WO2018128510A1 - 전이성 난소암, 자궁내막암 또는 유방암의 예방 또는 치료용 조성물 - Google Patents
전이성 난소암, 자궁내막암 또는 유방암의 예방 또는 치료용 조성물 Download PDFInfo
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- 0 CCN(CC1)CCN1*1ccc(*c2ncnc(N(C)C(*c(c(Cl)c(cc3*C)[U]C)c3Cl)=O)c2)cc1 Chemical compound CCN(CC1)CCN1*1ccc(*c2ncnc(N(C)C(*c(c(Cl)c(cc3*C)[U]C)c3Cl)=O)c2)cc1 0.000 description 2
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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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
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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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
Definitions
- the present invention relates to a pharmaceutical composition or nutraceutical for preventing or treating metastatic ovarian cancer, endometrial cancer or breast cancer.
- Ovarian cancer is the cancer with the highest mortality rate among all gynecological cancers, and its frequency has steadily increased with the recent westernization of lifestyles and the aging population.
- ovarian cancer there is no clear symptom in the early stage, so about 70% or more patients are first detected as advanced stage ovarian cancer with more than 3 stages, and about 75% or more patients have reported recurrence and metastasis within 2 years after the initial treatment.
- the method of treating ovarian cancer is determined according to the type and stage of the cancer, and there are surgical treatments and combination therapy, but they are not very effective in treating metastatic cancer caused by relapse. This is because cancer metastasis involves induction of neovascularization and cell migration, which is different from cancer itself, and in order to prevent cancer metastasis, it is necessary to inhibit neovascularization and cell migration. This is because the effects and anticancer effects are different from each other.
- Ovarian cancer does not show any special symptoms, so it is difficult to detect early, and most cases of ovarian cancer have been diagnosed as cancers.
- cancer cells infiltrate into surrounding tissues or metastasize faster than other carcinomas.As a result, about 70-75% of all ovarian cancer patients have at least three ovarian cancers. He is diagnosed with advanced ovarian cancer.
- the terminal ovarian cancer cells are known to exist as spherical bodies, which are spherical masses of cancer cells in the asctic fluid, and according to the specific properties of such ovarian cancer cells, cancer cell death may be caused by treatment with an anticancer agent that is effective in other cancers. It is reported that it is not effectively induced and has resistance to various anticancer drugs.
- An object of the present invention is to provide an anticancer adjuvant capable of blocking the anticancer drug resistance of cancer cells.
- An object of the present invention is to provide a health functional food that can exhibit excellent health functionalities for metastatic ovarian cancer and endometrial cancer and breast cancer.
- An object of the present invention is to provide a method for treating metastatic ovarian cancer and endometrial cancer and breast cancer.
- a pharmaceutical composition for the prevention or treatment of metastatic ovarian cancer, endometrial cancer or breast cancer comprising a compound of formula (1) or a pharmaceutically acceptable salt thereof:
- metastatic ovarian cancer is stage 3 or 4 ovarian cancer, pharmaceutical composition.
- chemocancer is a mitosis inhibitor or alkylating agent or cisplatin, pharmaceutical composition.
- composition of claim 1 wherein the pharmaceutical composition further comprises a chemotherapy agent that is a mitosis inhibitor or an alkylating agent.
- An anticancer adjuvant for metastatic ovarian cancer, endometrial cancer or breast cancer comprising a compound of formula (1) or a food acceptable salt thereof:
- anticancer adjuvant is administered in combination with a chemocancer, anticancer adjuvant.
- a health functional food for preventing or ameliorating metastatic ovarian cancer, endometrial cancer or breast cancer comprising a compound of formula 1 or a food acceptable salt thereof:
- a method of treating metastatic ovarian cancer, endometrial cancer or breast cancer comprising administering to a dog a compound of Formula 1 or a pharmaceutically acceptable salt thereof:
- metastatic ovarian cancer, endometrial cancer or breast cancer is at least a portion of the cancer cells in spheroid form.
