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WO2023224163A1 - Composition anticancéreuse contenant un extrait d'artemisia princeps - Google Patents

Composition anticancéreuse contenant un extrait d'artemisia princeps Download PDF

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Publication number
WO2023224163A1
WO2023224163A1 PCT/KR2022/008472 KR2022008472W WO2023224163A1 WO 2023224163 A1 WO2023224163 A1 WO 2023224163A1 KR 2022008472 W KR2022008472 W KR 2022008472W WO 2023224163 A1 WO2023224163 A1 WO 2023224163A1
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Prior art keywords
cancer
preventing
pharmaceutical composition
fraction
cells
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Korean (ko)
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이동선
최학선
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Industry Academic Cooperation Foundation of Jeju National University
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Industry Academic Cooperation Foundation of Jeju National University
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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)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • A61K36/282—Artemisia, e.g. wormwood or sagebrush
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/03—Organic compounds
    • A23L29/035—Organic compounds containing oxygen as heteroatom
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/308—Foods, ingredients or supplements having a functional effect on health having an effect on cancer prevention
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2250/00—Food ingredients
    • A23V2250/30—Other Organic compounds

Definitions

  • the present invention relates to the cancer treatment effect of Jeju mugwort extract, its fractions, and compounds isolated therefrom.
  • cancer stem cells As anti-cancer treatment fails to effectively target and treat the cell population within the tumor, leading to tumor recurrence and metastasis, interest in cancer stem cells (tumor stem cells) has emerged. Recently, it has been revealed that cancer stem cells exist in all tumors, and these cancer stem cells are known to be the origin of tumor cells and do not respond to treatments such as anticancer drugs. Cancer stem cells are cells that have the ability to self-renew, differentiate, and grow at the same time. For this reason, although cancer stem cells are small in number, they have the ability to restore cancer cells necrosized by anticancer drugs.
  • Cancer stem cells not only serve as the origin cells of tumor development, but have also been identified as a group of tumor origin cells that show resistance to anticancer treatment, and are used in oncology for tumor diagnosis, prognosis, treatment progress tracking, and development of new anticancer drugs targeting tumor stem cells. It is emerging as a core area of research. In most tumors, these cancer stem cells divide more slowly than normal stem cells and remain in a dormant state. Therefore, cancer stem cells can survive cytotoxic anticancer therapy using most cytotoxic anticancer drugs that target rapidly proliferating cells.
  • cancer stem cells CD133 +
  • cancer stem cells CD133 +
  • glioblastoma brain tumors
  • cancer stem cells are resistant to anticancer drugs and radiotherapy ( resistance).
  • Cancer stem cells were first identified in myeloid leukemia, and have since been discovered in a diverse group of solid cancers, including breast, brain, colon, ovarian, pancreas, and prostate cancer.
  • the cancer stem cells may be named tumor-initiating cells and cancer stem-like cells.
  • various cancer types including breast cancer, have been shown to originate from cancer stem cells (CSCs), a subpopulation of tumors.
  • Cancer stem cells are drug-resistant to chemotherapy and radiotherapy. and has radiation resistance, causing recurrence and metastasis of cancer. Therefore, targeted treatment for cancer stem cells is essential for cancer treatment. Cancer stem cells are known to express specific proteins including Oct4, Sox2, Nanog, and aldehyde dehydrogenase-1 (ALDH-1).
  • the ALDH is an enzyme that oxidizes genotoxic aldehydes, and its enzyme activity is widely used as a CSC marker for leukemia, head and neck, bladder, bone, colon, liver, lung, pancreas, prostate, thyroid, and cervical cancer. ALDH is known to be a therapeutic target for cancer stem cells.
  • Breast cancer is a common cancer in women and is known to be a major cause of death in female cancer patients (al A, Bray F, Center MM, Ferlay J, Ward E and Forman D. Globalcancer statistics. CA Cancer J Clin. 2011; 61( 2):69-90). Extensive mammography and adjuvant therapy along with polychemotherapy and tamoxifen for early breast cancer have reduced the mortality rate of breast cancer, but breast cancer is still known to be the most dangerous disease due to recurrence and metastasis.
  • the breast cancer population expressing CD44 high / CD24 low has an excellent ability to form tumors, and the breast cancer stem cells express CD44 high / CD24 low , biomarkers such as ESA + (epithelial-specific antigen) and ALDH1. It is known that it can be confirmed by (Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ and Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci US A. 2003; 100(7):3983 -3988). It is known that chemotherapy increases the proportion of cancer cells expressing CD44 high / CD24 low and mammosphere formation.
