WO2014168447A1 - Composition pharmaceutique et aliment naturel fonctionnel pour prévenir ou traiter un cancer, contenant un extrait naturel comme principe actif - Google Patents

Composition pharmaceutique et aliment naturel fonctionnel pour prévenir ou traiter un cancer, contenant un extrait naturel comme principe actif Download PDF

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WO2014168447A1
WO2014168447A1 PCT/KR2014/003138 KR2014003138W WO2014168447A1 WO 2014168447 A1 WO2014168447 A1 WO 2014168447A1 KR 2014003138 W KR2014003138 W KR 2014003138W WO 2014168447 A1 WO2014168447 A1 WO 2014168447A1
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cancer
kiom
extract
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Korean (ko)
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마진열
김애영
임남희
임민주
김태수
정영필
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한국한의학연구원
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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
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
    • A61K36/234—Cnidium (snowparsley)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/02—Medicinal preparations containing materials or reaction products thereof with undetermined constitution from inanimate materials
    • 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
    • A61K36/17—Gnetophyta, e.g. Ephedraceae (Mormon-tea family)
    • A—HUMAN NECESSITIES
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    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
    • A61K36/232—Angelica
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    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
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    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
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    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
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    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/29—Berberidaceae (Barberry family), e.g. barberry, cohosh or mayapple
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    • A61K36/18—Magnoliophyta (angiosperms)
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    • A61K36/18—Magnoliophyta (angiosperms)
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    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/484—Glycyrrhiza (licorice)
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
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    • A61K36/18—Magnoliophyta (angiosperms)
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    • A61K36/65—Paeoniaceae (Peony family), e.g. Chinese peony
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    • A61K36/18—Magnoliophyta (angiosperms)
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    • A61K36/18—Magnoliophyta (angiosperms)
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    • A61K36/708—Rheum (rhubarb)
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention administers a pharmaceutical composition for the prevention or treatment of cancer comprising a mixed medicinal herb extract derived from natural plants as an active ingredient, a health functional food for preventing or improving cancer, and a composition comprising a mixed medicinal herb extract derived from natural plants.
  • It relates to a method for preventing or treating cancer, including the step of, more specifically, cheongung, windproof, Angelica, peony, pontoon, peppermint, ephedra, manganese, rhubarb, gypsum, Giltyeong, golden, baekchul, gardenia, mold, ginger,
  • a method for preventing or treating cancer comprising administering a composition comprising an extract.
  • Cancer has the highest mortality rate worldwide and is the second most common cause of death in Western society after cardiovascular disease.
  • lung cancer is increasing due to the aging population and the increase of smoking population and air pollution.
  • eating habits are westernized due to westernized eating habits, and rapid increase in environmental pollutants and increase in alcohol consumption.
  • Prostate cancer is on the rise.
  • the creation of anti-cancer substances that can contribute to the promotion of human health, the improvement of healthy quality of life and the promotion of human health by enabling early prevention and treatment of cancer are urgently required.
  • Cancer metastasis refers to the migration of early tumors into blood vessels or lymphatic vessels to other organs with respect to the growth and proliferation of cancer cells (Cavallaro U, Christofori G. Cell adhesion in tumor invasion and metastasis: loss of the glue is not enough Biochem Biophys Acta 2001; 1552: 39-45), metastasis is a secondary process of metastatic cancer cells that proliferate at other sites by invasion through the blood vessels into the surrounding tissues after metastases are released from the site of origin. By a series of processes that form a tumor. This process begins with the breakdown of the extracellular matrix.
  • the enzymes that break down the extracellular matrix include matrix metalloproteinase (MMP), serine protease (plasmin), and urokinase plasminogen activator (urokinase).
  • MMP matrix metalloproteinase
  • plasmin serine protease
  • urokinase plasminogen activator
  • uPA urokinase plasminogen activator
  • cysteine protease cysteine protease
  • has Liotta LA, Trygguason K, Garbisa S, Hart I, Foltz CM, Shafie S. Metastasis potent alcor relate with enzymatic degradation of basement membrane collagen Nature 1980; 284.: 67-68).
  • MMPs Matrix metalloproteinases
  • MMPs are proteolytic enzymes that play an important role in inducing and metastasis of cancer cells by decomposing extracellular matrix and basement membrane. Thus, more than 20 species have been isolated and identified.
  • MMP is an endoproteinase that uses zinc as a coenzyme, and is divided into collagenase, gelatinase, stromelysins, and Membrane-type MMP according to structure and characteristics. .
  • MMP-2 72 kDa type IV collagenase; gelatinase A
  • MMP-9 92 kDa type IV collagenase; gelatinase B
  • MMP-9 is known to play an important role in the invasion and metastasis of breast cancer (Scorilas A. et al., Br. J. Cancer , 84, pp 1488-96, 2001).
  • cancer-causing stimulants such as cytokines and PMA (phorbol 12-mysistate 13-acetate) may It is known to regulate the expression of MMP-9 by regulating the activation of transcription factors such as NF- ⁇ B (Sato H., et al., Oncogene , 19, pp2904-2912, 2000; Lee SO, et al., Biochem Biophys.Res.Commun . , 354, pp165-171, 2007).
  • cytokines and PMA phorbol 12-mysistate 13-acetate
  • a method for treating cancer is to remove cancer tissue from the body at the cellular level.
  • Current cancer treatments are divided into surgical, radiotherapy, and chemotherapy.
  • Surgery is the removal of cancer from the body at the tissue level, which is most rational, but at the cellular level, it is difficult to completely remove the microscopic lesions that invade surrounding tissue or metastasize to the lymph gland. Therefore, surgery is very effective for early cancers or cancers with only a limited number of lesions (cancer stage 1 or 2), but for advanced stage 3 cancers, radiotherapy or chemotherapy is used. It is necessary to use together.
  • Radiotherapy and chemotherapy are mainly used for advanced cancer or terminal cancer after stage 3, but in laryngeal cancer and cervical cancer, even one stage of cancer is cured only by radiotherapy, and radiotherapy is the first priority.
  • the first stage in order to preserve the function of the vocal cords, the first stage may be radiotherapy only, and the second stage may be combined with partial surgery or chemotherapy.
  • small cell carcinoma of lung cancer has a poor prognosis even when conventionally performed by surgical therapy, but now chemotherapy is a priority and often use radiation therapy in combination. This therapy has recently been able to increase the survival rate, albeit slightly.
  • Cnidii Rhizoma is a dried perennial herbaceous perennial herb, Cnidium officinale MAKINO, which is taken from September to October to remove heat. It has a pain relief effect that helps blood circulation and alleviates pain, so it is often applied to headaches, and it is known to have a hematopoietic effect when applied to anemia in addition to activating the function of the liver.
  • Windproof (Ledebouriella seseloides WOLFF.) Is made using the roots and rhizomes of Sapshnikovia divaricata Schiskin. It has a peculiar smell, weakness, spicy, sweet and warm. It is effective for all kinds of symptoms such as external headache, chills, fever, systemic pain, sore throat, etc., and it is used for cold-limb joint pain, tetanus, muscle cramps, paralysis of paralysis, paralytic pain, itching, and ringworm.
  • antipyretics, anti-inflammatory, jingyeong, immune activation, anti-allergic, anti-ulcer, antibacterial, inhibiting skin improvement bacteria have been reported.
  • Angelica Gigantis Radix is the root of the umbeliferae plant, Angelicae, which is warm in nature, sweet in taste and very non-poisonous. It is known to be effective in improving blood circulation, blood pressure lowering effect, pain relief, spasm control, constipation improvement through promoting colon circulation, and removing blood blood, which alleviates all wind sickness, blood clots and pain.
  • Peony (Paeonia lactiflora Pall.) Is a perennial herb and peony perennial herb, distributed in Korea, Mongolia and East Siberia, and used for horticulture because of its beautiful flowers. Root is known to be effective in the treatment of pain, abdominal pain, amenorrhea, dysmenorrhea, hemostasis, anemia, bruises.