- the pharmaceutical composition of the present invention can effectively kill cancer cells existing as spheroids, it can be usefully used as a new medicine for metastatic ovarian cancer, endometrial cancer and breast cancer.
- Figure 1 shows the results of microscopic observation of the morphology of SKOV3ip1 ovarian cancer cells cultured after two-dimensional monolayer culture (2D MC) and three-dimensional spherical culture (3D SC).
- FIG. 2 is a diagram showing the results of confirming the expression of cell survival-related signaling molecules in SKOV3ip1 ovarian cancer cells cultured after two-dimensional monolayer culture (MC) and three-dimensional spherical culture (SC).
- FIG. 3 shows paclitaxel (PTX), BGJ398, TAE684 and imatinib treated at different concentrations in SKOV3ip1 ovarian cancer cells cultured after two-dimensional monolayer culture (2D MC) (A) and three-dimensional spherical culture (3D SC) (B). This is a diagram showing the results of confirming the survival rate of the cells.
- 2D MC two-dimensional monolayer culture
- 3D SC three-dimensional spherical culture
- Figure 4 is treated with different concentrations of paclitaxel (PTX), BGJ398, TAE684 and imatinib to SKOV3ip1 ovarian cancer cells cultured after two-dimensional monolayer culture (2D MC) and three-dimensional spherical culture (3D SC), according to the The survival rate was confirmed through crystal violet staining.
- PTX paclitaxel
- BGJ398, TAE684 imatinib
- FIG. 5 is a diagram showing the results of BGJ398, TAE684 and imatinib treated SKOV3ip1 ovarian cancer cells cultured after two-dimensional monolayer culture (2D MC) and three-dimensional spherical culture (3D SC), and confirmed the shape of the cells accordingly.
- FIG. 6 shows the results of BGJ398 treatment of SKOV3ip1 ovarian cancer cells cultured after two-dimensional monolayer culture (MC) and three-dimensional spherical culture (SC), and whether phosphorylation changes of cell survival signal molecules AKT and STAT3 are changed (A).
- spherical cultured SKOV3ip1 was treated with 5 ⁇ M BGJ398 (BGJ), 3 ⁇ M TAE648 (TAE), and 5 ⁇ M imatinib (IMT) and confirmed phosphorylation changes of AKT and STAT3. .
- Figure 7 shows the results of cell death after treatment with AG490 to SKOV3ip1 ovarian cancer cells cultured after two-dimensional monolayer culture (2D MC) and three-dimensional spherical culture (3D SC) (A) and three-dimensional spherical culture ( 3B SC) after treatment with cultured SKOV3ip1 ovarian cancer cells BGJ398 (BGJ) and AG490 (AG) after confirming the change in the degree of AKT and STAT3 phosphorylation is shown (B).
- 2D MC two-dimensional monolayer culture
- 3D SC three-dimensional spherical culture
- 3B SC three-dimensional spherical culture
- FIG. 8 is a diagram showing the results of confirming cell viability according to the treatment of paclitaxel alone (PTX), paclitaxel and BGJ398 in combination with SKOV3ip1 ovarian cancer cells cultured after 3D spherical culture (3D SC).
- PTX paclitaxel alone
- BGJ398 SKOV3ip1 ovarian cancer cells cultured after 3D spherical culture
- FIG. 9 is a diagram showing the results of BGJ398 treatment of cells after 3D spherical culture (3D SC) of HEC1B endometrial cancer cell line, and the morphology of the cells according to the microscope.
- FIG. 10 is a graph showing crystal violet staining and graphs as a result of confirming the killing effect of cells according to the concentration of paclitaxel anticancer agent in HEC1B endometrial cancer cell line and BGJ398 in combination treatment.