  • the IL-6/JAK1/2/STAT3 (Signal transducers and activators of transcription 3) signaling pathway is known to be important in the conversion of non-cancer stem cells (NSCCs) to cancer stem cells (CSCs), and blocking the STAT3 signaling pathway CD44 high / CD24 low - It has been reported to inhibit the growth of stem cell-like breast cancer cells.
  • Mammosphere is applied to human breast stem cells by artificially creating conditions without a substrate through suspension culture, where cells with stem cell properties attach to each other and form a spherical cell mass.
  • Mammospheres contain 8 times more progenitor cells than regular human breast cells, can be continuously subcultured, and have the characteristic of growing 100% of the cells into bi-potent precursors after multiple subcultures.
  • Mammospheres can be differentiated into adult breast cells such as mammary gland epitherlial cells, ductal epithelial cells, and alveolar epitherlial cells, and within Matrigel. It is observed that a complex functional breast structure is formed with a three-dimensional structure.
  • Mammospheres have the ability to self-proliferate, which is one of the most important characteristics of stem cells, so multiple mammospheres or mammary stem cells can be obtained in large quantities from one mammosphere. Additionally, compared to hematopoietic stem cells, neural stem cells, embryonic stem cells, etc., many expressed genes were confirmed to be overlapping, so it was reported that mammospheres are actual breast stem cells.
  • the standard analysis method for the self-renewal ability of cancer stem cells is to analyze transplantation in vivo and mammosphere formation in vitro .
  • An object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer.
  • an object of the present invention is to provide an anticancer adjuvant that improves sensitivity to anticancer drugs.
  • an object of the present invention is to provide a food composition for improving or preventing cancer.
  • the present invention provides a pharmaceutical composition for preventing or treating cancer containing Jeju mugwort extract or a fraction thereof as an active ingredient.
  • the present invention provides a pharmaceutical composition for preventing or treating cancer containing 5-desmethylsinensetin, or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.
  • the present invention provides an anti-cancer adjuvant that improves sensitivity to anti-cancer drugs comprising Jeju mugwort extract, a fraction thereof, or 5-desmethylsinensetin or a pharmaceutically acceptable salt or solvate thereof as an active ingredient. .
  • the present invention provides a food composition for improving or preventing cancer comprising a Jeju mugwort extract, a fraction thereof, or 5-desmethylsinensetin or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a method for preventing or treating cancer, including the step of administering the pharmaceutical composition for preventing or treating cancer of the present invention to a subject.
  • the Jeju mugwort extract and its fractions of the present invention inhibit the formation of cancer stem cells, and 5-desmethylsinensetin isolated therefrom inhibits the proliferation, tumor formation, and metastatic ability of cancer cells, and inhibits the formation and metastasis of cancer stem cells. Since it has the effect of inhibiting growth and killing it, it can be usefully used for the prevention or treatment of cancer, especially resistant cancer caused by cancer stem cells.
  • Figure 1 is a diagram showing the isolation of mugwort-derived breast cancer stem cell inhibitors using mammosphere formation analysis:
  • Figure 2 is a diagram showing the molecular structure of the CSC inhibitory compound 5-desmethylsinensetin isolated and purified from mugwort extract.
  • Figure 3 is a diagram confirming the effect of 5-desmethylsinensetin on cell proliferation and mammosphere formation:
  • Figure 4 is a diagram confirming the effect of 5-desmethylsinensetin on reducing CD44 + /CD24 - and ALDH1 + breast cancer cell populations:
  • Figure 5 is a diagram confirming the mammosphere death-inducing and growth-inhibiting effects of 5-desmethylsinensetin:
  • Figure 6 is a diagram confirming the effect of 5-desmethylsinensetin on the Stat3 signaling pathway:
  • ESA Electrophoresis mobility shift assays
  • Lane 2 nuclear extract without 5-desmethylsinensetin treatment and Stat3 probe
  • Lane 3 5-desmethylsinensetin (20 ⁇ M) treated nuclear protein and Stat3 probe;
  • Lane 4 nuclear protein without 5-desmethylsinensetin treatment and incubated with self-competitor (200X) oligo;
  • Lane 5 Nuclear extract without 5-desmethylsinensetin treatment and incubated with mutant-Stat3 (200X) probe.
  • Figure 7 is a diagram confirming the effect of 5-desmethylsinensetin on regulating the secretion and transcription levels of IL-6 and IL-8:
  • Figure 8 is a diagram confirming the inhibitory effect of 5-desmethylsinensetin on the YAP1 pathway through Stat3:
  • A YAP1 protein expression level in total and nuclear proteins of mammospheres
  • FIG. 9 is a schematic diagram showing the inhibition of breast cancer stem cells (BCSCs) formation through Stat3-IL6 signaling and Stat3-YAP1 signaling by 5-desmethylsinensetin.
