WO2020106051A2 - Composition pharmaceutique à utiliser dans la prévention ou le traitement du cancer, comprenant à la fois de la streptonigrine et un agent anticancéreux - Google Patents

Composition pharmaceutique à utiliser dans la prévention ou le traitement du cancer, comprenant à la fois de la streptonigrine et un agent anticancéreux

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Publication number
WO2020106051A2
WO2020106051A2 PCT/KR2019/015908 KR2019015908W WO2020106051A2 WO 2020106051 A2 WO2020106051 A2 WO 2020106051A2 KR 2019015908 W KR2019015908 W KR 2019015908W WO 2020106051 A2 WO2020106051 A2 WO 2020106051A2
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WIPO (PCT)
Prior art keywords
cancer
gemcitabine
streptonigrin
streptonigreen
bortezomib
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PCT/KR2019/015908
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English (en)
Korean (ko)
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WO2020106051A3 (fr
Inventor
김수열
이호
심성훈
Original Assignee
(주)엠디바이오랩
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Publication of WO2020106051A2 publication Critical patent/WO2020106051A2/fr
Publication of WO2020106051A3 publication Critical patent/WO2020106051A3/fr

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    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/69—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention is streptoni green; And one or more additional anti-cancer agents selected from the group consisting of bortezomib, rapamycin and gemcitabine; It relates to a pharmaceutical composition or an anti-cancer adjuvant for use in the prevention or treatment of cancer comprising all.
  • the present invention is streptoni green; And one or more additional anti-cancer agents selected from the group consisting of bortezomib, rapamycin and gemcitabine; It relates to a cancer prevention or treatment method comprising the step of administering a pharmaceutical composition comprising all of the.
  • Cancer cells can perform regular and elastic proliferation and suppression as needed, whereas cancer cells proliferate indefinitely, which is also called a tumor as a cell mass composed of undifferentiated cells. These cancer cells penetrate into surrounding tissues and metastasize to other organs of the body, causing severe pain and eventually death.
  • a tumor as a cell mass composed of undifferentiated cells.
  • These cancer cells penetrate into surrounding tissues and metastasize to other organs of the body, causing severe pain and eventually death.
  • the number of cancer patients in Korea has increased continuously, increasing by about 44% in the last 10 years, and the market for anticancer drugs has also increased internationally, and has been reported to have a size of about 100 billion dollars per year.
  • Anticancer drugs are chemotherapy drugs, which are first-generation anti-cancer drugs, and targeted anti-cancer drugs, which are second-generation anti-cancer drugs.
  • immuno-cancer drugs have been developed as third-generation anti-cancer drugs and research is ongoing.
  • the biggest problem in the treatment of cancer is the recurrence of cancer, which is why it is difficult to target a specific cancer due to various mutations in cancer, and resistance to anticancer drugs used in the treatment of recurrent cancer occurs. This is because the case is non-existent.
  • a strategy to combine and treat the anti-cancer agent has been proposed.
  • Transglutaminase (Transglutaminase 2, TGase2) is an enzyme that promotes the binding between ⁇ -carboxamide groups of glutamine residues bound to specific peptides and various amines, and primarily promotes the prevention, repair, and repair of damage.
  • TGase2 Transglutaminase 2, TGase2
  • TGase2 is an enzyme that promotes the binding between ⁇ -carboxamide groups of glutamine residues bound to specific peptides and various amines, and primarily promotes the prevention, repair, and repair of damage.
  • diseases such as neurodegenerative diseases, atherosclerosis, inflammatory diseases, and autoimmune diseases.
  • TGase2 polymerizes and destabilizes p53 and thus disappears. Accordingly, it has been reported that the inhibition of TGase2 may have an anti-cancer effect on overexpressed kidney cancer.
  • Republic of Korea Patent Publication No. 10-2016-0009146 provides a pharmaceutical composition for treating or preventing a disease caused by an increase in transglutaminase 2 activity including streptonigreen, pancreatic cancer, uterine cancer to the disease It is disclosed that breast cancer is included.