- FIG. 11 is a diagram showing the results of microscopic examination of morphological changes of cells following treatment with paclitaxel anticancer agents by concentration in HEC1B endometrial cancer cell lines and in combination with BGJ398.
- FIG. 12 is a diagram showing the results of BGJ398 treatment of cells in Hs578T breast cancer cell line after 3D spherical culture (3D SC), and the morphology of the cells according to the microscope.
- FIG. 13 is a graph showing crystal violet staining and graphs of Hs578T breast cancer cell lines treated with paclitaxel anticancer agents by concentration and confirming the killing effect of cells according to the combination treatment with BGJ398.
- FIG. 14 is a diagram showing the results of microscopic examination of morphological changes of cells following treatment with paclitaxel anticancer agents in Hs578T breast cancer cell lines at different concentrations and in combination with BGJ398.
- Figure 16 shows the anticancer drug resistance change by various kinase inhibitors BGJ398, TAE648, AG490 in the anticancer drug paclitaxel resistant ovarian cancer cell line SKOV3-TR.
- BGJ398, TAE684 and AG490 was treated to visualize the viability of the cells by crystal violet staining.
- Figure 17 shows the comparison of paclitaxel alone, BGJ398 alone or in combination with paclitaxel in paclitaxel resistant ovarian cancer cell line SKOV3-TR cells for the effect of inhibiting the concentration-dependent survival rate of BGJ398 on paclitaxel by crystal violet staining and quantifying by graph It is.
- FIG. 18 is a visualization of crystal violet staining of the effect of inhibiting the concentration-dependent cell viability of paclitaxel against BGJ398 upon paclitaxel alone or in combination with paclitaxel and BGJ398 in 2D planar culture and 3D spherical culture of paclitaxel resistant ovarian cancer cell line SKOV3-TR cells. Will be compared.
- FIG. 19 is a visual comparison of paclitaxel concentration-dependent cell survival inhibition effect of paclitaxel against BGJ398 upon paclitaxel-resistant ovarian cancer cell line SKOV3-TR cells or in combination with paclitaxel and BGJ398. .
- Figure 20 shows microscopic analysis of morphological changes due to cytotoxicity when administered paclitaxel alone, BGJ398 alone or in combination with paclitaxel to paclitaxel resistant ovarian cancer cell line SKOV3-TR cells.
- Figure 21 shows the microscopic analysis of morphological changes due to cytotoxicity of paclitaxel alone or BGJ398 in combination with various concentrations of paclitaxel resistant cell line SKOV3ip1-TR prepared through gradual increase in paclitaxel concentration of SKOV3ip1 ovarian cancer cell line.
- FIG. 22 shows the effect of cytotoxicity on cytotoxicity when measured in paclitaxel resistant ovarian cancer cell line SKOV3-TR cells by paclitaxel alone, BGJ398 alone, or in combination with paclitaxel.
- FIG. 23 compares the degree of apoptosis (Sub-G1) by graphing the FACS analysis performed in FIG. 21 with Sub-G1, G1, S / M, and G2 cell cycles.
- Figure 24 shows the apoptosis effect with time of the administration of paclitaxel alone, BGJ398 alone or in combination with paclitaxel to SKOV3-TR ovarian cancer cells by immunostaining of cleaved PARP and Actin.
- Fig. 25 shows the concentration-dependent apoptosis effect of BGJ398 upon administration of paclitaxel alone, BGJ398 alone or in combination with paclitaxel to SKOV3-TR ovarian cancer cells by immunostaining of cleaved PARP and Actin.
- Fig. 26 confirms the inhibition of AKT phosphorylation and induction of PARP cleavage in paclitaxel alone or in combination with paclitaxel of BGJ398 to SKOV3-TR ovarian cancer cells with PathScan Intracellular Signaling Array Kit (Cell Signaling Technology).