  • the present invention relates to a pharmaceutical composition for preventing or treating cancer containing an extract of Jeju mugwort ( Artemisia princeps ) or a fraction thereof as an active ingredient.
  • the extract may be extracted with one or more solvents selected from the group consisting of water, organic solvents, subcritical fluids, and supercritical fluids, such as water, anhydrous or hydrous alcohol having 1 to 4 carbon atoms, ethyl acetate, and acetone.
  • the extract may be extracted with at least one extraction solvent selected from the group consisting of glycerin, ethylene glycol, propylene glycol, and butylene glycol, and the organic solvent is a lower alcohol having 1 to 4 carbon atoms, hexane (n-hexane), and ether.
  • glycerol propylene glycol, butylene glycol, ethyl acetate, methyl acetate, dichloromethane, chloroform, ethyl acetate, acetone, methylene chloride, cyclohexane, petroleum ether, benzene and mixed solvents thereof. It may be any one, and methanol is most preferable.
  • the fraction may be an ethanol fraction, a methanol fraction, a dichloromethane fraction, an ethyl acetate fraction, a water fraction, an n-hexane fraction, a chloroform fraction, an ethyl acetate or a butanol fraction.
  • the cancer may express a cancer stem cell (CSC) marker, and the cancer stem cell marker may be one or more selected from the group consisting of Oct4, c-Myc, Nanog, and CD44.
  • CSC cancer stem cell
  • the composition of the present invention can inhibit the formation of cancer stem cells, and it is more preferable to inhibit the formation of mammospheres, which are breast cancer stem cells.
  • the cancer is brain tumor, melanoma, myeloma, non-small cell lung cancer, oral cancer, liver cancer, stomach cancer, colon cancer, breast cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cervical cancer, ovarian cancer, colon cancer, Small intestine cancer, rectal cancer, fallopian tube carcinoma, anal cancer, endometrial carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, lymph node cancer, bladder cancer, gallbladder cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, Soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, renal or ureteral cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system tumor, primary central nervous system lymphoma, spinal cord tumor, brainstem glioma, and It may be any one selected from the group consisting of pitu
  • the extract may be extracted from the above-ground or underground part of Jeju mugwort, and it is more preferable to extract the above-ground part.
  • extract used in the present invention refers to a preparation made by squeezing a herbal medicine into an appropriate leachate and evaporating the leachate to concentrate it. It is commonly used as a crude extract in the art, but is broadly used. Also includes fractions obtained by additional fractionation of the extract. In other words, Jeju mugwort extracts include not only those obtained using the above-mentioned extraction solvent, but also those obtained by applying an additional purification process. For example, fractions obtained by passing the extract through an ultrafiltration membrane with a certain molecular weight cut-off value, separation by various chromatographs (designed for separation according to size, charge, hydrophobicity, or affinity), etc. Fractions obtained through various purification methods are also included in the extract.
  • the extract is not limited thereto, but may be an extract obtained through extraction treatment, a diluted or concentrated liquid of the extract, a dried product obtained by drying the extract, and a crude or purified product thereof.
  • the Jeju mugwort extract can be prepared using general extraction, separation and purification methods known in the art.
  • the extraction method is not limited thereto, but preferably includes boiling water extraction, hot water extraction, cold needle extraction, reflux cooling extraction, or ultrasonic extraction.
  • the extract can be prepared by extracting with an extraction solvent or fractionating the extract by adding a fractionating solvent to the extract prepared by extraction with an extraction solvent.
  • the extraction solvent is not limited to this, but water, an organic solvent, or a mixed solvent thereof may be used.
  • the organic solvent may be an alcohol having 1 to 4 carbon atoms, a polar solvent such as ethyl acetate or acetone, hexane, or dichloromethane.
  • a non-polar solvent of methane or a mixed solvent thereof can be used.
  • water, alcohol with 1 to 4 carbon atoms, or a mixed solvent thereof can be preferably used, and methanol can be more preferably used.
  • a Jeju mugwort extract was prepared using methanol as the solvent.
  • the Jeju mugwort extract obtained in this way is suspended in water, separated using an extraction solvent according to a conventional method, and concentrated under reduced pressure to obtain fractions of the Jeju mugwort extract by extraction solvent.
  • solvents used to obtain Jeju mugwort extract include purified water or organic solvents having 1 to 6 carbon atoms.