  • Forsythia Viridissima Lindley or Forsythia suspensa Vahi which belongs to Oleaceae. It has a peculiar smell, taste and bitterness. Yeonkyo lowers and detoxifies the fever, so the heart heat is lowered early in the fever and used for high fever and mental confusion. Boils, rashes, appendicitis, lung abscesses, lymphadenitis, and sore throat are known to have diuretic and anti-inflammatory effects. In addition, pharmacological action is known to have antibacterial action, anti-inflammatory action, blood pressure lowering, hemostatic action, liver treatment action, fever, clay, diuretic action.
  • Peppermint leaf is a leaf of Mentha arvensis var. Piperascens, a perennial herb that is a dicotyledon plant moth plant. It is cold, sour, dry, dry, and feverish. Therefore, it is widely used as a treatment for indigestion, chest bloating, bloating (cold), headache, toothache, sore throat, purpose, and sores.
  • Ephedra sinica is a medicinal herb made from Ephedra sinica Stepf or soft stems of the same plant. It has a tendency to numb the tongue slightly, tastes spicy, bitter, and warm. . Dissipate the wind, sweating, chills, fever, headache, asthma, seawater, species, paralysis of the upper body, skin paralysis, hyperemia, blood is used.
  • the forget-me-not (Erigeron canadensis) is a biennial plant of the dicotyledon plant Campanula Asteraceae. It is known to be effective in stomatitis, globules, stool irritation, swelling, pain, diarrhea, sebum, detoxification, fever, fatigue, and customs.
  • Rhubarb is an adverse odor that is made by using the root stems of Rheum palmatum L., Rheum tanguticum Maximowicz, and Rheum officinale Baillon, a perennial herb that belongs to the genus. If you chew it in, it feels like chewing on the fine sand, and it is steamed, bitter, and cold. Headache, congestion, sore throat, constipation, nosebleeds, bleeding, boils and is effective for diuretic, edema. Pharmacological action is known to promote colon movement, fever, body temperature, bile secretion, blood clotting time, antibacterial, diuretic, liver function protection.
  • Gypsum fibrosum is a very good medicine that lowers heat, tastes sweet and sweet and is very cold. It is also effective for headaches and toothaches caused by severe heat in the body. Recently, it is known that it is used for epidemic type B encephalitis, epidemic meningitis, and pneumonia. In addition, antipyretic, sedative, hypoglycemic, anti-inflammatory, mild diuretic effects have been reported.
  • Gilkyung is a medicine made by removing the roots or cuticles of Platycodon grandiflorum A.
  • De Candolle which has a slight smell, tastes bitter, and has a flat nature. It is used for sore throat, cold cough, phlegm, nasal congestion, asthma, bronchitis, pleurisy, headache, chills, tonsillitis, etc.As pharmacological actions include expectorant action, hypoglycemic action, cholesterol lowering action, and inhibitory action. have.
  • Gold is a medicinal herb made from the root of Scutellaria baicalensis GEORGE, a perennial herb that belongs to the Lamiaceae family.It is effective in pediatric acute respiratory infections, chronic bronchitis, acute dysentery, infectious hepatitis, nephritis, pyelonephritis, and hypertension. Pharmacological actions include anti-inflammatory, antipyretic, diuretic, lowering blood pressure, lowering blood sugar and hyperlipidemia, promoting bile secretion, and sedative effects.
  • Baekchul is a dried herb that removes rhizome or bark of Atractylodes japonica Koidzumi or Atractylodes macrocephala Koidzumi. It is slightly viscous and chewy and warm when chewed. Intestinal inhibitory and excitatory control, anti-ulcer and hepatic function protection, immune hyperactivity, vasodilation, diuretic and hypoglycemic activity have been reported.
  • Gardenia jasminoides is the fruit of the gardenia jasminoides, which is known for its effects on diarrhea, rhizome, clear heat, diuresis, bleeding and detoxification.
  • Schizonepeta rhizome is an annual herb that belongs to the Lamiaceae family. It has antipyretic effect and is used for sweating and antipyretic in the early stage of cold. It is used for sore throat, skin disease, stroke, etc., and it is applied to uterine bleeding, nosebleed, fecal bleeding, hemorrhage, urine bleeding when it is blackened. .
  • Ginger means fresh rhizome of Zingiber officinale Roscoe in Korea, China and Japan. Ginger treats chills, fever, headache, vomiting, seawater, and phlegm caused by an external cold, and it is effective for abdominal diarrhea and abdominal pain caused by food poisoning. Pharmacological action has been reported to promote gastric juice secretion, digestion, cardiac excitement, blood circulation, fungi.
  • Talc is a drug whose main effect is to stimulate water metabolism. Temper is sweet, light and cold. Talc has been reported to protect the skin mucosa, antibacterial action, diuresis, sedation (stop thirst), fever, detoxification, anti-inflammatory, urination pain, fever of heat stroke, canning, diarrhea.
  • Licorice (Glycyrrhiza uralensis Fischer or Glycyrrhiza glabra L.) is a perennial herb of the dicotyledonous rosewood legume, with an unusual smell and taste. Licorice harmonizes the toxic effects of all drugs to make the drug appear well, manages the heat and morale of the book, and communicates all blood vessels, and strengthens muscles and bones. Pharmacological action is effective in detoxification, hepatitis, urticaria, dermatitis, eczema, etc. It is known to have antitussive, expectorant, muscle relaxation, diuretic, anti-inflammatory and inhibit peptic ulcer.
  • Gold and silver coins refer to the buds of the locust (Lonicera japonica Thunberg) or its varieties. It has a peculiar smell, sweet taste and cold nature. Gold and silver coins are used to reduce heat, when the chest is stuffy and thirsty. It is used for inflammation, and it is used to release boils, skin toxins, organ inflammation, and pus. In addition, it is used for necrosis of the skin tissue due to dysentery and heat poisoning, mastitis, etc., and has been applied to colitis, gastric ulcer, cystitis, sore throat, tonsillitis, bronchitis, conjunctivitis and swelling, mumps and musculitis. Pharmacological action, antibacterial action, anti-inflammatory action, antipyretic action, leukocyte phagocytosis increase, central nervous system excitability, serum cholesterol lowering, ulcer prevention effect has been reported.
  • Eum yang-gyeok means the perennial herbaceous plant (Epimedium koreanum Nakai) or other perennial roots (stems and leaves) of dicotyledonous plant (Prunus paniculata). It is odorless, tastes sweet and warm.
  • Yin and Yang are used for erectile dysfunction, oil well, cold uterus, cold limb, skin paralysis, ophthalmology, forgetfulness, paraplegia, low back and knee weakness, hypertension, polio.
  • Pharmacological actions include semen secretion promotion, blood pressure strengthening, coronary blood flow increase, hypoglycemia, cholesterol lowering, immune function enhancement, Jinhae, expectoration, Pyeongcheon, sedation, fungi, anti-inflammatory action, chicken femoral growth and protein polysaccharide activation Is reported.
  • Polygala tenuifolia is a perennial herb of the dicotyledonous mouse handicap grass family. It is used as an expectorant, tonic, or pill.
  • the elecampane refers to the root of the perennial herbaceous Aucklandia lappa Decne., Which has a peculiar smell, the taste is spicy, bitter and warm. Mokyang is used for abdominal pain caused by the abdomen, flat stomach symptoms, vomiting and diarrhea. It is effective for chronic inflammation of the digestive organs and stomach pain. Pharmacological action is to release bronchial and small intestine spasms, blood pressure lowering action, antibacterial action is known.
  • HT1080 is a classic cancer cell line extract consisting of Peony, Peony, Mint Leaf, Ephedra, Forget-me-not, Rhubarb, Gypsum, Giltyeong, Golden, Whitening, Gardenia, Hungae, Ginger, Talc, Licorice, Gold Silver Coin, Yin Yang Kwak, Wonji and Mokji.