- FIG. 27 shows phosphorylation of BAD, XIAP expression, and expression of CASP9, which are known as downstream regulators of apoptosis in response to changes in AKT activity in cells when paclitaxel alone or in combination with paclitaxel of BGJ398 is administered to SKOV3-TR ovarian cancer cells , P42 / 44 phosphorylation was confirmed by immunostaining method.
- Figure 28 shows the effect of paclitaxel cell death according to AKT inhibition by crystal violet staining when paclitaxel alone or co-administration of wortmannin (CAS 19545-26-7), which is an AKT selective inhibitor, to SKOV3-TR ovarian cancer cells.
- wortmannin CAS 19545-26-7
- 29 to 31 are analyzed by crystal violet staining analysis of the change according to the combination administration of cisplatin alone, BGJ398 alone or cisplatin to SKOV3ip1 and SKOV3-TR.
- the present invention relates to a pharmaceutical composition for the prevention or treatment of metastatic ovarian cancer, endometrial cancer or breast cancer comprising a compound of formula (1) or a pharmaceutically acceptable salt thereof.
- the compound of Formula 1 is BGJ398 (CAS Number: 872511-34-7) is an FGFR inhibitor, and can target all of FGFR 1-4. Its chemical formula is C 26 H 31 Cl 2 N 7 O 3 And has the name 3- (2,6-dichloro-3,5-dimethoxyphenyl) -1- [6- [4- (4-ethylpiperazin-1 yl) anilino] pyrimidin-4-yl] -1-methylurea .
- the kind of salts may include without limitation various salts retaining the biological effectiveness and properties of the compounds.
- pharmaceutically acceptable acid addition salts include inorganic and organic acids, for example acetates, aspartates, benzoates, besylates, bicarbonates, carbonates, bisulfates, sulfates, camphor sulfonates, chlorides, hydrochlorides, chlors Theophyllineronate, citrate, ethanedisulfonate, fumarate oxalate, palmitate, pamoate, phosphate, hydrogen phosphate, dihydrogen phosphate, propionate, stearate, succinate, salicylate, tartrate, tosyl Rate and trifluoro acetate salts, and the like.
- Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
- a phosphate salt may be used as a preferable example of the BGJ398 or a pharmaceutically acceptable salt thereof of the present invention.
- metastatic ovarian cancer refers to ovarian cancer in which cancer cells have metastasized to the abdominal cavity, unlike primary ovarian cancer derived from and attached to the ovarian surface epithelium. Terminal metastatic ovarian cancer cells are characterized in that they exist in the form of a globular (spheroid) in the ascites.
- the state of metastasis from ovarian cancer to the abdominal cavity is defined as "the third stage of ovarian cancer," and the liver, large intestine, small intestine, bladder, abdominal cavity, and peritoneum are located in the abdominal cavity. It refers to the state of metastasis to lymph nodes.
- "Ovarian cancer stage 4" refers to a condition in which cancer cells spread out of the abdominal cavity and spread to other organs, such as the lungs, bones, neck, and lymph nodes around the brain, which can be referred to as distant metastasis.
- endometrial cancer refers to a cancer occurring in the endometrium that covers the uterine space, and to define the stage of endometrial cancer in relation to the degree of metastasis, the "endometrial cancer stage 3 Is defined as cancer that has spread to the surrounding tissues of the uterus but has not metastasized out of the pelvis and has not invaded the bladder or rectum and has metastasized to the membranes, ovaries, fallopian tubes, vagina, pelvic wall, and lymph nodes around the aorta.
- End stage endometrial cancer is defined as cancer invading the bladder or rectum or metastasizing out of the pelvis.
- breast cancer refers to a cancer occurring in the breast, and in terms of the stage of metastasis of breast cancer, "breast cancer stage 3" means that the cancer has spread to the lymph nodes under the armpits, It is defined as a state that is tightly bound together, fixed to surrounding tissues, or metastasized to lymph nodes above or below the clavicle, and "4th breast cancer” is defined as a distant metastasis to organs such as bone, lung, liver, and brain. .