  • the organic solvent include ethanol, methanol, propanol, butanol, glycerin, ethyl acetate, butylene glycol, and propylene glycol. glycol), dichloromethane, chloroform, ethyl ether, hexane, etc. These can be used individually or in combination of two or more.
  • composition of the present invention prevents cancer by additionally containing Jeju mugwort extract or a fraction thereof, as well as other active ingredients with the same or similar functions, or by additionally containing other active ingredients with different functions from the above ingredients. Or it can be prepared as a pharmaceutical composition for treatment.
  • the present invention uses 5-desmethylsinensetin (C 19 H 18 O 7 ; 358) represented by the following formula 1, or a pharmaceutically acceptable salt or solvate thereof: It relates to a pharmaceutical composition for preventing or treating cancer containing as ingredients:
  • the cancer may express a cancer stem cell (CSC) marker, and the cancer stem cell marker may be one or more selected from the group consisting of Oct4, c-Myc, Nanog, and CD44.
  • CSC cancer stem cell
  • the composition of the present invention can inhibit the formation of cancer stem cells, and it is more preferable to inhibit the formation of mammospheres, which are breast cancer stem cells.
  • the cancer is brain tumor, melanoma, myeloma, non-small cell lung cancer, oral cancer, liver cancer, stomach cancer, colon cancer, breast cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cervical cancer, ovarian cancer, colon cancer, Small intestine cancer, rectal cancer, fallopian tube carcinoma, anal cancer, endometrial carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, lymph node cancer, bladder cancer, gallbladder cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, Soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, renal or ureteral cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system tumor, primary central nervous system lymphoma, spinal cord tumor, brainstem glioma, and It may be any one selected from the group consisting of pitu
  • the composition inhibits cancer cell proliferation, inhibits the formation of CD44 + /CD24 - or ALDH1 + cancer cells, suppresses tumor formation and metastatic ability, kills cancer stem cells, and inhibits the growth of cancer stem cells. It can inhibit the transcription of Oct4, c-Myc, Nanog and CD44, inhibit the expression and protein activity of Stat3, inhibit the secretion and transcription of IL-6 and IL-8, and inhibit the nuclear movement of YAP1. there is.
  • the composition of the present invention may include 5-desmethylsinensetin at a concentration of 0.01 to 1,000 ⁇ M.
  • prevention refers to all actions that inhibit or delay the occurrence, spread, and recurrence of cancer by administration of the pharmaceutical composition according to the present invention
  • treatment refers to the administration of the composition of the present invention. It refers to all actions that improve or beneficially change the symptoms of cancer.
  • therapeutically effective amount used in combination with an active ingredient in the present invention refers to an amount effective in preventing or treating cancer, and the therapeutically effective amount of the composition of the present invention depends on several factors, such as the method of administration, It may vary depending on the target area, patient condition, etc. Therefore, when used in the human body, the dosage must be determined as appropriate by considering both safety and efficiency. It is also possible to estimate the amount used in humans from the effective amount determined through animal testing. These considerations in determining an effective amount include, for example, Hardman and Limbird, eds., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th ed. (2001), Pergamon Press; and E.W. Martin ed., Remington's Pharmaceutical Sciences, 18th ed. (1990), Mack Publishing Co.
  • the pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount refers to an amount that is sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment and does not cause side effects, and the effective dose level is determined by the patient's Factors including health status, type of cancer, cause of cancer, severity, activity of drug, sensitivity to drug, method of administration, time of administration, route of administration and excretion rate, treatment period, drugs combined or used simultaneously, and other medical It can be determined based on factors well known in the field.
  • the composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. Considering all of the above factors, it is important to administer an amount that can achieve maximum effect with the minimum amount without side effects, and this can be easily determined by a person skilled in the art.
  • the pharmaceutical composition of the present invention may contain a carrier, diluent, excipient, or a combination of two or more commonly used in biological products.
  • a carrier diluent, excipient, or a combination of two or more commonly used in biological products.
  • pharmaceutically acceptable means that the composition exhibits non-toxic properties to cells or humans exposed to the composition.
  • the carrier is not particularly limited as long as it is suitable for in vivo delivery of the composition, for example, Merck Index, 13th ed., Merck & Co. Inc.
  • saline solution sterilized water, Ringer's solution, buffered saline solution, dextrose solution, maltodextrin solution, glycerol, ethanol, and one or more of these ingredients can be mixed and used, and if necessary, other ingredients such as antioxidants, buffers, and bacteriostatic agents. Normal additives can be added.