  • the present inventors tried to provide a composition having a significantly elevated anti-cancer effect by using streptonigrin and other anti-cancer agents, and as a result, streptonirin and bortezomib, rapamycin, or gemcitabine were used in combination to form cancer cells, particularly breast cancer.
  • streptonirin and bortezomib, rapamycin, or gemcitabine were used in combination to form cancer cells, particularly breast cancer.
  • the object of the present invention is streptoni green; And one or more additional anti-cancer agents selected from the group consisting of bortezomib, rapamycin and gemcitabine; It provides a pharmaceutical composition, an anti-cancer adjuvant to a method for preventing or treating cancer, comprising all of which is used for preventing or treating cancer.
  • the present invention is a streptoni green; And one or more additional anti-cancer agents selected from the group consisting of bortezomib, rapamycin and gemcitabine; It provides a pharmaceutical composition or an anti-cancer adjuvant for use in the prevention or treatment of cancer comprising all.
  • the streptonigreen and the additional anti-cancer agent may be included in a concentration ratio of 0.01: 1 to 100000: 1.
  • the streptonigreen and the additional anticancer agent may be included in a concentration ratio of 1: 0.1 to 1: 100000.
  • the cancer may be breast cancer.
  • the present invention is streptoni green; And one or more additional anti-cancer agents selected from the group consisting of bortezomib, rapamycin and gemcitabine; It provides a method for preventing or treating cancer comprising the step of administering to a patient a pharmaceutical composition comprising all.
  • the streptonigreen and the additional anti-cancer agent may be included in a concentration ratio of 0.01: 1 to 100000: 1.
  • the streptonigreen and the additional anticancer agent may be included in a concentration ratio of 1: 0.1 to 1: 100000.
  • the cancer may be breast cancer.
  • the anti-cancer effect can be exhibited by using the transglutaminase (TGase2) inhibitory effect of streptonigreen, and when used in combination with the anti-cancer agent, the anticancer effect is significantly increased. No studies or descriptions of synergistic effects have been disclosed.
  • TGase2 transglutaminase
  • composition comprising both streptonigreen and other anticancer agents according to the present invention inhibits the growth or growth of cancer, it generates a significant anticancer effect, and thus can be effectively used in cancer prevention or treatment compositions, anticancer adjuvants or cancer prevention or treatment Can be.
  • the present invention is a streptonigrin (streptonigrin); And any one or more additional anticancer agents selected from the group consisting of bortezomib, rapamycin and gemcitabine; It can provide a pharmaceutical composition for use in the prevention or treatment of cancer comprising all.
  • the Streptonigreen is a Tgase2 inhibitor produced by Streptomyces floculus, and refers to an antibiotic that causes chromosomal cleavage.
  • the bortezomib is an anticancer agent and a proteasome inhibitor for treatment, and serves to inhibit the degradation of proteins that kill cancer cells.
  • the rapamycin is an antifungal or anticancer agent produced by Streptomyces hygroscopicus, and has an immunosuppressive effect by reducing the sensitivity of T cells or B cells to IL-2 through mTOR inhibition.
  • the gemcitabine (gemcitabine) is an anti-cancer agent of the nucleoside analog drug group, induces apoptosis by preventing the production of new DNA.
  • the additional anti-cancer agent means an anti-cancer agent that may be included in the pharmaceutical composition of the present invention in addition to streptonigrin, and refers to bortezomib, rapamycin, or gemcitabine. Additional anticancer agents such as bortezomib, rapamycin, or gemcitabine may all be included, but are preferably included alone.
  • the streptonigreen and the additional anticancer agent are preferably included in a concentration ratio of 0.01: 1 to 100000: 1, but are not limited thereto.
  • streptonigreen and bortezomib are preferably included in a concentration ratio of 0.1: 1 to 10000: 1, but more preferably are included in a concentration ratio of 1: 1 to 1000: 1.
  • Streptonigreen and rapamycin are preferably included in a concentration ratio of 0.1: 1 to 10000: 1, more preferably in a concentration ratio of 1: 1 to 5000: 1.