  • One object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of cancer, which is safe for the human body and contains a mixed medicinal herb extract having an effective anticancer effect as an active ingredient.
  • Another object of the present invention to provide a health functional food for the prevention or improvement of cancer comprising the mixed medicinal herb extract as an active ingredient.
  • Still another object of the present invention is to provide a method for preventing or treating cancer, comprising administering to a subject in need thereof a composition comprising the mixed medicinal extract.
  • the present invention relates to a natural extract effective for the prevention or treatment of cancer, and has an effective metastasis inhibition, induction of cell death and cell growth inhibitory activity against cancer cells, as well as pharmaceutically usable as a composition for the prevention or treatment of cancer It can also be usefully used as a dietary supplement.
  • Figure 1 shows the results of analyzing the cell death induction effect of the mixed medicinal herb extract (KIOM-C) against various classical cancer cell lines (B16F10, HT1080, AGS and A431).
  • KIOM-C mixed medicinal herb extract
  • Figure 2 shows the results of analyzing the effect on the HT1080 cell cycle progression according to the treatment of the mixed medicinal extract (KIOM-C).
  • Figure 3 shows the results of analyzing the expression of the cell cycle-related protein changes according to the treatment of the mixed medicinal extract (KIOM-C).
  • 4A to 4E show the results of analysis of apoptosis and autophagy induction according to the treatment of the mixed medicinal extract (KIOM-C).
  • 5a to 5e show the results of analyzing the cell death induction mechanism by the treatment of the mixed medicinal extract (KIOM-C) by Western blot.
  • 6a to 6c show the results of analyzing the effect of tumor cell death caused by the induction of intracellular oxidative stress following the treatment of the mixed medicinal herb extract (KIOM-C).
  • Figure 8 shows the non-adherent colony forming ability of cancer cells (B16F10 (A) and HT1080 (B)) according to the treatment of the mixed medicinal extract (KIOM-C).
  • 9A and 9B show wound healing assay results according to the treatment of the mixed medicinal herb extract (KIOM-C).
  • 10A and 10B show the results of a transwell migration and invaation assay according to the treatment of the mixed medicinal herb extract (KIOM-C).
  • Figure 11 shows the effect of mixed medicinal herb extract (KIOM-C) on MMP-9 activity according to the treatment of mixed medicinal herb extract (KIOM-C) RT-PCR (A), Western blot (B and D) and gelatin The results are analyzed by Gelatin zymography (B and C).
  • KIOM-C mixed medicinal herb extract
  • Figure 12 shows the results of Western blot analysis of the effect of the mixed medicinal extract (KIOM-C) on NF- ⁇ B activation by PMA stimulation.
  • the mixed medicinal herb extract (KIOM-C) was administered to mice injected with B16F10 lung cancer cell line, and the degree of lung metastasis was analyzed by visual observation analysis (FIG. 13A) and the number of colonies (FIG. 13B). One result is shown.
  • FIG. 14a shows the tumor volume change for about 15 days (Fig. 14a) and tumors extracted 15 days later.
  • FIG. 14b The results of the mass observation (FIG. 14b), tumor mass change (FIG. 14c) and interferon-gamma (IFN- ⁇ ) secretion concentration (FIG. 14d) are shown.
  • Fig. 15 shows the results of comparative analysis of cancer cell viability (cancer apoptosis effect) of the mixed medicinal herb extracts (KIOM-C) and the extracts of each sweetener component.
  • FIG. 16 shows the results of analysis of gelatin zymography on the change of MMP-9 activity caused by rhubarb extract and ephedra extract in the sweetening ingredients.
  • the present invention is a cheongung, windproof, donkey, peony, yeonkyo, peppermint, ephedra, forget-me-not, rhubarb, gypsum, gilyeong, golden, white leach, gardenia, mold, ginger, talc, licorice It provides a pharmaceutical composition for the prevention or treatment of cancer, including the extract of the mixed medicinal herb, gold and silver, yin and yang, paper and neck.
  • the composition is based on 1 part by weight of yin and yang, 1 part by weight to 3 parts by weight, 1 part by weight to 3 parts by weight windproof, 1 part by weight to 3 parts by weight, peony 1 part by weight to 3 parts by weight, 1 part by weight of duct bridge To 3 parts by weight, peppermint 1 to 3 parts by weight, ephedra 1 to 3 parts by weight, 1 to 3 parts by weight of forget-me-not, 1 to 3 parts by weight of rhubarb, 0.5 to 3 parts by weight of gypsum, 0.5 to 3 parts by weight, 0.5 to 3 parts by weight of gold, 0.5 to 2 parts by weight, 0.5 to 2 parts by weight, 0.5 to 2 parts by weight of gardenia, 0.5 to 2 parts by weight, 1 part by weight of ginger 3 parts by weight, talc 1 part by weight to 5 parts by weight, licorice 1 part by weight to 3 parts by weight, 1 part by weight to 3 parts by weight of gold coins, 1 part by weight to 3 parts by weight
  • extract refers to a formulation prepared by squeezing the herbal medicine with a suitable leach solution and evaporating the leach solution, but not limited thereto, but the extract obtained by the extraction treatment, the dilution or concentrate of the extract, the extract It may be a dried product obtained by drying, these adjustment products, or a refined product.
  • the mixed medicinal extract can be prepared using common extraction methods, separation and purification methods known in the art.
  • the extraction method is not limited thereto, but preferably, hot water extraction, hot water extraction, cold needle extraction, reflux cooling extraction, or ultrasonic extraction may be used.
  • the extract may be prepared by extracting with an extracting solvent or by fractionating the fractional solvent to an extract prepared by extracting with an extracting solvent.
  • the extraction solvent is not limited thereto, but water, an organic solvent or a mixed solvent thereof may be used, and the organic solvent may be a C 1-4 alcohol, a polar solvent such as ethyl acetate or acetone, hexane or dichloro Non-polar solvents of methane or mixed solvents thereof can be used.
  • preferably water, alcohols having 1 to 4 carbon atoms or mixed solvents thereof may be used, and more preferably ethanol may be used.
  • an extract using ethanol was prepared as the solvent.
  • the extract of the mixed medicinal herb of the present invention is the above-mentioned ratios of Cheongung, Windproof, Angelica, Peony, Yeongyo, Peppermint, Ephedra, Forget-me-not, Rhubarb, Gypsum, Giltyeong, Golden, White, Red Gardenia, Penguin, Ginger, Active, Licorice, Gold and Silver Coin ,
  • the mixed medicine consisting of raw paper and wood was obtained by adding 2-10 times the amount of water and hot water extraction for 3 to 4 hours at a temperature of 70 °C to 125 °C.
  • the mixed medicinal herb extract was concentrated and lyophilized, and the lyophilized sample was dissolved in distilled water and used for the experiment.
  • cancer refers to a lump grown abnormally by autonomous overgrowth of body tissue, and may be classified into benign tumor and malignant tumor. While benign tumors grow relatively slowly and do not metastasize, malignant tumors grow rapidly as they infiltrate surrounding tissues and spread or spread to various parts of the body, thereby threatening life. Malignant tumors can therefore be thought of as cancer.
  • the subject cancer which can be prevented or treated by the composition of the present invention is not limited to a particular cancer, preferably breast cancer, lung cancer, stomach cancer, liver cancer, blood cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer , Skin or eye melanoma, uterine sarcoma, ovarian cancer, rectal cancer, anal cancer, colon cancer, fallopian tube cancer, endometrial cancer, cervical cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, kidney cancer, soft tissue tumor, urethral cancer It may be prostate cancer, bronchial cancer or bone marrow cancer. More preferably, the cancer may be fibrosarcoma, skin cancer, lung cancer, breast cancer, gastric cancer, but is not limited thereto.