- the compound of formula 1 or a pharmaceutically acceptable salt thereof according to the present invention can degrade the spheroid form of cancer cells.
- the spheroid form of cancer cells refers to a spherical body which is a spherical mass formed by cancer cells, and refers to a structure in which cells form a three-dimensional 3D aggregate.
- the spheroid may be used interchangeably with spheres, spheres, and spheres, and may be used to include ellipsoids and spheres without limitation.
- the present inventors confirmed that when 3D culture of cancer cells to induce a metastatic cancer-like state, the cancer cells form a spheroid form and have a floating form. Unlike the other anticancer treatments, the cancer cells maintaining such a spheroid aggregation form are different.
- the pharmaceutical composition of the present invention may be a pharmaceutical composition that exhibits efficacy against cancer in which at least some of the cancer cells form a spheroid form.
- the compound of formula (1) or a pharmaceutically acceptable salt thereof inhibits the maintenance of spheroidal form in 3D cultured ovarian cancer cells, which can reflect metastatic ovarian cancer cells with microenvironments suspended in spheroidal form in ascites, By inhibiting the viability signaling pathway, anticancer effects specific to metastatic ovarian cancer can be exhibited, rather than general adherent primary ovarian cancer. Accordingly, the present invention can be used for the prevention or treatment of stage 3 or 4 ovarian cancer, for example.
- the compound of Formula 1 or a pharmaceutically acceptable salt thereof may inhibit the phosphorylation of AKT and STAT3, thereby preventing or metastatic ovarian cancer characterized by increased phosphorylation of fibroblast growth factor receptor (FGFR). It can be cured.
- FGFR fibroblast growth factor receptor
- the present invention provides a pharmaceutical composition for preventing or treating ovarian cancer, wherein the compound of Formula 1 or a pharmaceutically acceptable salt thereof inhibits phosphorylation of AKT and STAT3, wherein the metastatic ovarian cancer is FGFR. It is possible to provide a pharmaceutical composition for preventing or treating ovarian cancer, which is characterized by an increased phosphorylation of fibroblast growth factor receptor.
- the metastatic ovarian cancer, endometrial cancer or breast cancer may be cancer resistant to chemocancer agents, such resistance may be reduced by treatment of the compound of Formula 1 or a pharmaceutically acceptable salt thereof.
- Chemocancer agents are widely used in the art and include, for example, nitrogen mustard, imatinib, oxaliplatin, rituximab, erlotinib, trastuzumab, zefitinib, bortezomib, sunitinib, carboplatin, sorafenib, Bevacizumab, cetuximab, biscumalbum, asparaginase, tretinoin, hydroxycarbamide, dasatinib, estramastin, gemtuzumab ozogamycin, ibritumab tucetan, heptaplatin, methylaminole Fluoric acid, amsacrine, alemtuzumab, procarbazine, alprostadil, holmium nitrate chitosan, gemcitabine, doxyfluidine, pemetrexed, tegapur, capecitabine, gimerasine, or
- the chemocancer agent may be a mitosis inhibitor or an alkylating agent.
- Mitosis inhibitors can be, for example, paclitaxel, docetaxel, vinblastine, vincristine, vinorelbine, colchicine, griseofulvin, and the alkylating agent can be cisplatin, for example. More specifically, it may be paclitaxel.
- resistive means that cancer cell death is not expected to be effectively expected when treated with chemotherapy.
- the cancer cells When at least some of the cancer cells are in spheroidal form, they may exhibit high resistance to chemocancer agents as compared to adherent cancer cells that are not.
- the compound of formula (1) or a pharmaceutically acceptable salt thereof may degrade the spheroid form of cancer cells, and thus may exhibit excellent efficacy against such chemo-resistant cancers.
- the pharmaceutical composition of the present invention may be co-administered with a chemocancer agent.