  • streptonigreen and gemcitabine are preferably included in a concentration ratio of 1: 0.1 to 1: 100000, but more preferably, in a concentration ratio of 1: 1 to 1: 10000. It is preferred.
  • the cancer of the present invention is breast cancer.
  • the pharmaceutical composition for use in the prevention or treatment of cancer of the present invention may be various oral or parenteral formulations.
  • buffers e.g. saline or PBS
  • antioxidants e.g. bacteriostatic agents
  • chelating agents e.g. EDTA or glutathione
  • fillers e.g. extenders, binders
  • adjuvants e.g. Aluminum hydroxide
  • suspending agents thickener wetting agents, disintegrating agents or surfactants, diluents or excipients.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc. These solid preparations include at least one excipient in one or more compounds, such as starch (corn starch, wheat starch, rice starch, potato Starch, etc.), calcium carbonate, sucrose, lactose, dextrose, sorbitol, mannitol, xylitol, erythritol maltitol, cellulose, methyl cellulose, sodium carboxymethylcellulose and hydroxypropylmethyl -It is prepared by mixing cellulose or gelatin. For example, tablets or dragees can be obtained by blending the active ingredient with a solid excipient and then grinding it and adding a suitable adjuvant to the granular mixture.
  • starch corn starch, wheat starch, rice starch, potato Starch, etc.
  • calcium carbonate sucrose, lactose, dextrose, sorbitol, mannitol, xylitol, ery
  • lubricants such as magnesium stearate, talc and the like are used in addition to simple excipients.
  • Liquid preparations for oral administration include suspending agents, intravenous solutions, emulsions or syrups, etc.
  • simple diluents such as water and liquid paraffin
  • various excipients such as wetting agents, sweeteners, flavoring agents or preservatives, etc. are included.
  • cross-linked polyvinylpyrrolidone, agar, alginic acid, or sodium alginate may be added as a disintegrant, and may further include an anti-coagulant, lubricant, wetting agent, fragrance, emulsifier, and preservative. .
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspension solutions, emulsions, lyophilized preparations or suppositories.
  • non-aqueous solvent and suspension solvent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used.
  • injectable ester such as ethyl oleate
  • a base for suppositories witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, gelatin, etc. may be used.
  • composition of the present invention may be administered orally or parenterally, and for parenteral administration, external application to the skin; Injections that are injected intraperitoneally, rectal, intravenous, intramuscular, subcutaneous, intrauterine dura mater or cerebrovascular; Transdermal administration; Alternatively, nasal inhalants may be formulated according to methods known in the art.
  • suitable carriers include, but are not limited to, solvents or dispersion media including water, ethanol, polyols (eg, glycerol, propylene glycol and liquid polyethylene glycol, etc.), mixtures thereof and / or vegetable oils.
  • suitable carriers include Hanks' solution, Ringer's solution, phosphate buffered saline (PBS) with triethanol amine or sterile water for injection, isotonic solutions such as 10% ethanol, 40% propylene glycol and 5% dextrose. Etc. can be used.
  • various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid, thimerosal, etc. may be further included.
  • the injection may additionally contain isotonic agents such as sugars or sodium chloride in most cases.
  • transdermal administration means that the pharmaceutical composition is topically administered to the skin, so that an effective amount of the active ingredient contained in the pharmaceutical composition is delivered into the skin.
  • the compounds used according to the invention may be used in the form of pressurized packs, using suitable propellants, for example dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gases. It can be conveniently delivered in the form of an aerosol spray from a nebulizer.
  • the dosage unit can be determined by providing a valve that delivers a metered amount.
  • gelatin capsules and cartridges used in inhalers or insufflators can be formulated to contain a powder mixture of a compound and a suitable powder base such as lactose or starch.
  • the pharmaceutical composition for use in the prevention or treatment of cancer of the present invention is administered in a pharmaceutically effective amount.
  • a pharmaceutically effective amount means an amount sufficient to treat the disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level is the patient's disease type, severity, drug activity, sensitivity to the drug, and administration time. , The route of administration and rate of excretion, duration of treatment, factors including co-drugs and other factors well known in the medical field.