  • HT1080 human fibroscarcoma
  • B16F10 murine melanoma
  • A431 human epidermoid carcinoma
  • AGS human gastric carcinoma
  • the cancer is a disease that is the object of prevention or treatment by the mixed medicinal herb extract of the present invention, the composition comprising the mixed medicinal herb extract to inhibit the metastasis of cancer cells, induce cell death or inhibit cell growth It can show anticancer effect by showing activity.
  • the mixed medicinal herb extracts were treated in the classical ear cancer cell line and the effects on cell metastasis (cell migration and cell invasion activity), cell death and cell growth through in vitro and in vivo animal experiments. Confirmed.
  • the mixed medicinal herb extracts KIOM-C
  • the extracts of each of the sweeteners constituting the same the cancer cell killing effect and metastasis after treatment of each extract to HT1080, respectively.
  • the anti-cancer effect such as cell death or metastasis inhibition did not show when the individual extracts of sweeteners were treated at low concentrations equal to the concentration ratios of the sweeteners contained in the mixed medicinal extracts (KIOM-C). 15 and 16.
  • the mixed medicinal herb extract of the present invention was confirmed to have a synergistic effect of the mixing of the 22 medicinal herbs.
  • prevention means any action that inhibits or delays the disease by administration of the composition containing the mixed drug extract.
  • treatment used in the present invention means all the actions that improve or cure the symptoms of the disease by administration of the composition containing the mixed drug extract.
  • the composition of the present invention may include a pharmaceutically acceptable carrier, excipient or diluent in addition to the above-described active ingredient for administration.
  • the carrier, excipient and diluent may include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, Polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • compositions of the present invention can be used in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, or the like, oral preparations, suppositories, or sterile injectable solutions, respectively, according to conventional methods.
  • oral preparations suppositories, or sterile injectable solutions, respectively, according to conventional methods.
  • it may be prepared by using diluents or excipients such as fillers, weighting agents, binders, wetting agents, disintegrating agents, and surfactants which are commonly used.
  • Solid preparations for oral administration include, but are not limited to, tablets, pills, powders, granules, capsules, and the like.
  • Such solid preparations may be prepared by mixing at least one excipient, for example, starch, calcium carbonate, sucrose, lactose, gelatin, and the like, in the mixed medicinal extract.
  • excipients for example, starch, calcium carbonate, sucrose, lactose, gelatin, and the like
  • lubricants such as magnesium stearate, talc can also be used.
  • It may be prepared by adding various excipients such as humectants, sweeteners, fragrances, preservatives and the like in addition to liquid oral liquids or liquid paraffin for oral use.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations and tasks.
  • non-aqueous solvent and suspending agent propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate and the like can be used.
  • base of the suppository uthepsol, macrosol, tween 61, cacao butter, laurin butter, glycero gelatin and the like can be used.
  • composition of the present invention can be administered orally or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, and the dosage is based on the condition and weight of the patient, the extent of the disease, Depending on the drug form, route of administration, and time, it may be appropriately selected by those skilled in the art.
  • the daily dosage of the mixed medicinal extract is preferably 1 mg / kg to 600 mg / kg, may be administered once to several times daily if necessary.
  • the present invention provides a method for preventing or treating cancer, comprising administering to a subject in need thereof a composition comprising a mixed medicinal extract.
  • the cancer-related diseases may be various cancer diseases such as skin cancer, stomach cancer, lung cancer, but are not limited thereto.
  • the term "individual” means all animals, including humans, who have already developed or may develop cancer, and the composition of the present invention is effective in effectively preventing and treating the disease by administering to the individual. have.
  • composition of the present invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment in a medical treatment, the effective dose level being the type of subject and its severity, age , Sex, activity of the drug, sensitivity to the drug, time of administration, route of administration and rate of release, duration of treatment, factors including concurrently used drugs, and other factors well known in the medical arts.
  • the compositions of the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents and may be administered sequentially or simultaneously with conventional therapeutic agents. And single or multiple administrations. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect in a minimum amount without side effects, and can be easily determined by those skilled in the art.
  • the present invention is a cheongungung, windproof, donkey, peony, yeonkyo, peppermint, ephedra, forget-me-not, rhubarb, gypsum, Gilgyeong, golden, baekchul, gardenia, hyungge, ginger, talc, licorice, gilding, yin and yang, It provides a health functional food for the prevention or improvement of cancer containing the extract of the mixed medicinal herb consisting of raw paper and throat.
  • the health functional food includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, coloring and neutralizing agents (such as cheese and chocolate), pectic acid and salts thereof, alginic acid and salts thereof, Organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks and the like. It may also contain natural fruit juices and pulp for the production of fruit juices and vegetable drinks. These components can be used independently or in combination.
  • the dietary supplement may be any one of meat, sausage, bread, chocolate, candy, snacks, confectionary, pizza, ramen, gum, ice cream, soup, beverage, tea, functional water, drink, alcohol and vitamin complex. Can be.
  • the health functional food may further include food additives, and the suitability as a "food additive" is applied to the item according to the General Regulations of the Food Additives Code and General Test Law, etc., unless otherwise specified. Determined by the relevant standards and standards.
  • Items listed in the "Food Additives Code” include, for example, chemical compounds such as ketones, glycine, potassium citrate, nicotinic acid, cinnamon acid, natural additives such as color pigments, licorice extract, crystalline cellulose, high-quench pigments, guar gum, L Mixed preparations, such as a sodium glutamate preparation, a noodles addition alkali preparation, a preservative preparation, and a tar pigment preparation, etc. are mentioned.
  • the mixed medicinal extract according to the present invention added to the food in the process of manufacturing a health functional food can be appropriately added or subtracted as needed, preferably 1 to 15% by weight in 100% by weight food It is preferable to add as much as possible.
  • KIOM a mixed herb consisting of Cheongung, Windproof, Angelica, Peony, Episode, Peppermint, Ephedra, Forget-me-not, Rhubarb, Gypsum, Giltyeong, Golden, White, Gardenia, Hungae, Ginger, Talc, Licorice, Gold and Silver Coins, Yin and Yang
  • the herbal medicines were purchased from the Yeongcheon Herbal Medicine Market (Youngcheon, South Korea), and large-scale hot water extraction was performed.
  • KIOM-C is a mixed medicine, 1 part by weight of Cheongung, windproof, Angelica, Peony, Peony, Peppermint Leaf, ephedra, forget-me-not and rhubarb, based on 1 part by weight of yin and yang, and 0.5 parts by weight of gypsum, gilyeong and gold 1 part to 2 parts by weight, 1 part to 3 parts by weight, 1 part to 3 parts by weight, 1 part to 5 parts by weight of talc, 1 part to 5 parts by weight of licorice, gold and silver, and 1 part to 3 parts by weight of raw wood, 1 part by weight It is made by mixing the medicines in a ratio of 3 to 3 parts by weight, and 15 L of distilled water is added to 2456.5 g of KIOM-C mixed medicines, and the extractor (Cosmos-600 extractor, Gyeongseo Machinery Industry, Incheon, South Korea) is 115 °C. Hot water was extracted for 3 hours to the temperature.
  • the extracted KIOM-C blended medicinal herb extract was filtered using a standard test sieve (sieve) (150 ⁇ m, Retsch, Han, Germany) and concentrated to dryness in a freeze dryer.
  • the lyophilized KIOM-C mixed medicinal herb extract powder (50 mg) was dissolved in 1 ml of distilled water, filtered through a 0.22 ⁇ m disk filter, and stored at ⁇ 20 ° C. until use.
  • the hot water extracted sweetwood extract was filtered using a test sieve (150 ⁇ m, Retsch, Han, Germany), and concentrated to dryness in a freeze dryer.
  • the freeze-dried sweetwood extract powder 50 mg was dissolved in 1 ml of distilled water, filtered through a 0.45 ⁇ m syringe filter, and stored at 4 ° C. until use.