- the pharmaceutical composition of the present invention shows excellent efficacy even against chemocancer resistant cancer, and can be used in combination with a chemocancer to maximize its efficacy.
- the chemocancer agent used in combination may include at least one of the above-described chemocancer agents.
- the order of administration in combination is not particularly limited, and may be administered simultaneously or sequentially with the chemocancer agent.
- composition of the present invention may comprise a pharmaceutically acceptable carrier.
- Carriers included in the pharmaceutical composition of the present invention and acceptable carriers are those commonly used in the preparation, such as lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, Microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, saline, phosphate buffered saline (PBS) or And the like, but are not limited thereto.
- PBS phosphate buffered saline
- the pharmaceutical composition of the present invention may further include a lubricant, a humectant, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like.
- the pharmaceutical composition of the present invention may be administered orally or parenterally, preferably orally.
- Suitable dosages of the pharmaceutical compositions of the present invention may be prescribed in various ways depending on factors such as formulation method, mode of administration, age, weight, sex, morbidity, condition of food, time of administration, route of administration, rate of excretion and response to response of the patient. Can be.
- the present invention also relates to an anticancer adjuvant for metastatic ovarian cancer, endometrial cancer or breast cancer comprising a compound of formula (1) or a pharmaceutically acceptable salt thereof.
- an anticancer adjuvant is used in combination with a chemocancer to aid / improve the efficacy of an anticancer agent.
- the compound of Formula 1 or a pharmaceutically acceptable salt thereof may block the anticancer agent resistance / tolerance of cancer cells.
- Can be used in combination with chemocancer drugs can maximize anticancer drug efficacy.
- chemocancer agent used in combination at least one of the above-described chemocancer agents can be exemplified, and when used in combination, the order of administration is not particularly limited, and can be administered simultaneously or sequentially with the chemocancer agent.
- the present invention also relates to a dietary supplement for the prevention or improvement of metastatic ovarian cancer, endometrial cancer or breast cancer comprising the compound of formula (1) or a pharmaceutically acceptable salt thereof.
- the health functional food refers to a food having a bioregulatory function, such as prevention or improvement of disease, biological defense, immunity, recovery from a disease, and aging inhibition, and should be harmless to the human body when taken in the long term.
- Metastatic ovarian cancer, endometrial cancer or breast cancer to which the health functional food of the present invention can be applied may be as described above.
- the compound of formula 1 or a pharmaceutically acceptable salt thereof can be formulated as a nutraceutical by itself and added to the food.
- the compound of formula 1 or a pharmaceutically acceptable salt thereof is added in an amount of up to 15% by weight, preferably up to 10% by weight relative to the raw material.
- the active ingredient may be used in an amount above the above range because there is no problem in terms of safety.
- foods to which the substance may be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, dairy products including gum, ice cream, various soups, beverages, teas, drinks, Alcoholic beverages and vitamin complexes, and the like and include all of the health foods in the conventional sense.
- the health beverage composition of the present invention may include various flavors or natural carbohydrates, and the like as an additional ingredient, as in a general beverage.
- the natural carbohydrates described above may be used as monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, and natural sweeteners such as dextrin and cyclodextrin, and synthetic sweeteners such as saccharin and aspartame.
- the proportion of the natural carbohydrate is generally about 0.01 to 10 g, preferably about 0.01 to 0.1 g per 100 ml of the composition of the present invention.
- the health functional food of the present invention includes various nutrients, vitamins, electrolytes, flavors, coloring agents, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, Alcohols, carbonating agents used in carbonated drinks, and the like.
- the health functional food of the present invention may include a flesh for preparing natural fruit juice, fruit juice drink and vegetable drink. These components can be used independently or in combination.
- the ratio of such additives is not critical, but is generally selected in the range of 0.01 to 0.1 parts by weight per 100 parts by weight of the health functional food of the present invention.