  • the composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with a conventional therapeutic agent, and may be administered single or multiple.
  • the total effective amount of the composition of the present invention can be administered to a patient in a single dose, and can be administered by a fractionated treatment protocol that is administered for a long time in multiple doses. . Considering all of the above factors, it is important to administer an amount that can achieve the maximum effect in a minimal amount without side effects, which can be easily determined by those skilled in the art.
  • the dosage of the pharmaceutical composition of the present invention may vary depending on the patient's weight, age, sex, health status, diet, administration time, administration method, excretion rate, and disease severity.
  • a daily dose when administered parenterally, it is preferably administered in an amount of 0.01 to 50 mg per kg of body weight per day, more preferably 0.1 to 30 mg per kg of body weight per day, based on streptonigreen and an anticancer agent used in combination, and orally
  • it can be divided into 1 to several times to be administered in an amount of preferably 0.01 to 100 mg, more preferably 0.01 to 10 mg per 1 kg of body weight per day, based on the streptonigrin of the present invention and an anticancer agent used in combination. have.
  • the dosage since the dosage may be increased or decreased depending on the route of administration, the severity of obesity, sex, weight, and age, the above dosage does not limit the scope of the present invention in any way.
  • composition of the present invention may be used alone or in combination with methods using surgery, radiation therapy, hormonal therapy, chemotherapy and biological response modifiers.
  • the pharmaceutical composition of the present invention can also be provided as a formulation of an external preparation containing streptonigreen and an anticancer agent used in combination therewith as an active ingredient.
  • an external preparation for skin, fat substances, organic solvents, solubilizers, thickeners and gelling agents, emollients, antioxidants, suspending agents, stabilizers, blowing agents (foaming agent), fragrance, surfactant, water, ionic emulsifier, nonionic emulsifier, filler, metal ion blocker, chelating agent, preservative, vitamin, blocker, wetting agent, essential oil, dye, pigment, hydrophilic active agent, It may contain adjuvants commonly used in the field of skin science, such as lipophilic actives or any other ingredients commonly used in external skin preparations such as lipid vesicles. In addition, the ingredients may be introduced in an amount commonly used in the field of skin science.
  • the pharmaceutical composition for use in the prevention or treatment of cancer of the present invention is provided as an external preparation for skin
  • the present invention is not limited thereto, and may be a formulation such as ointment, patch, gel, cream or spray.
  • the present invention is a streptonigrin (streptonigrin); And any one or more additional anticancer agents selected from the group consisting of bortezomib, rapamycin and gemcitabine; It can provide an anti-cancer adjuvant containing all.
  • the streptonigrin, bortezomib, rapamycin and gemcitabine are the same as those used in the composition for preventing or treating cancer, so the description is replaced by the above description.
  • the anti-cancer adjuvant of the present invention means all forms for enhancing the anti-cancer effect of the anti-cancer agent or suppressing or improving side effects of the anti-cancer agent.
  • the anti-cancer adjuvant of the present invention may be administered in combination with various types of anti-cancer agents or anti-cancer adjuvants. Treatment can be performed.
  • the route of administration of the anticancer adjuvant may be administered through any general route as long as it can reach the target tissue.
  • the anti-cancer adjuvant of the present invention may be administered intraperitoneally, intravenously, intramuscularly, subcutaneously, orally, pulmonarily, intrarectally, as desired, but is not limited thereto.
  • the anti-cancer adjuvant may be administered by any device capable of transporting the active substance to the target cell.
  • the anticancer adjuvant of the present invention can be preferably formulated as an anticancer adjuvant by including at least one pharmaceutically acceptable carrier in addition to the active ingredient for administration.
  • Carriers, excipients, or diluents that may be included in the anticancer treatment adjuvant of the present invention 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.
  • the anti-cancer adjuvant of the present invention may be an agent for oral or parenteral administration, and the description of the agent is replaced by the description of the agent of the pharmaceutical composition.