  • HT1080 human fibroscarcoma; human fibrosarcoma
  • AGS human gastric carcinoma
  • A431 human epidermoid carcinoma
  • B16F10 murine melanoma; Mouse melanoma
  • HT1080 human fibroscarcoma; human fibrosarcoma
  • AGS human gastric carcinoma
  • A431 human epidermoid carcinoma; human squamous cell carcinoma
  • B16F10 murine melanoma; mouse melanoma
  • the various cancer cell lines were prepared using DMEM medium (Dulbecco's modified Eagle's medium) containing 10% fetal bovine serum (FBS), 100 U / ml penicillin and 100 ug / ml streptomycin. Incubation was carried out in an incubator where temperature (37 ° C.) and humidity were kept constant and supplied with 5% CO 2 .
  • MTT assay was performed. At this time, using the normal hepatocyte (hepatocyte) as a control, the cytotoxicity of the mixed medicinal herb extract (KIOM-C) of the Example to the normal cells was evaluated. In addition, using an inverted microscope, the change in cell morphology of the cancer cell line by the mixed medicinal extract (KIOM-C) was also observed.
  • each cancer cell line (5 ⁇ 10 3 cells / Well / 96-well plate) was incubated after treatment with the mixed medicinal herb extract (KIOM-C) at a concentration of 100 ⁇ g / ml to 1000 ⁇ g / ml prepared in Example 1.
  • 10 ⁇ l of MTT solution (5 mg / ml in PBS) was added to the cells and further incubated for 4 hours.
  • the formazan precipitate was dissolved in dimethyl sulfoxide (DMSO), and then absorbance was measured at 570 nm using an Infinite® M200 microplate reader (TECAN Group Ltd, Switzerland) to confirm cell viability. It was.
  • DMSO dimethyl sulfoxide
  • hepatic cells did not show any cytotoxicity even when the mixed medicinal extract (KIOM-C) was treated at a concentration of 1000 ⁇ g / ml (FIG. 1A). This means that the mixed medicinal extract (KIOM-C) exhibits a concentration-dependent cancer cell proliferation inhibitory effect specifically for all cancer cell lines.
  • the mixed medicinal extract does not show cytotoxicity to normal hepatocytes, and has the effect of inhibiting concentration-dependent cancer cell proliferation and autophagic and apoptotic cancer cells in all cancer cell lines except normal hepatocytes. It means to have an effect.
  • HT1080 cells were seeded to 5 ⁇ 10 5 per 60 mm dish and then incubated for 24 hours in a 37 ° C., 5% CO 2 incubator. After incubation, the mixed medicinal extract (KIOM-C) prepared in Example 1 was treated at a concentration of 1000 ⁇ g / ml, and further cultured for 12 hours and 24 hours. After further incubation, the cells that were not attached to the dish and attached cells were collected and washed twice with PBS, and the cells were fixed by the slow addition of 70% ethanol. Fixed cells were stored at ⁇ 20 ° C. for 24 hours.
  • KIOM-C mixed medicinal extract
  • the mixed medicinal herb extract (KIOM-C) of the present invention induces G 1 cell cycle arrest (cell cycle arrest) to delay cell proliferation, which means that effectively induced cell death.
  • Example 1 In order to determine how the mixed medicinal extract (KIOM-C) prepared in Example 1 affects the expression of the G 1 phase regulatory proteins p21, p27 and cyclin D1, Western blot was performed.
  • HT1080 cells were seeded to 5 ⁇ 10 5 cells per 60 mm dish, and then cultured in 37 ° C., 5% CO 2 incubator for 24 hours. After incubation, the mixed medicinal herb extract (KIOM-C) prepared in Example 1 was treated at a concentration of 500 ⁇ g / ml and 1000 ⁇ g / ml, and further cultured for 12 hours and 24 hours. After further incubation, the cells that were not attached to the dish and attached cells were collected and washed twice with PBS, and the whole cell lysate of the cells was washed with M-PER Mammalian Protein Extraction. Reagent) (Thermo Scientific, Rockford, Ill.).
  • KIOM-C mixed medicinal herb extract
  • Cell lysates were quantified for protein concentration by BCA protein assay (Bicinchoninic Acid) assay, and the same amount of protein was obtained from 10% sodium dodecyl sulfate polyacrylamide gel (SDS). Each well was injected and electrophoresed. Proteins developed on gels were transferred to Immunobilon PVDF transfer membranes (Millipore, Bedford, Mass.). After transferring the expression protein to the membrane, immunoblotting was performed using anti- p21 Waf1 / Cip1 , anti-p27 Kip1 and anti-cyclin D1.
  • the mixed medicinal herb extract (KIOM-C) of the present invention regulates cyclin-dependent kinase inhibitors such as cell cycle regulators p21 and p27, thereby inhibiting abnormal cell proliferation and cell death It can be derived.
  • Example 2-5 Induction Assay of Apoptosis and Autophagy Action
  • Example 2-5-1 Absorption Detection of YO-PRO-1
  • the HT1080 cell line was treated with the mixed medicinal extract (KIOM-C) prepared in Example 1 at concentrations of 500 ⁇ g / ml and 1000 ⁇ g / ml and incubated for 12 hours and 24 hours.
  • KIOM-C mixed medicinal extract
  • YO-PRO-1 (1 uM, Molecular Probes, Eugene, OR), which is an apoptosis-specific dye, was added thereto, followed by shading staining at 4 ° C. for 30 minutes. After staining, YO-PRO-1 uptake was measured using a FACSSCalibur flow cytometer without cell washing or fixation, and analyzed using WinMDI 2.8 software.
  • TUNEL staining was performed using an in situ cell death detection kit (Roche diagnostics GmbH, Mannheim, Germany).
  • Example 2-5-3 RFP-LC3 distribution fluorescence analysis and LC3 protein expression analysis
  • microtubule-associated protein1 light chain 3 (LC-3), which is an important molecular marker of autophagy Fluorescence analysis was performed using this fluorescently labeled RFP-LC3, and Western blot was performed to confirm the expression level of the LC3 protein.
  • Bafilomycin A1 a lysosomal inhibitor known to exacerbate cell death
  • it has no effect on autophagy-inducing activity. Influence was also confirmed.
  • the HT1080 cell line (5 ⁇ 10 4 ) grown in a 24-well culture plate containing coverslips was prepared by transiting an LC3 plasmid tagged with RFP to TransIT2020 (Mirus, Madison, WI). Transfection was performed using.
  • the transfected cells were cultured as described above for 24 hours, and after the culture, the mixed medicinal extracts (KIOM-C) were treated with the concentration of 500 ⁇ g / ml and 1000 ⁇ g / ml for 24 hours.
  • a loading medium (Vector Laboratories, Burlingame, Calif.) Containing DAPI, which stains the nucleus, was added and then sealed with a coverslip to confocal microscope (FV10i-W; Olympus Optical Co. LTD) was examined and photographed the distribution of RFP-LC3.
  • confocal microscope FV10i-W; Olympus Optical Co. LTD
  • Western blots were performed using antibodies LC3 and anti-p62 / SQSTM1, the major markers of autophagy, as described in Examples 2-4 above.
  • Bacillomycin A1 at a concentration of 10 nM a lysosomal inhibitor known to exacerbate cell death
  • a mixed medicinal extract KIOM-C
  • RFP-LC3 fluorescence dot was increased more than the mixed medicinal extract (KIOM-C) alone compared to the untreated control group.
  • KIOM-C mixed medicinal extract
  • Western blot analysis of LC-3 protein it was confirmed that the amount of LC-3II protein was increased.
  • Example 2-5-4 Autophagic Vacuole Detection
  • the HT1080 cell line was treated with the mixed medicinal extract (KIOM-C) prepared in Example 1 at a concentration of 500 ⁇ g / ml and 1000 ⁇ g / ml and incubated for 24 hours. At this time, 50 uM of MDC (monodansyl cadaverine; Sigma Chemical), an autophagy vacuole tracer, was added thereto, and stained at 37 ° C. for 40 minutes. After staining, the cells were washed twice with PBS, and then microscopically and photographed using a fluorescence microscope.