  • diluents, dispersants, surfactants, binders, and lubricants can be additionally added to formulate dosage forms such as aqueous solutions, suspensions, emulsions, etc., into pills, capsules, granules, or tablets.
  • it can be preferably formulated according to each disease or ingredient using an appropriate method in the art or a method disclosed in Remington's Pharmaceutical Science (Mack Publishing Company, Easton PA, 18th, 1990).
  • the pharmaceutical composition may be one or more formulations selected from the group including oral formulations, topical formulations, suppositories, sterile injectable solutions, and sprays, with oral or injectable formulations being more preferable.
  • the term "administration” means providing a predetermined substance to an individual or patient by any appropriate method, and is administered parenterally (e.g., intravenously, subcutaneously, intraperitoneally) according to the desired method. Alternatively, it can be applied topically as an injection formulation) or orally administered, and the dosage range varies depending on the patient's weight, age, gender, health status, diet, administration time, administration method, excretion rate, and severity of the disease.
  • Liquid preparations for oral administration of the composition of the present invention include suspensions, oral solutions, emulsions, syrups, etc., and in addition to the commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives are used. etc. may be included together.
  • Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, suppositories, etc.
  • the pharmaceutical composition of the present invention may be administered by any device capable of transporting the active agent to target cells.
  • Preferred administration methods and formulations include intravenous injection, subcutaneous injection, intradermal injection, intramuscular injection, and drip injection.
  • Injections include aqueous solvents such as physiological saline solution and Ringer's solution, non-aqueous solvents such as vegetable oil, higher fatty acid esters (e.g., ethyl oleate, etc.), and alcohols (e.g., ethanol, benzyl alcohol, propylene glycol, glycerin, etc.).
  • stabilizers to prevent deterioration
  • emulsifiers e.g., ascorbic acid, sodium bisulfite, sodium pyrosulphite, BHA, tocopherol, EDTA, etc.
  • buffers for pH adjustment e.g., buffers for pH adjustment
  • agents to prevent microbial growth e.g., ascorbic acid, sodium bisulfite, sodium pyrosulphite, BHA, tocopherol, EDTA, etc.
  • emulsifiers e.g., ascorbic acid, sodium bisulfite, sodium pyrosulphite, BHA, tocopherol, EDTA, etc.
  • emulsifiers e.g., buffers for pH adjustment
  • agents to prevent microbial growth e.g., buffers for pH adjustment, and
  • the term "individual” refers to a monkey, cow, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, or This refers to all animals, including guinea pigs, and the above diseases can be effectively prevented or treated by administering the pharmaceutical composition of the present invention to the subject.
  • the pharmaceutical composition of the present invention can be administered in combination with existing therapeutic agents.
  • the pharmaceutical composition of the present invention may further include pharmaceutically acceptable additives, wherein the pharmaceutically acceptable additives include starch, gelatinized starch, microcrystalline cellulose, lactose, povidone, colloidal silicon dioxide, and calcium hydrogen phosphate. , lactose, mannitol, taffy, gum arabic, pregelatinized starch, corn starch, powdered cellulose, hydroxypropyl cellulose, Opadry, sodium starch glycolate, lead carnauba, synthetic aluminum silicate, stearic acid, magnesium stearate, aluminum stearate, Calcium stearate, white sugar, dextrose, sorbitol, and talc may be used.
  • the pharmaceutically acceptable additive according to the present invention is preferably contained in an amount of 0.1 to 90 parts by weight based on the composition, but is not limited thereto.
  • the present invention relates to a composition for inhibiting cancer stem cell formation
  • a composition for inhibiting cancer stem cell formation comprising Jeju mugwort extract, a fraction thereof, or 5-desmethylsinensetin or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.
  • the present invention provides an anticancer adjuvant that improves sensitivity to an anticancer agent comprising Jeju mugwort extract, a fraction thereof, or 5-desmethylsinensetin or a pharmaceutically acceptable salt or solvate thereof as an active ingredient. It's about.
  • the anti-cancer agent may be a chemotherapy drug or an anti-cell division drug.
  • the anticancer agent is eribulin, carboplatin, cisplatin, Halaven, 5-fluorouracil (5-FU), gleevec, vincristine ( Vincristine, Vinblastine, Vinorelvine, Paclitaxel, Docetaxel, Etoposide, Topotecan, Irinotecan, Dactinomycin, It may be Doxorubicin, Daunorubicin, valrubicin, flutamide, gemcitabine, Mitomycin, or Bleomycin.
  • the cancer may be cancer stem cell, multi-drug resistant cancer, or anticancer drug resistant cancer.