  • the present invention is a streptonigrin (streptonigrin); And any one or more additional anticancer agents selected from the group consisting of bortezomib, rapamycin and gemcitabine; It may provide a method for preventing or treating cancer, comprising the step of administering a pharmaceutical composition comprising all to a patient.
  • streptonigrin streptonigrin
  • additional anticancer agents selected from the group consisting of bortezomib, rapamycin and gemcitabine
  • the streptonigrin, bortezomib, rapamycin, gemcitabine, and pharmaceutical compositions are the same as those used in the pharmaceutical compositions for use in the prevention or treatment of cancer, so the description is replaced by the above description.
  • the administration is a concept including both administration of streptonigreen and bortezomib, rapamycin or gemcitabine simultaneously or sequentially.
  • the cancer is breast cancer.
  • the composition comprising both the streptonigreen and other anti-cancer agents of the present invention is effective as a composition for preventing or treating cancer because it has an excellent effect of inhibiting the growth of cancer cells, especially the effect of inhibiting the growth of breast cancer cells.
  • Figure 1 shows the size of the tumor when treated with a breast cancer tumor (MDA-MB-231 cells) in combination with a solvent (DMSO 1%, PBS 99%), streptonigrin, gemcitabine or streptonigrin and gemcitabine. It was confirmed that the tumor size was most significantly reduced when treated with streptonigrin and gemcitabine in combination with a solvent or a single treatment group.
  • a solvent DMSO 1%, PBS 99%
  • Figure 2 shows the volume of the tumor when treated in combination with a breast cancer tumor (MDA-MB-231 cells) in a solvent (DMSO 1%, PBS 99%), streptonigreen, gemcitabine or streptonigrin and gemcitabine. It was confirmed that the tumor volume was most significantly reduced when treated with streptonigrin and gemcitabine in combination with a solvent or a single treatment group.
  • Figure 3 shows the weight of the tumor when treated in combination with a breast cancer tumor (MDA-MB-231 cells) solvent (DMSO 1%, PBS 99%), streptonigreen, gemcitabine or streptonigreen and gemcitabine. It was confirmed that the weight of the tumor decreased most significantly when treated with streptonigrin and gemcitabine in combination with the solvent or alone treatment group.
  • MDA-MB-231 cells breast cancer tumor
  • solvent DMSO 1%, PBS 99%
  • Figure 4 shows the growth of the cells when treated with a solvent (DMSO 1%, PBS 99%), streptonigrin or bortezomib alone, or a combination of streptonigrin and bortezomib in breast cancer cells. It was confirmed that the growth rate of breast cancer cells was significantly reduced when treated with streptonigrin and bortezomib in combination with a solvent or a single treatment group.
  • a solvent DMSO 1%, PBS 99%
  • FIG. 5 shows changes in cell growth when breast cancer cells are treated with a solvent (DMSO 1%, PBS 99%), streptonigreen or rapamycin alone, or in combination with streptonigreen and rapamycin. It was confirmed that the growth rate of breast cancer cells was significantly decreased when streptonigrin and rapamycin were treated in combination with a solvent or a single treatment group.
  • a solvent DMSO 1%, PBS 99%
  • FIG. 6 shows changes in cell growth when breast cancer cells were treated with a solvent (DMSO 1%, PBS 99%), streptonigreen or gemcitabine (100 nM) alone or in combination with streptonigreen and gemcitabine. It was confirmed that the growth rate of breast cancer cells was significantly decreased when streptonigrin and gemcitabine were used in combination with a solvent or a single treatment group.
  • a solvent DMSO 1%, PBS 99%
  • streptonigreen or gemcitabine 100 nM
  • FIG. 7 shows changes in cell growth when breast cancer cells were treated with a solvent (DMSO 1%, PBS 99%), streptonigreen or gemcitabine (10 ⁇ M) alone or in combination with streptonigreen and gemcitabine. It was confirmed that the growth rate of breast cancer cells was significantly decreased when streptonigrin and gemcitabine were used in combination with a solvent or a single treatment group.
