WO2020138548A1 - Composition pharmaceutique et aliment fonctionnel de santé contenant chacun de la delphinidine - Google Patents

Composition pharmaceutique et aliment fonctionnel de santé contenant chacun de la delphinidine Download PDF

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Publication number
WO2020138548A1
WO2020138548A1 PCT/KR2018/016784 KR2018016784W WO2020138548A1 WO 2020138548 A1 WO2020138548 A1 WO 2020138548A1 KR 2018016784 W KR2018016784 W KR 2018016784W WO 2020138548 A1 WO2020138548 A1 WO 2020138548A1
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WO
WIPO (PCT)
Prior art keywords
delphinidin
osteosarcoma
functional food
health functional
autophagy
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PCT/KR2018/016784
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English (en)
Korean (ko)
Inventor
김동희
Original Assignee
경상대학교병원
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Priority to PCT/KR2018/016784 priority Critical patent/WO2020138548A1/fr
Publication of WO2020138548A1 publication Critical patent/WO2020138548A1/fr

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a pharmaceutical composition for preventing or treating osteosarcoma containing delphinidin and a health functional food for preventing or improving osteosarcoma.
  • delphinidin is known to inhibit the normalization of cancer cells and the proliferation of cancer cells during tumorigenesis, and induces cell death in cancer cells such as breast cancer, colorectal cancer, liver cancer, lung cancer, prostate cancer, and skin cancer.
  • cancer cells such as breast cancer, colorectal cancer, liver cancer, lung cancer, prostate cancer, and skin cancer.
  • delphinidin there are no studies on the treatment mechanism using delphinidin in osteosarcoma.
  • An object of the present invention is to provide a pharmaceutical composition for preventing or treating osteosarcoma containing delphinidin and a health functional food for preventing or improving osteosarcoma.
  • a pharmaceutical composition for preventing or treating osteosarcoma comprising delphinidin.
  • composition of 1 above, wherein the composition further comprises an autophagy inhibitor 2. The composition of 1 above, wherein the composition further comprises an autophagy inhibitor.
  • the health functional food is a health functional food further comprising an autophagy inhibitor.
  • the autophagy inhibitor is at least one selected from the group consisting of 3MA, BafA1, SP600125, U0126, chloroquine, LY294002, SB202190, SB203580, SC79 and bortmannin.
  • the pharmaceutical composition of the present invention has excellent osteosarcoma prevention or treatment effect including delphinidin, and the health functional food of the present invention has excellent osteosarcoma prevention or improvement effect including delphinidin.
  • Figure 1 shows a graph (A) of the results of analyzing the survival rate of osteosarcoma cells in a concentration-dependent manner of delphinidin by MTT assay and micrographs (B) of each concentration-treated group.
  • Figure 2 is a micrograph (A) and graph (B) confirming the ROS generation of delphinidin induction, it can be seen that the cell viability reduction is not confirmed in the group pretreated with delphinidin and NAC.
  • FIG. 3 confirms that delphinidin induces the formation of autophagy through the expression and time-dependent increase of delphinidin expression of LC3-II.
  • 6 is to evaluate the potential mechanism of cell cycle arrest and cell death by delphinidin, cells were cultured together at different concentrations of delphinidin for 24 hours, and protein levels were measured.
  • Osteosarcoma is the most common primary malignant tumor (cancer) that develops in the bone, most commonly occurring during the growing teens and a little more common in men.
  • the frequency of occurrence in the United States is known to occur about 500 to 1,000 people per year, and it is estimated that about 100 people per year occur in Korea. It can occur anywhere on the human bones, such as the arms, legs, and pelvis, but the most common area is the bones around the knee. It is a common symptom that a cancerous area is sore or swollen.
  • the present invention provides a pharmaceutical composition for preventing or treating osteosarcoma comprising delphinidin.
  • the autophagy inhibitor may be at least one selected from the group consisting of 3MA, BafA1, SP600125, U0126, chloroquine, LY294002, SB202190, SB203580, SC79, and bortmannin, but may be combined with delphinidin to inhibit the pathway by autophagy. If possible, it is not particularly limited.
  • composition of the present invention may further include a pharmaceutically acceptable carrier, and may be formulated with a carrier.
  • pharmaceutically acceptable carrier refers to a carrier or diluent that does not stimulate the organism and does not inhibit the biological activity and properties of the administered compound.
  • a pharmaceutical carrier that is acceptable in a composition formulated as a liquid solution, as a sterile and biocompatible material, saline, sterile water, Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol and One or more of these components may be mixed and used, and other conventional additives such as antioxidants, buffers and bacteriostatic agents may be added as necessary.
  • diluents such as aqueous solutions, suspensions, emulsions, pills, capsules, granules or tablets.
  • composition of the present invention can be applied to any formulation containing delphinidin as an active ingredient, and can be prepared in oral or parenteral formulations.