  • it may be resistant cancer caused by the formation of cancer stem cells.
  • the anticancer adjuvant of the present invention can increase apoptosis of cancer cells, multidrug-resistant cancer cells, or cancer stem cells.
  • the anti-cancer adjuvant of the present invention may be administered in combination with an anti-cancer agent, and may be administered simultaneously, separately, or sequentially with the anti-cancer agent.
  • the cancer is brain tumor, melanoma, myeloma, non-small cell lung cancer, oral cancer, liver cancer, stomach cancer, colon cancer, breast cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cervical cancer, ovarian cancer, and colon cancer.
  • soft tissue sarcoma urethral cancer
  • penile cancer prostate cancer
  • chronic or acute leukemia lymphocytic lymphoma
  • renal or ureteral cancer renal cell carcinoma, renal pelvic carcinoma
  • central nervous system tumor primary central nervous system lymphoma
  • spinal cord tumor brainstem glioma
  • pituitary adenoma more preferably breast cancer, and most preferably triple negative breast cancer (TNBC).
  • drug-resistance refers to symptoms that show extremely low sensitivity to anticancer drug treatment and do not show improvement, relief, relief, or treatment symptoms due to the treatment.
  • Anticancer drug resistance may occur when a cancer develops resistance to a specific anticancer drug treatment regimen from the beginning, and may not initially show resistance, but due to long-term treatment, the properties of cancer cells change and they no longer show sensitivity to the same treatment drug. .
  • anticancer adjuvant refers to an agent that can improve, improve or increase the anticancer effect of an anticancer agent. It does not exhibit anticancer activity by itself, but when used together with an anticancer agent, improves or enhances the anticancer effect of the anticancer agent. Or it may be an agent that can increase. In addition, when an agent that exhibits concentration-dependent anticancer activity is used together with an anticancer agent at a level that does not show anticancer activity on its own, it may be an agent that can improve, enhance, or increase the anticancer effect of the anticancer agent.
  • Anticancer adjuvants can be administered through any general route as long as they can reach the target tissue.
  • the anti-cancer adjuvant of the present invention may be administered intraperitoneally, intravenously, intramuscularly, subcutaneously, intradermally, orally, intranasally, pulmonaryly, or rectally, depending on the purpose, but is not limited thereto. No. Additionally, the anti-cancer adjuvant can be administered by any device that allows the active substance to move to target cells.
  • the present invention relates to an anticancer composition
  • an anticancer composition comprising the anticancer adjuvant and anticancer agent of the present invention as active ingredients.
  • the present invention relates to a food composition for preventing or improving cancer comprising a Jeju mugwort extract, a fraction thereof, or 5-desmethylsinensetin or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention relates to a method for preventing or treating cancer, comprising administering the pharmaceutical composition for preventing or treating cancer of the present invention to a subject.
  • Example 1 Preparation of Jeju mugwort extract and isolation of substances that inhibit breast cancer stem cells (BCSCs)
  • Jeju mugwort extract was prepared with 100% methanol (MeOH 36 L) (24 3L flasks each) 50 g of mugwort and 1.5 L of methanol).
  • the five extracted fractions were divided according to color and the degree of inhibition of mammosphere formation, a breast cancer stem cell, was evaluated to screen Jeju mugwort for inhibitors of breast cancer stem cell formation.
  • the breast cancer cell line MDA-MB-231 (KCLB, Seoul, Korea) was seeded at 2 ⁇ 10 cells/well in a 6 -well plate and cultured in MammoCultTMculture medium (StemCell Technologies, Vancouver, BC) containing hydrocortisone and heparin. , Canada) for 7 days, and the degree of mammosphere formation was analyzed by mammosphere formation efficiency (MFE%) using the NICE (NIST's integrated colony enumerator) program.
  • MFE mammosphere formation efficiency
  • the Jeju mugwort extract appeared to inhibit mammosphere formation ( Figure 1B), which was purified using a Sephadex LH-20 gel column (2.5 ⁇ 30 cm, 25-100 micron article size) and divided into five fractions. The five fractions were collected and evaluated by performing mammosphere formation analysis, and the fifth fraction, which was shown to inhibit mammosphere formation, was loaded onto a prep-TLC (preparatory TLC plate) (glass plate; 20 ⁇ 20 cm) and TLC glass. It was developed in a chamber (CHCl 3 :MeOH, 30:1). Afterwards, the main band was separated on a silicon dioxide gel plate, and the inhibitory effect of the fraction on mammosphere formation was confirmed.