  • MDC monodansyl cadaverine
  • the mixed medicinal extract means that cancer cells can be killed by inducing autophagy as well as apoptosis (apoptosis).
  • Example 1 How does the mixed medicinal extract (KIOM-C) prepared in Example 1 affect the protein expression of various factors related to induction of apoptosis and autophagy, and inhibition of cancer cell proliferation and death-inducing activity Western blots were analyzed to confirm their association with the activation of this cellular signaling system.
  • KIOM-C mixed medicinal extract
  • Example 1 In order to determine how the mixed medicinal extract (KIOM-C) prepared in Example 1 affects the protein expression of various factors related to induction of apoptosis and autophagy, various cancer cell lines (HT1080) , B16F10 and AGS) treated with the mixed medicinal extract (KIOM-C) at a concentration of 500 ⁇ g / ml or 1000 ⁇ g / ml and after 24 and 48 hours, the protein was recovered from each cell and then important for cell death.
  • Western blot analysis revealed the expression of Beclin-1, which is important for the caspase-3 activity, PARP cleavage, LC3 and p62 proteins involved in autophagy, and autophagosome formation.
  • the B16F10 and AGS cell lines like the HT1080 cell line, after 24 hours of treatment with the mixed medicinal extract (KIOM-C), confirmed that the autophagy marker LC3 protein was converted from 16 kDa LC3 I to 14 kDa LC3 II. It was.
  • the expression level of Beclin-1 protein which is important for the formation of autophagosomes during autophagy, was markedly increased and PARP cleavage was identified (FIG. 5B).
  • Example 2-6-2 Analysis of Cell Signaling System Related to Tumor Apoptosis Induction
  • Example 1 In order to determine whether cancer cell proliferation inhibition and death-inducing activity by the mixed medicinal herb extract (KIOM-C) prepared in Example 1 is related to activation of related cellular signaling systems, various cancer cell lines (HT1080, B16F10 and AGS) treated with the mixed medicinal extract (KIOM-C) at a concentration of 500 ⁇ g / ml or 1000 ⁇ g / ml and after 3 hours, 6 hours and 24 hours, the protein was recovered from each cell, and then cell death was controlled. Expression patterns of AMPK, ULK, JNK, c-jun, p53, p38 and ERK 1/2, which are factors related to signal transduction system activation, were confirmed by Wester blot analysis.
  • the B16F10 and AGS cell lines like the HT1080 cell line, when the activity of JNK, which is important for induction of autophagy and apoptosis, was measured after 3 hours of the mixed medicinal extract (KIOM-C) treatment, the mixed medicinal extract (KIOM) -C) showed an increase in phosphorylation with time. In contrast, there was no effect on the activation of p38 and ERK 1/2 (FIG. 5E).
  • the mixed medicinal extract (KIOM-C) is involved in apoptosis and autophagy by regulating various signaling systems.
  • the mixed medicinal extract self-kills cancer cells by regulating the protein expression and cell signaling system of various factors related to induction of apoptosis and autophagy. (apoptosis) as well as autophagy (induced autophagy), it was confirmed that the cells can be killed.
  • KIOM-C mixed medicinal extract
  • ROS reactive oxygen species
  • SP600125 which is a NAC (N-acetyl-L-cysteine) or a JNK-specific inhibitor (JNK-specific inhibitor), which is known as an antioxidant, is treated simultaneously with the mixed medicinal extract (KIOM-C), and the mixed medicinal extract (KIOM- JNK activity by C) was directly related to ROS activity and CHOP expression.
  • NAC N-acetyl-L-cysteine
  • JNK-specific inhibitor JNK-specific inhibitor
  • Example 2-7-1 Measurement of Reactive Oxygen Species (ROS) Levels in Cells
  • Intracellular reactive oxygen species (ROS) levels were measured using DCF-DA, a peroxide-sensitive fluorescent probe.
  • the mixed medicinal extract (KIOM-C) prepared in Example 1 was treated with cells at a concentration of 500 ⁇ g / ml or 1000 ⁇ g / ml and incubated for 3 hours.
  • NAC (1 mM) or J600-specific inhibitor SP600125 (5 uM) was pretreated for 1 hour.
  • 5 M of DCF-DA was added to the cells incubated as above and incubated at 37 ° C. for 30 minutes.
  • Example 2-7-2 Reverse Transcriptase Chain Reaction (RT-PCR)
  • RNA of the cell is extracted PureHelix RNA
  • cDNA was synthesized using the Helixcript 1'st strand cDNA synthesis kit (NanoHelix, Daejeon), and then PCR was performed.
  • the hCHOP and GAPDH primer sequence information used is shown in Table 1 below.
  • the mRNA expression level of CHOP which is an important factor of cell death process, was increased depending on the treatment concentration and time-dependently of the mixed medicinal extract (KIOM-C), and more specifically, about 20 times in the high concentration treatment group after 48 hours.
  • the amount of CHOP mRNA expression could be increased (Fig. 6b). Accordingly, it was found that the mixed medicinal extract (KIOM-C) induces oxidative stress in cells and increases the mRNA expression of CHOP, which is an important factor in the cell death process, thereby causing cell death.
  • Example 2-7-3 Western blot analysis
  • the mixed medicinal herb extract (KIOM-C) prepared in Example 1 affects the protein expression level of CHOP, SP600125 (5 uM), a JNK-specific inhibitor, was used for 1 hour.
  • the mixed medicinal extract (KIOM-C) was treated with cells at a concentration of 500 ⁇ g / ml or 1000 ⁇ g / ml and incubated for 24 hours.
  • Whole cell lysates of cells incubated as described above were prepared using M-PER Mammalian Protein Extraction Reagent, according to the manufacturer's instructions.
  • Cell lysates were quantified for protein concentration by BCA protein assay (Bicinchoninic Acid) assay, and after immunoblotting, the protein was subjected to a power-opti-chemiluminescent Weston blotting detection reagent ( Visualization was performed using Power Opti-ECL Western blotting detection reagent (Animal Genetics, Inc., Korea) and ImageQuant LAS 4000 mini (GE Healthcare, Piscataway, NJ, USA). The degree of expression of CHOP was derived by quantifying the visualized protein bands using software ImageJ (National Institutes of Health, USA).
  • the expression level of CHOP protein was significantly increased depending on the treatment concentration of the mixed medicinal extract (KIOM-C) compared to the untreated control group.
  • the simultaneous treatment of the JNK-specific inhibitor SP600125 it was confirmed that the expression of the CHOP protein is inhibited when the generated active oxygen species are lost (Fig. 6c). Accordingly, it can be seen that the mixed medicinal extract (KIOM-C) induces oxidative stress in cells and increases the expression level of CHOP protein, which is an important factor in the cell death process, thereby inducing cell death.
  • Example 2-8 Simultaneous Induction of Apoptosis and Autophagy Actions
  • JNK-specific inhibitor and JNK-targeted siRNA the following experiment was performed.
  • Example 2-8-1 Inhibition of Apoptosis Induction of Mixed Medicinal Herb Extracts (KIOM-C) by JNK-Specific Inhibitors
  • the HT1080 cell line was pretreated with pharmaceutical inhibitors such as JNK-specific inhibitor SP600125, p38 inhibitor SB203580, ERK 1/2 inhibitor PD98059, and lysosome inhibitor Bafilomycin A1 for 1 hour.
  • pharmaceutical inhibitors such as JNK-specific inhibitor SP600125, p38 inhibitor SB203580, ERK 1/2 inhibitor PD98059, and lysosome inhibitor Bafilomycin A1 for 1 hour.
  • the mixed medicinal extract (KIOM-C) at a concentration of 500 ⁇ g / ml
  • After recovering the protein in each cell, including JNK a factor involved in the activation of signal transduction systems that regulate cell death,
  • the expression of Beclin-1 important for autophagosome formation, PARP cleavage and Bcl-2 important for cell death, and p62 protein involved in autophagy were confirmed by Wester blot analysis.