  • the pharmaceutical formulation of the present invention is oral, rectal, nasal, topical (including cheek and sublingual), subcutaneous, vaginal or parenteral; intramuscular and subcutaneous. And intravenous) or forms suitable for administration by inhalation or insufflation.
  • composition of the present invention may further contain a compound that maintains/increases the solubility and/or absorption of one or more active ingredients showing the same or similar function in relation to the treatment of osteosarcoma.
  • chemotherapeutic agents, anti-inflammatory agents, anti-viral agents and/or immunomodulators may be further included.
  • compositions of the present invention can be formulated using methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal.
  • Formulations may be in the form of powders, granules, tablets, emulsions, syrups, aerosols, soft or hard gelatin capsules, sterile injectable solutions, sterile powders.
  • the present invention provides a health functional food for preventing or improving osteosarcoma containing delphinidin.
  • the health functional food may further include an autophagy inhibitor, which may serve to further inhibit osteosarcoma cell death in other pathways by inhibiting the pathway by autophagy among the pathologies of osteosarcoma cell death.
  • an autophagy inhibitor which may serve to further inhibit osteosarcoma cell death in other pathways by inhibiting the pathway by autophagy among the pathologies of osteosarcoma cell death.
  • the autophagy inhibitor may be at least one selected from the group consisting of 3MA, BafA1, SP600125, U0126, chloroquine, LY294002, SB202190, SB203580, SC79, and bortmannin, but may be combined with delphinidin to inhibit the pathway by autophagy. If possible, it is not particularly limited.
  • Examples of the food additives receivable include chemical compounds such as ketones, glycine, calcium citrate, nicotinic acid, and cinnamonic acid; Natural additives such as chromic pigment, licorice extract, crystalline cellulose, high color pigment, and guar gum; L-sodium glutamate formulations, mixed additives such as noodle additive alkalis, preservatives, tar colorants, and the like, but are not limited thereto.
  • the dietary supplement in the form of tablets, is granulated by mixing the mixture of delphinidin with excipients, binders, disintegrants, and other additives in a conventional manner, followed by compression molding with a lubricant, or directly compressing the mixture. It can be molded.
  • the health functional food in the form of tablets may contain a mating agent or the like as necessary.
  • the health functional food in the form of a ring may be prepared by molding a mixture of delphinidin and excipients, a binder, a disintegrant, etc. by a conventionally known method, and may be peeled with a white sugar or other skin repellent if necessary, or starch, The surface may be coated with a material such as talc.
  • the health functional food in the form of granules may be prepared in a granular form by mixing a mixture of delphinidin and excipients, a binder, a disintegrant, etc., and may contain a flavoring agent, a mating agent, and the like, if necessary.
  • U2OS cells Human osteosarcoma derived from U2OS cell line was prepared from Korean Cell Line Bank, Seoul, Korea, and delphinidin was obtained from Extrasynthese (Genay, France).
  • U2OS cells were DMEM/F-12 supplemented with 10% heat inactivated fetal bovine serum (FBS, Gibco), 2 mM L-glutamine and 1% antibiotic-antibiotic (Gibco) (Gibco, Grand Island, NY, USA) Cultured at 37° C. and incubated under humidified 5% CO 2 conditions. Delphinidin was dissolved in DMSO (Sigma Aldrich, St Quentin Fallavier, France) used for vehicle control in all assays.
  • An enhanced chemiluminescence (ECL) detection system was purchased from Amersham (Arlington Heights, IL). Other chemical agents are Sigma Chemical Co. (St. Louis, MO).
  • MTT assay 3-[4, 5-dimethyldiazole-2-yl]-2,5-diphenyl tetrazolium-bromide.
  • Cells were plated on a 96-well microtiter plate in 200 mL complete medium of 1 X 10 4 cells per well, and 0 to 200 ⁇ M of delphinidin was treated for 48 hours in a humidified chamber at 37°C.
  • MTT (5 mg/ml in PBS; diluted in 10 ml of serum-free culture medium) was added to each well, and after further incubation for 2 hours, the plates were centrifuged at 1000 rpm for 5 minutes at 4°C.
  • a 50 ⁇ L green fluorescent protein (GFP)-LC3-labeled transgenic osteosarcoma cell line was cultured to subfusion density. Cells were maintained for 16 hours in a humidified incubator at 37°C. Samples were cultured on cover slides, washed with PBS and fixed with 3% formaldehyde. Then, it was permeated with 0.5% Triton-X100 and then blocked with 1% BSA solution. Confocal microscopy (Olympus FV1000, OLYMPUS, Tokyo, Japan) analysis was performed during reaction with primary and FITC or TRITC-labeled secondary antibodies. GFP-fluorescence was analyzed by confocal microscopy immediately after cell fixation.
  • GFP green fluorescent protein
  • LC3-II known as a marker protein of autophagy induced by delphinidin
  • puncta After induction of autophagy, puncta representing autophagy was recorded 6, 12, and 24 hours after treatment (FIG. 3).
  • FIG. 4A Western blot was used to determine whether delphinidin could promote the formation of autophagy, resulting in degradation of p62 (one of the cargo proteins) and LC3-II (marker of autophagy). It was confirmed that the conversion of was increased in a concentration-dependent manner (p ⁇ 0.001). However, when the cells were pretreated with NAC, it was confirmed that the conversion of LC3-II was reduced (Fig. 4B).
  • Example 6 Inhibitory ability of delphinidin and autophagy inhibitor to inhibit osteosarcoma cell survival