  • Figure 1B was purified using a Sephadex LH-20 gel column (2.5 ⁇ 30 cm, 25-100 micron article size) and divided into five fractions. The five fractions were collected and evaluated by performing mammosphere formation analysis, and the fifth fraction, which was shown to inhibit mammosphere formation, was loaded onto
  • the purified compound was confirmed by analyzing the lower fraction on an HPLC instrument equipped with an ODS column (10 ⁇ 250-mm, flow rate: 2 ml/min, mobile phase: acetonitrile-water) (Figure 1C).
  • the main peaks were collected and evaluated by mammosphere formation analysis, and each of the main peaks was collected and structural analysis was performed.
  • Example 1-2 The compounds purified in Example 1-2 were confirmed using NMR and mass spectrometry (ESI-Mass). As a result, the molecular weight was confirmed to be 358 by ESI-mass measurement, and the structure was confirmed using NMR, and the active compound that inhibits breast cancer stem cell formation isolated from the methanol extract of Jeju mugwort was identified as 5-desmethylsinensetin (5- It was confirmed as desmethylsinensetin)(C 19 H 18 O 7 ; 358) (Formula 1) ( Figure 2).
  • breast cancer cell lines MDA-MB-453 and MDA-MB were used.
  • the antiproliferative effect was confirmed by treating -231 and MCF-7 with increasing concentrations, respectively.
  • breast cancer cell lines were distributed in 96-well plates at 1 ⁇ 10 6 (MDA-MB-231) and 1.5 ⁇ 10 6 (MCF-7), respectively, and cultured for 24 hours, followed by 5-desmethylsinensetin. were treated with 0, 5, 10, 20, 30, 40, and 50 ⁇ M, respectively, and incubated for one day. Afterwards, the degree of proliferation of cancer cell lines was measured using the EZ-Cytox kit (DoGenBio, Seoul, Korea).
  • CD44 + /CD24 - and ALDH (aldehyde dehydrogenase)1 + are associated with stem cell-like activity in breast cancer
  • CD44 + /CD24 - and ALDH1 + MDA-MB-231 cells are CD44 - /CD24 + and ALDH1 - MDA-MB-231 cells exhibit higher tumorigenic and metastatic potential compared to MDA-MB-231 cells, and thus changes in the marker expression population due to 5-desmethylsinensetin treatment were confirmed.
  • the MDA-MB-231 cell line was treated with 5-desmethylsinensetin (20 ⁇ M) for 24 hours and incubated with ALDH assay buffer and 37 cells using the Alde-fluorTM assay kit (StemCell Technologies, Vancouver, BC, Canada). Reacted at °C for 20 minutes. ALDH-positive cells were tested with an Accuri C6 cytometer (BD, San Jose, CA, USA).
  • 5-desmethylsinensetin induces apoptosis of breast cancer stem cells
  • primary mammospheres derived from MDA-MB-231 cells cultured for 5 days were treated with 5-desmethylsinensetin (20 ⁇ M). Then, the mammospheres were separated into single cells by treating them with trypsin (0.05% Trypsin-EDTA 1 ⁇ , Gibco, Thermo Fisher Scientific, CA, USA). 1 ⁇ 10 6 cells were incubated with Annexin V (FITC) and PI in binding buffer. and incubated for 30 minutes at room temperature in dark conditions. The cells were then analyzed by flow cytometry.
  • trypsin 0.05% Trypsin-EDTA 1 ⁇ , Gibco, Thermo Fisher Scientific, CA, USA
  • 5-desmethylsinensetin inhibits the growth of breast cancer stem cells
  • the growth rate of mammospheres and changes in mRNA levels of cancer stem cell-specific marker genes were confirmed after 5-desmethylsinensetin treatment.
  • MDA-MB-231-derived mammospheres were treated with 5-desmethylsinensetin (20 ⁇ M), mammospheres were separated into single cells, distributed in 6-well plates, and the number of cells was counted for 3 days. .
  • 5-desmethylsinensetin was found to inhibit the growth of mammospheres (Figure 5B) and to reduce the transcription levels of Oct4, c-Myc, Nanog, and CD44 in breast cancer stem cells (Figure 5B). 5C).
  • Stat3 Since activation of Stat3 is required for the growth of CD44 + /CD24 - stem cell-like breast cancer cells in human tumors, mammospheres were treated with 5-desmethylsinensetin and then Stat3, p- in their total and nuclear extracts were examined. The expression of Stat3 and NF ⁇ p65, a cofactor of Stat3, was confirmed by Western blot analysis.