  • the observed cytotoxicity and cell morphological changes may be induced.
  • Example 2-8-2 Inhibition of apoptosis induction of mixed medicinal herb extracts (KIOM-C) by siRNA targeted to JNK
  • HT1080 cells were cultured about 60% confluent in a 60 mm culture dish.
  • Cells cultured as described above were transfected with JNK-specific siRNA (small interfering RNA) using TransIT2020 (Mirus, Madison, Wis.).
  • Mcr siRNA scrambled siRNA
  • the transfected cells were cultured as described above for 72 hours, and after the culture, the mixed medicinal extract (KIOM-C) was treated for 24 hours at a concentration of 500 ⁇ g / ml.
  • KIOM-C Mixed medicinal extract prepared in Example 1 (25 ⁇ g / ml, 50 ⁇ g / ml, 100 ⁇ g / ml and 250 ⁇ g / ml), 3 ml containing 0.3% agar, and 10% FBS Suspension of cancer cells (B16F10 and HT1080) (1 ⁇ 10 4 ) in the medium of and applied to the solidified bottom agar containing 0.6% agar and 10% FBS, followed by a phase-contrast with incubation for 3 weeks. The microscope observed colonies formed in soft agar and photographed them.
  • KIOM-C Mixed medicinal extract prepared in Example 1 (25 ⁇ g / ml, 50 ⁇ g / ml, 100 ⁇ g / ml and 250 ⁇ g / ml), 3 ml containing 0.3% agar, and 10% FBS Suspension of cancer cells (B16F10 and HT1080) (1 ⁇ 10 4 ) in the medium of and applied to
  • cancer cells B16F10 and HT1080 were suspended in 1 ml of 10% FBS / DMEM medium, plated in a 12-well plate, and cultured to adhere to the plate, followed by mixed medicinal extract (KIOM-C). (25 ⁇ g / ml, 50 ⁇ g / ml, 100 ⁇ g / ml and 250 ⁇ g / ml) were incubated for 10 days. After 10 days, the colonies formed were stained with 0.2% crystal violet / 20% methanol stain and observed under a microscope.
  • KIOM-C mixed medicinal extract
  • wound healing assays were performed as follows to determine whether cell migration ability was inhibited.
  • cancer cell lines (B16F10 and HT1080) were cultured in a 60 mm culture dish about 80% confluent. To exclude the healing by cell proliferation after wound formation, as described above, about 25% of mitomycin C (mitomycin C) in cancer cells (B16F10 and HT1080) proliferated in monolayers was about 25%. C; Sigma chemical Co.) was stopped for 30 minutes to stop cell proliferation, and then the single layer was about 2 mm wide. Then, after removing the suspended cell suspension, and filled with 10% FBS-DMEM culture medium containing the mixed medicinal extract (KIOM-C) (50 ⁇ g / ml-250 ⁇ g / ml) prepared in Example 1 , And cultured in the medium.
  • mitomycin C mitomycin C
  • C mixed medicinal extract
  • the cells were cultured for 24 hours and 48 hours for the B16F10 cell line and 40 hours for the HT1080 cell line. After incubation for the above time, the ability of cell migration at the site of injury was observed through a phase contrast microscope. The interval between the time points at which the wound was formed (0 hour) was set at 100% and the extent to which the interval was narrowed due to cell movement was calculated as time passed.
  • the mixed medicinal herb extract (KIOM-C) of the present invention means that it effectively inhibited cell migration.
  • Mobility analysis was performed by filling 600 ⁇ l of 10% FBS / DMEM medium in the lower chamber of a 10 mm diameter transwell chamber with an 8 ⁇ m pore size polycarbonate membrane (Corning costar, Cambridge, Mass.), the upper chamber and then fill in the mixed medicine extract (KIOM-C) and tumor cells (B16F10 and HT1080) (1 ⁇ 10 5 gae / 100 ⁇ l) a, 100 ⁇ l DMEM medium without serum containing the 24 hours at 37 °C to Incubate for 36 hours.
  • KIOM-C mixed medicine extract
  • B16F10 and HT1080 tumor cells
  • the HT1080 cell line was confirmed the efficacy of the mixed medicinal extract (KIOM-C) under PMA stimulation conditions.
  • Invasion assays were performed by coating the transwell chamber with a 20 ⁇ l of Matrigel: DMEM 1: 2 mixture (Matrigel, BD Biosciences, Bedford, Mass., USA) to form an intervening invasive barrier. It was performed after.
  • the mixed medicinal herb extract (KIOM-C) of the present invention effectively inhibits cell migration and cell invasion of cancer cell lines.
  • MMP-9 is known to play an essential role in cancer metastasis by breaking down the extracellular matrix (ECM).
  • ECM extracellular matrix
  • KIOM-C mixed drug extract
  • B16F10 and HT1080 cancer cells
  • RT-PCR Reverse Transcriptase Polymerase Chain Reaction
  • PMA phorbol myristate acetate
  • RNA of PMA-stimulated cells was isolated using PureHelix RNA extraction kit (NanoHelix, Daejeon), and then synthesized Helixcript 1'st strand cDNA. PCR was performed after cDNA was synthesized using the kit (NanoHelix, Daejeon).
  • the hMMP-9 and GAPDH primer sequence information used is shown in Table 3 below.
  • the total cell lysate and nuclear / cytosolic extract of PMA-stimulated cells according to the manufacturer's instructions M-PER Mammalian Protein Extraction Reagent and NE-PER Nuclear & Cytosolic Extraction Reagent (Pierce Biotechnology, Inc., Rockford, IL, USA Each).
  • Cell lysates were quantified for protein concentration by BCA protein assay (Bicinchoninic Acid) assay, and after immunoblotting, the protein was subjected to a power-opti-chemiluminescent Weston blotting detection reagent ( Visualization was performed using Power Opti-ECL Western blotting detection reagent (Animal Genetics, Inc., Korea) and ImageQuant LAS 4000 mini (GE Healthcare, Piscataway, NJ, USA). The expression level of MMP-9 was derived by quantifying the visualized protein bands using software ImageJ (National Institutes of Health, USA).
  • the culture medium of the PMA-stimulated cells was electrophoresed in 8% sodium dodecyl sulfate-polyacrylamide gel (SDS-PAGE) containing 0.1% gelatin, and the gel was washed with buffer (50 mM Tris-HCl, pH 7.5, 100). After washing thoroughly with mM NaCl, 2.5% Triton X-100), it was soaked in active buffer (50 mM Tris-HCl, pH 7.5, 150 mM NaCl, 10 mM CaCl 2 , 0.02% NaN 3 , 1 ⁇ M ZnCl 2 ) And incubated at 37 ° C.
  • buffer 50 mM Tris-HCl, pH 7.5, 150 mM NaCl, 10 mM CaCl 2 , 0.02% NaN 3 , 1 ⁇ M ZnCl 2
  • the gel was then stained with Coomassie Brilliant Blue R-250 staining solution (Bio-Rad Laboratories, Hercules, Calif., USA) and 10% isopropanol / 10% acetic acid (v / v) Destained with solution.
  • the gelatin degradation capacity of MMP-9 was detected at 92 kDa with a transparent band on a dark blue background.
  • Example 7 Analysis of Efficacy of Mixed Herbal Extract (KIOM-C) on NF- ⁇ B Activity by PMA Stimulation
  • NF- ⁇ B is a transcription factor known to regulate MMP-9 gene expression and enhance cancer cell migration and invasiveness.
  • KIOM-C mixed medicinal extract
  • Example 1 inhibits NF- ⁇ B activity
  • the degree of pI ⁇ B and I ⁇ B expression and the degree of nuclear transfer of the NF- ⁇ B p65 subunit were analyzed by Western blot as described in Example 6-2.
  • the cell lysate was performed by dividing the cytosol and the nuclear part.