- the present invention also relates to a method for treating metastatic ovarian cancer, endometrial cancer or breast cancer comprising administering a compound of formula 1 or a pharmaceutically acceptable salt thereof to a dog.
- the subject is a mammal, including a human, and includes a patient in need of cancer treatment, a patient who has been treated for cancer, a patient who has been treated for cancer, and a patient who needs to receive cancer treatment. Patients who have undergone surgical operations to remove the organs may also be included.
- Metastatic ovarian cancer, endometrial cancer or breast cancer to which the treatment method of the present invention can be applied may be as described above.
- the compound of Formula 1 or a pharmaceutically acceptable salt thereof may be administered in combination with a chemocancer agent.
- the cancer to which the treatment method of the present invention is applied may be a chemo-resistant cancer.
- the cancer of the individual is identified as a chemo-resistant drug, and when the cancer is identified as a chemo-resistant cancer,
- the compound of Formula 1 or a pharmaceutically acceptable salt thereof may be co-administered with a chemocancer agent, but is not limited thereto.
- chemocancer agent examples include at least one of the above-described chemocancer agents, and when used in combination, the order of administration is not particularly limited, and may be administered simultaneously or sequentially with the chemocancer agent.
- the compound of formula (1) or a pharmaceutically acceptable salt thereof may be administered as a composition with ingredients other than the active ingredient as described above, which may be administered orally or parenterally, preferably orally.
- Appropriate dosages can be prescribed in various ways, such as by the method of formulation, the mode of administration, the age, weight, sex, morbidity, food, time of administration, route of administration, rate of excretion and reaction sensitivity of the patient.
- the invention also relates to the use of a compound of formula (1) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention or treatment of metastatic ovarian cancer, endometrial cancer or breast cancer.
- Metastatic ovarian cancer, endometrial cancer or breast cancer in the use of the present invention may be as described above.
- the compound of formula 1 or a pharmaceutically acceptable salt thereof exhibits excellent efficacy against metastatic ovarian cancer, endometrial cancer or breast cancer, and thus can be used in the manufacture of a medicament for preventing or treating the same.
- the medicine according to the present invention may be the above-mentioned pharmaceutical composition.
- Example 1 In 2D monolayer culture model and 3D spherical culture model SKOV3ip1 Comparison of Ovarian Cancer Cells
- SKOV3ip1 cell line containing SKOV3 ovarian cancer cell line as a parent cell was used.
- SKOV3 cell line is characterized by metastatic ovarian cancer isolated from the ascites of human ovaries and is a cell line with high metastasis capacity as a separate cell line after primary proliferation in the abdominal cavity of nude mice used as an animal model.
- SKOV3ip1 cell line was provided by Professor Sood AK (University of Texas MD Anderson Cancer Center, USA) and used for later experiments.
- 2D monolayer culture was performed in the following manner: cells were RPMI 1640 (Corning, NY, USA) supplemented with 10% fetal bovine serum (Gibco, NY, USA) and 10 U / ml penicillin / streptomycin (Gibco). The medium was incubated in a humidified atmosphere at 37 ° C., 5% CO 2 .
- SKOV3ip1 cells (1 ⁇ 10 6 ) were dispensed in ultra-low attachment 6-well plates (Corning NY, USA), 10% fetal calf serum (Gibco, NY, USA) and 10 U Cultures were incubated in a 5% CO 2 incubator using RPMI 1640 medium supplemented with / ml penicillin / streptomycin (Gibco).
- SKOV3ip1 ovarian cancer cells were divided into 2D monolayer cultures (2D MC) and 3D spherical cultures (3D SC), and microscopic analysis was performed to observe whether they showed different morphology depending on the culture method and the results are shown in FIG. 1. It was.
- aggregates were not formed in 2D monolayer culture, but after 72 hours of 3D spherical culture, SKOV3ip1 ovarian cancer cells formed loose sheet-like aggregates and accumulated in a dense spheroid form.
