4′- O -glucose-luteolin at a concentration of 20 μg / ml was analyzed.

After incubating cells treated with TNF-a and 4'- O -glucose-luteolin for another 12 hours, harvesting and lysing the cells, luciferin fluorescence emitted by adding 50 luciferin as a substrate to the cell solution protein Was measured. Cell lysates and substrate luciferin were obtained from the Dual-Glo Luciferase Assay System Kit purchased from Promega (Madison, WI, USA). Luciferin fluorescence measurements were measured using a Centro LB 960 luminometer (Berthold). Technology, German).

Treatment with TNF-a alone increased 3.8-fold intracellular luciferase enzyme activity as compared to untreated cells as shown in FIG. 1. This result means that NF-κB activity is increased by TNF-a. At this time, it was observed that the treatment of 4'- 0 -glucose-luteolin of the present invention in parallel with TNFα inhibits luciferase activity increased by TNF-a by about 75% or more.

In summary, the results of the present invention can be confirmed that the 4'- O -glucose-luteolin of the present invention can exert an anticancer effect by inhibiting NF-κB activity induced by TNF-a.

1 is chemical formula 1 It is a reporter gene analysis table analyzing NF-κB activity.

Claims (5)

4'-O-glucose-luteolin (4'-O-glucose-luteolin) represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient comprising a pharmaceutical composition for preventing or treating cancer. [Formula 1]

The method of claim 1, The pharmaceutical composition is a pharmaceutical composition for preventing or treating cancer, further comprising at least one pharmaceutically acceptable carrier. An NF-κB activity inhibitor comprising 4'-O-glucose-luteolin or a pharmaceutically acceptable salt thereof represented by Formula 1 as an active ingredient. Food composition comprising 4'-O-glucose-luteolin (4'-O-glucose-luteolin) represented by the formula (1) of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. The method of claim 4, wherein The food composition is a food composition, characterized in that any one form selected from beverages, bread, capsules and tablets.

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