  • the expression levels of pI ⁇ B, I ⁇ B and the nuclear transfer NF- ⁇ B p65 subunits were quantified by standardizing ⁇ -tublin or TBP, which is an internal control.
  • HT1080 cell line pretreated with 250 ⁇ g / ml of mixed medicinal extract (KIOM-C) was treated with PMA 5 nM to stimulate NF- ⁇ B by stimulating the cell line.
  • PMA 5 nM mixed medicinal extract
  • each protein was harvested, and the expression levels of pI ⁇ B, I ⁇ B, and NF- ⁇ B p65 subunits transferred in the nucleus were confirmed.
  • -C pI ⁇ B was increased after PMA stimulation and I ⁇ B expression was decreased in the untreated control group, but there was no increase in pI ⁇ B due to PMA stimulation in the group treated with the mixed medicinal extract (KIOM-C). I ⁇ B expression did not decrease.
  • the mixed medicinal extract inhibits the expression and activity of MMP-9 by inhibiting the activity of NF- ⁇ B, resulting in the effect of inhibiting the migration and invasion of cancer cells.
  • B16F10 cell line 3 ⁇ 10 5 cells / 0.2 ml PBS
  • mice After 17 days, the mice were sacrificed and the lungs of each mouse were fixed with Bowin's solution (Sigma), and the number of black colonies of B16F10 cells on the surface of the lungs was visually examined. The test results were calculated as the average number of colonies in each group.
  • the mixed medicinal herb extract (KIOM-C) of the present invention is a result supporting the excellent efficacy of inhibiting cancer cell metastasis in vivo.
  • Example 8-2 Anticancer Activity Evaluation of Mixed Medicinal Extracts (KIOM-C) Using Tumor xenograft Model
  • the dosage of the mixed medicinal extract (KIOM-C) was divided into three dose groups of 85 mg / kg, 170 mg / kg, and 340 mg / kg in consideration of the amount taken by a 60 kg adult and the yield of agar.
  • saline administration group was included.
  • the mixed medicinal extract (KIOM-C) was orally administered daily for about 15 days, and the tumor volume was measured and calculated through the following calculation formula.
  • interferon-gamma an important cytokine that kills cancer
  • INF- ⁇ interferon-gamma
  • the negative control group began to observe tumor mass after 5 days of tumor inoculation, and showed rapid growth after about 10 days, whereas the group of the mixed medicinal extract (KIOM-C) showed significantly reduced tumor growth. It was confirmed (Fig. 14a). In addition, it was confirmed that the size of the tumor mass extracted after 15 days was also significantly smaller in the group to which the mixed medicinal extract (KIOM-C) was administered (FIG. 14B). After 15 days, tumors were collected from nude mice and the tumor weight was measured. The average weight of the tumors in the negative control group was 0.62 ⁇ 0.18g, and the mixed medicinal extract 85 mg / kg administered group was 0.16 ⁇ 0.06g, 170 mg / g.
  • the kg administration group was 0.16 ⁇ 0.09g and the 340 mg / kg administration group was 0.19 ⁇ 0.11g (Fig. 14c).
  • the INF- ⁇ concentration significantly increased compared to the untreated control (FIG. 14D).
  • the mixed medicinal herb extract (KIOM-C) of the present invention significantly inhibits tumor growth even in in-vivo experiments, and there is no specific toxicity by repeated long-term administration.
  • Example 9-1 Analysis of tumor cell death effect of the mixed medicinal extract and each sweetener
  • KIOM-C Mixed medicinal herb extract prepared in Example 1 and the sweet constituents (Kungung, Windproof, Angelica, Peony, Yeongyo, Peppermint, Ephedra, Manganese, Rhubarb, Gypsum, Giltyeong, Golden, Baekchul, Maize , Ginseng, ginger, talc, licorice, gilding, yin and yang, and paper and neck).
  • sweet constituents Kungung, Windproof, Angelica, Peony, Yeongyo, Peppermint, Ephedra, Manganese, Rhubarb, Gypsum, Giltyeong, Golden, Baekchul, Maize , Ginseng, ginger, talc, licorice, gilding, yin and yang, and paper and neck.
  • the group treated with the mixed medicinal herb extract (KIOM-C) prepared in Example 1 showed cancer cell survival rate (77.7% cancer cell death) of 22.3% compared to the group not treated, but each sweet rice Processed ash extracts (bowung, windbreak, donkey, peony, pontoon, peppermint, ephedra, forget-me-not, rhubarb, gypsum, gilsheng, gold, white peach, wild jasmine, hedgehog, ginger, talc, licorice, sterling silver, yin and yang, spring and wood) In the group, cancer cell survival inhibition (cancer apoptosis) efficacy was not confirmed (FIG. 15).
  • the mixed medicinal herb extract (KIOM-C) of the present invention exhibits an effective anticancer activity (apoptosis) that can not be provided by each of the sweeteners alone by using a mixture of each of the sweeteners of low concentration that does not exhibit cancer cell death effects. It was confirmed.
  • Example 9-2 Analysis of Tumor Metastasis Inhibitory Effects of the Mixed Medicinal Extracts and Each Sweet Rice
  • the mixed medicinal herb extract (KIOM-C) of the above example has an effect of remarkably improving anti-transduction activity by using a mixture of low concentrations of safe sweeteners having no cancer cell killing effect (cytotoxicity).

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Abstract

La présente invention concerne une composition pharmaceutique, qui permet de prévenir ou de traiter un cancer et qui contient, comme principe actif, un extrait de médicament mixte obtenu de plantes naturelles ; un aliment naturel fonctionnel pour prévenir ou améliorer un cancer ; un procédé pour prévenir ou traiter un cancer, comportant une étape consistant à administrer une composition contenant un extrait de médicament mixte obtenu de plantes naturelles et, plus particulièrement, une composition pharmaceutique pour prévenir ou traiter un cancer, contenant un extrait de médicaments mixtes composés de Cnidium officinale, Ledebouriella seseloides, Korean angelica, Paeonia lactiflora, Forsythia viridissima, Mentha arvensis, Ephedra sinica, Rheum palmatum, gypse, Platycodon grandiflorum, Scutellaria baicalensis, Atractylodes japonica, Gardenia jasminoides, Schizonepeta tenuifolia, gingembre, talc, réglisse, Lonicera japonica, Epimedium koreanum, Polygala tenuifolia et Inula helenium ; un aliment naturel fonctionnel pour prévenir ou améliorer un cancer ; un procédé pour prévenir ou traiter un cancer comprenant une étape consistant à administrer une composition contenant un extrait de médicament mixte obtenu de plantes naturelles. L'extrait de médicament mixte présente des activités pour inhiber une métastase, induire une apoptose et inhiber une croissance cellulaire, qui sont efficaces contre des cellules cancéreuses, ledit extrait pouvant donc être utilisé d'une manière pharmaceutique comme composition pour prévenir ou traiter un cancer et étant utile comme aliment naturel fonctionnel.
PCT/KR2014/003138 2013-04-11 2014-04-11 Composition pharmaceutique et aliment naturel fonctionnel pour prévenir ou traiter un cancer, contenant un extrait naturel comme principe actif WO2014168447A1 (fr)

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KR102294477B1 (ko) * 2019-10-17 2021-08-25 경희대학교 산학협력단 삼지구엽초 추출물의 신규용도

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* Cited by examiner, † Cited by third party
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CN104366622A (zh) * 2014-11-24 2015-02-25 郴州大诚中药饮片有限责任公司 保健饮料及其制备方法
CN104383340A (zh) * 2014-12-05 2015-03-04 苗艳秋 用于新生儿肺热咳嗽症状的中成药及其制备方法
CN105168944A (zh) * 2015-10-20 2015-12-23 青岛云天生物技术有限公司 一种治疗乳腺癌的中药组合物及其用途
CN115088833A (zh) * 2022-05-20 2022-09-23 唛迪森营养科技(江苏)有限公司 一种用于预防和/或治疗肿瘤患者肠道损伤的功能性食品

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