  • MDA-MB-231 cell-derived mammospheres were treated with 5-desmethylsinensetin (20 ⁇ M) for 48 hours, and their total and nuclear proteins were extracted and analyzed by SDS-PAGE (8% or 10% ) and then transferred to PVDF (Millipore, Billerica, MA, USA), followed by phosphate buffered saline with Tween 20 (PBST) containing Odyssey blocking buffer (927-70001, LI-COR, Lincoln, NB, USA). , 0.1%, v/v) for 60 minutes at room temperature.
  • the membrane was incubated with p-Stat3 (#9145s, Cell Signaling Technology, Denver, CO, USA); Stat3 and sc-482; NF ⁇ p65 and sc-8008; YAP1 (FNab09559, FineTest, Wuhan, China); Incubation was performed overnight at 4°C in blocking buffer containing primary antibodies against Lamin B, sc-6216, ⁇ tin, and sc-47778 (Santa Cruz Biotechnology, Dallas, TX, USA).
  • EMSA Electrophoretic mobility shift assay
  • MDA-MB-231 cell-derived mammospheres were treated with 5-desmethylsinensetin (20 ⁇ M) for 48 hours, and the nuclear extract thereof was incubated with Mol. Pharmacol. 67 (5) (2005) 1674-1683.
  • Nuclear extracts were incubated with IRDye-labeled Stat3-specific probes and incubated with wild-type Stat3 oligonucleotides (positive control) or mutant Stat3 oligonucleotides (negative control). ) and were incubated at room temperature for 10 minutes, respectively.
  • EMSA for Stat3 binding was performed for 20 minutes at room temperature using IRDye 700-labeled special Stat3 oligonucleotide (LI-COR). Samples were mixed with a loading die, electrophoresed on a 6% native PAGE gel, and EMSA data were obtained using ODYSSEY CLx (LI-COR).
  • 5-desmethylsinensetin The levels of human IL-6 and IL-8 secreted in the culture medium of MDA-MB-231-derived mammospheres treated with methylsinensetin (20 ⁇ M) or DMSO for 48 hours were measured using BDTMCBA (Cytometric Bead array). It was confirmed on a flow cytometer (BD, Accuri C6, San Jose, CA, USA) using an inflammatory cytokine analysis kit.
  • YAP1 a transcriptional coactivator involved in the Hippo pathway
  • Stat3 was knocked down.
  • the Stat3-YAP1 pathway induced by 5-desmethylsinensetin was confirmed in breast cancer cell lines.
  • human Stat3-specific siRNAs Booneer, Daejeon, Korea
  • human YAP-specific siRNAs (Bioneer) were added to the MDA-MB-231 cell line or its mammospheres using Lipofectamine 3000 (Invitrogen, Carlsbad, CA, USA).
  • 5-desmethylsinensetin inhibits the movement of YAP1 to the nucleus through Stat3 inhibition.

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Abstract

La présente invention se rapporte à l'efficacité d'un extrait d'Artemisia princeps, à un fractionnement de ce dernier, et à un composé isolé à partir de ce dernier destiné au traitement du cancer. L'extrait d'Artémisia princeps et un fractionnement de ce dernier de la présente invention inhibent la formation de cellules souches cancéreuses, et la 5-desméthylsinensetine isolée de ces derniers inhibe la prolifération, la formation tumorale et la métastase de cellules cancéreuses, et inhibe la formation et la croissance de cellules souches cancéreuses pour les tuer, et ainsi la présente invention peut être efficacement utilisée pour prévenir ou traiter le cancer, en particulier le cancer résistant au traitement, provoqué par des cellules souches cancéreuses.
PCT/KR2022/008472 2022-05-19 2022-06-15 Composition anticancéreuse contenant un extrait d'artemisia princeps Ceased WO2023224163A1 (fr)

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WO2000019998A1 (fr) * 1998-10-06 2000-04-13 Kgk Synergize Compositions et procedes pouvant inhiber des maladies neoplastiques au moyen de composes apparentes a limocitrine et 5-desmethyl-sinensetine

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HAN HYE-YEON, KIM HYUNG JOON, JEONG SEUNG-HWA, KIM JIYEON, JEONG SUNG-HEE, KIM GYOO CHEON, HWANG DAE-SEOK, KIM UK-KYU, RYU MI HEON: "The Flavonoid Jaceosidin from Artemisia princeps Induces Apoptotic Cell Death and Inhibits the Akt Pathway in Oral Cancer Cells", EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE, OXFORD UNIVERSITY PRESS, US, vol. 2018, 1 January 2018 (2018-01-01), US , pages 1 - 9, XP093109412, ISSN: 1741-427X, DOI: 10.1155/2018/5765047 *
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