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Mycology (AREA)
  • Nutrition Science (AREA)
  • Engineering & Computer Science (AREA)
  • Food Science & Technology (AREA)
  • Polymers & Plastics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition pharmaceutique pour la prévention ou le traitement de l'ostéosarcome et un aliment fonctionnel de santé pour la prévention ou le soulagement de l'ostéosarcome, la composition pharmaceutique et l'aliment fonctionnel de santé contenant chacun de la delphinidine.
PCT/KR2018/016784 2018-12-27 2018-12-27 Composition pharmaceutique et aliment fonctionnel de santé contenant chacun de la delphinidine WO2020138548A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/KR2018/016784 WO2020138548A1 (fr) 2018-12-27 2018-12-27 Composition pharmaceutique et aliment fonctionnel de santé contenant chacun de la delphinidine

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/KR2018/016784 WO2020138548A1 (fr) 2018-12-27 2018-12-27 Composition pharmaceutique et aliment fonctionnel de santé contenant chacun de la delphinidine

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WO2020138548A1 true WO2020138548A1 (fr) 2020-07-02

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002322055A (ja) * 2001-04-26 2002-11-08 Sanei Gen Ffi Inc デルフィニジン化合物を含有する制癌剤
US20040132672A1 (en) * 2000-01-28 2004-07-08 Board Of Trustees Of Michigan State University Method for inhibiting cancer cells
KR20180069534A (ko) * 2016-12-15 2018-06-25 고려대학교 산학협력단 델피니딘을 포함하는 상피성 난소암 예방 또는 치료용 약학적 조성물

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040132672A1 (en) * 2000-01-28 2004-07-08 Board Of Trustees Of Michigan State University Method for inhibiting cancer cells
JP2002322055A (ja) * 2001-04-26 2002-11-08 Sanei Gen Ffi Inc デルフィニジン化合物を含有する制癌剤
KR20180069534A (ko) * 2016-12-15 2018-06-25 고려대학교 산학협력단 델피니딘을 포함하는 상피성 난소암 예방 또는 치료용 약학적 조성물

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DONG-YEONG LEE, PARK YOUNG-JIN, HWANG SUN-CHUL, KIM KWANG-DONG, MOON DONG-KYU, KIM DONG-HEE: "Cytotoxic effects of delphinidin in human osteosarcoma cells", ACTA ORTHOPAEDICA ET TRAUMATOLOGICA TURCICA, 28 December 2017 (2017-12-28), pages 58 - 64, XP055721902 *
HAE-MI KANG, BONG-SOO PARK, HYUN-KYUNG KANG, HAE-RYOUN PARK, SU-BIN YU, IN-RYOUNG KIM: "Delphinidin induces apoptosis and inhibits epithelial-to- mesenchymal transition via the ERK/p38 MAPK-signaling pathway in human osteosarcoma cell lines", ENVIRONMENTAL TOXICOLOGY, 6 June 2018 (2018-06-06), pages 640 - 649, XP055721906 *

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