  • a solvent DMSO 1%, PBS 99%
  • FIG. 8 shows changes in cell growth when breast cancer cells are treated with a solvent (DMSO 1%, PBS 99%), streptonigreen or doxorubicin alone or in combination with streptonigreen and doxorubicin. It was confirmed that the synergistic effect by the combination treatment did not appear.
  • a solvent DMSO 1%, PBS 99%
  • FIG. 9 shows changes in cell growth when breast cancer cells are treated solely with solvent (DMSO 1%, PBS 99%), streptonigrin or paclitaxel, or when streptonigrin and paclitaxel are used in combination. It was confirmed that the synergistic effect by the combination treatment did not appear.
  • FIG. 10 shows changes in cell growth when breast cancer cells are treated with solvent (DMSO 1%, PBS 99%), streptonigreen, pazopanib, or streptonigreen and pazopanib in combination. It was confirmed that the synergistic effect by the combination treatment did not appear.
  • solvent DMSO 1%, PBS 99%
  • a preclinical xenograft tumor model was prepared to confirm the effect of streptonigreen and / or gemcitabine on breast cancer tumors.
  • mice were induced in Balb / c-nu mice (Central Lab Animal, Seoul, Korea) of 6 to 8 weeks of age.
  • MDA-MB-231 cells (1.0 ⁇ 10 7 ) were inoculated subcutaneously using a 1 ml syringe. After 2 weeks, mice were treated with solvent (DMSO 1%, PBS 99%), streptonigrin, gemcitabine or streptonigrin and gemcitabine (streptonigrin 0.1 mg / kg / 100 ⁇ l (PO), gemcitabine 100 mg / Kg / 100 ⁇ l (IP), 6 animals in each group).
  • solvent DMSO 1%, PBS 99%
  • streptonigrin 0.1 mg / kg / 100 ⁇ l (PO)
  • gemcitabine 100 mg / Kg / 100 ⁇ l (IP), 6 animals in each group).
  • Breast cancer cells MDA-MB-231, MDA-MB-468, T47D, MCF7 and BT549 cells were received in the laboratory of ph.D Heo Kyun.
  • the breast cancer cells were cultured in a complete RPMI 1640 medium (Hyclone, UT, USA) containing 10% fetal bovine serum (Hyclone, UT, USA) in an environment of 5% CO 2, 100% humidity and 37 ° C.
  • cells 100 ⁇ l were seeded in 96-well microtiter plates with plating densities of 5000 to 40000 cells / well depending on the doubling time of individual cell lines. After cell inoculation, the cells were cultured for 24 hours prior to the addition of the experimental drug. After 100 ⁇ l of each drug was added to each well, the plate was incubated for 48 hours in a 37 ° C. CO 2 incubator. Cells were treated with cold 50% TCA (trichloroacetic acid, 50 ⁇ l / well), and then incubated at 4 ° C. for 60 minutes to fix the cells. The supernatant was discarded, washed 5 times with tap water and naturally dried at room temperature for 12 to 24 hours.
  • TCA trichloroacetic acid
  • GI50 0.4% (w / v) solution of sulforhodamine B (100 ⁇ l) in 1% acetic acid was added to each well, and the plate was left at room temperature for 10 minutes. After staining, washing was performed 5 times with 1% acetic acid to remove non-binding dyes and allowed to air dry. The bound dye was then solubilized with 10 mM Trizma base and absorbance was recorded using an automated plate reader at 515 nm. The effect of the drug was expressed as GI50 (50% growth inhibition), TGI (total growth inhibition) or LC50 (lethal concentration).
  • the concentration of each drug is 10nM, 0.1 ⁇ M or 1 ⁇ M for streptonigreen, 10nM or 50nM for bortezomib, 1nM or 10nM for rapamycin, 100nM or 10nM for gemcitabine, 100nM or 500nM for doxorubicin, Paclitaxel is 10 nM or 100 nM, pazopanib is 5 ⁇ M or 10 ⁇ M.
  • Streptonigrin provided in the present invention (streptonigrin); And any one or more additional anticancer agents selected from the group consisting of bortezomib, rapamycin and gemcitabine; Since the composition containing all has excellent synergistic effect and inhibits cancer, especially breast cancer, it can be effectively used in a pharmaceutical composition, an anticancer adjuvant, or a cancer prevention or treatment method using the same for preventing or treating cancer, There is great industrial availability.

Abstract

La présente invention concerne une composition pharmaceutique ou un adjuvant anticancéreux à utiliser dans la prévention ou le traitement du cancer, la composition ou l'adjuvant comprenant à la fois : de la streptonigrine ; et au moins un agent anticancéreux supplémentaire choisi dans le groupe constitué par le bortézomib, la rapamycine et la gemcitabine. De plus, la présente invention concerne une méthode de prévention ou de traitement du cancer, laquelle comprend une étape d'administration à un patient d'une composition pharmaceutique comprenant là la fois : de la streptonigrine ; et au moins un agent anticancéreux supplémentaire choisi dans le groupe constitué par le bortézomib, la rapamycine et la gemcitabine. Ainsi, la composition comprenant de la streptonigrine et d'autres agents anticancéreux selon la présente invention a un excellent effet d'inhibition de la croissance des cellules cancéreuses, en particulier, des cellules du cancer du sein et, en tant que telle, peut être efficacement utilisée dans une composition de prévention ou de traitement du cancer ou une méthode de prévention ou de traitement du cancer l'utilisant.
PCT/KR2019/015908 2018-11-20 2019-11-20 Composition pharmaceutique à utiliser dans la prévention ou le traitement du cancer, comprenant à la fois de la streptonigrine et un agent anticancéreux WO2020106051A2 (fr)

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PCT/KR2019/015907 WO2020106050A1 (fr) 2018-11-20 2019-11-20 Composition pharmaceutique comprenant à la fois de la streptonigrine et un agent anticancéreux pour empêcher ou traiter le cancer
PCT/KR2019/015906 WO2020106049A1 (fr) 2018-11-20 2019-11-20 Composition pharmaceutique comprenant à la fois de la streptonigrine et un agent anti-cancéreux permettant la prévention ou le traitement d'un cancer

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PCT/KR2019/015906 WO2020106049A1 (fr) 2018-11-20 2019-11-20 Composition pharmaceutique comprenant à la fois de la streptonigrine et un agent anti-cancéreux permettant la prévention ou le traitement d'un cancer

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US6482802B1 (en) * 1998-05-11 2002-11-19 Endowment For Research In Human Biology, Inc. Use of neomycin for treating angiogenesis-related diseases
EP1599196A4 (fr) * 2003-01-17 2006-05-31 Threshold Pharmaceuticals Inc Polytherapies anticancereuses
US7354580B2 (en) * 2004-06-10 2008-04-08 Regeneron Pharmaceuticals, Inc. Method of administering and using VEGF inhibitors for the treatment of human cancer
CA2570887C (fr) * 2004-06-18 2014-09-16 Genentech, Inc. Traitement tumoral
US7939564B2 (en) * 2006-08-31 2011-05-10 Synta Pharmaceuticals Corp. Combination with bis(thiohydrazide amides) for treating cancer
KR101643459B1 (ko) * 2014-07-15 2016-07-28 국립암센터 스트렙토니그린을 포함하는 트랜스글루타미나제２ 관련 질환 치료 또는 예방용 약제학적 조성물 및 이의 용도
KR102147721B1 (ko) * 2017-10-24 2020-08-25 (주)엠디바이오랩 스트렙토니그린 및 라파마이신을 유효성분으로 포함하는, 암 예방 또는 치료용 약학적 조성물
CN108703958B (zh) * 2018-08-11 2021-02-23 西华大学 一种协同链黑菌素制备抗肿瘤纳米组合药物的方法

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KR102387565B1 (ko) 2022-04-18
KR20200059177A (ko) 2020-05-28
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WO2020106050A1 (fr) 2020-05-28
KR102387564B1 (ko) 2022-04-18

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