- 2D monolayer culture and 3D spherical culture can induce different types of cells, and when 3D spherical culture is carried out, the metastasized state is present in the form of floating in the ascites in the abdominal cavity rather than attached state. It may reflect the morphology of ovarian cancer.
- 2D monolayer culture (2D MC) and 3D spherical culture (3D SC) immunostaining was performed to confirm whether or not changes in the signaling pathways involved in cell survival. More specifically, SKOV3ip1 Cells (1 ⁇ 10 6 ) were cultured according to 2D monolayer culture or 3D spherical culture method of 1.1, respectively, and then expression of cellular signal molecules including AKT, STAT3, p42 / 44 ERK and p38 MAPK was confirmed. And activation status in spherical cultured cells.
- Monolayer or spherical cultured SKOV3ip1 cells were harvested and washed once with ice-cold 1X phosphate buffered saline, and 100 ⁇ l ice-cold RIPA buffer (20 mM Tris-Cl, pH 8.0, 125 mM NaCl, 100 mM phenylmethylsulfonyl fluoride, 1 mM ethylene diamine tetraacetic acid, 1% Triton X-100, 0.5% sodium deoxycholate, 0.1% sodium dodecyl sulfate, 1X cOmplete protease inhibitor cocktail (Roche, Mannheim, Germany)) was dissolved on ice.
- 1X phosphate buffered saline 100 ⁇ l ice-cold RIPA buffer (20 mM Tris-Cl, pH 8.0, 125 mM NaCl, 100 mM phenylmethylsulfonyl fluoride, 1 mM ethylene diamine
- Protein concentration was analyzed using the Bradford Protein Assay Kit (Biorad, CA, USA), and the same amount of protein (30 ⁇ g) was separated by SDS-PAGE and transferred to nitrocellulose membranes followed by a horseradish peroxidated conjugated secondary antibody. And immunostaining using specific antibodies. Immunoactivation bands were detected by SuperSignal West Pico Chemiluminescent Substrate (Thermo, IL, USA) using a Fusion Solo chemiluminescence analyzer (Vilber Rourmat Marne la Vallee, France). Antibodies to STAT3 (H-190), STAT3 (B-7) and Actin (C-2) phosphorylated at Tyr 705 were purchased from Santa Cruz Biotechnology.
- SKOV3ip1 cells cultured in each culture environment were treated with BGJ398 and cell viability was confirmed accordingly.
- Antitumor activity was also compared in SKOV3ip1 cells using the tyrosine kinase inhibitor TAE684 (NVP-TAE684, CAS 761439-42-3), imatinib, also known as Gleevec, and paclitaxel, a standard anti-ovarian cancer chemotherapy.
- TAE684 tyrosine kinase inhibitor
- imatinib also known as Gleevec
- paclitaxel a standard anti-ovarian cancer chemotherapy.
- TAE684 (against ALK), and imatinib (against Abl) used in the experiment were purchased from Selleckchem (USA) and AG490 (against JAK, CAS 133550-30-8) was purchased from Tocris (Bristol, UK). .
- Crystal violet staining was performed to confirm cell viability in monolayer and spherical cultured cell models.
- SKOV3ip1 cells 5 ⁇ 10 4
- Drugs were then injected into each well at the concentrations required for the experiment and further incubated for 72 hours.
- 300 microliters 0.2% crystal violet solution was added to each well and incubated for 20 minutes with gentle stirring. Stained cells were washed with distilled water until a clean background was confirmed.
- crystal violet dye was extracted with 1% SDS / PBS and absorbance was measured with an EMax PLUS microplate reader (Molecular Device, USA) at 570 nm wavelength.
- SKOV3ip1 cells (5 ⁇ 10 4 ) were aliquoted into ultra-low attachment 24-well plates and incubated overnight. Cells from each well were harvested and transferred to commercial 24 well plates and further incubated for 12 hours. Attached visualized cells were stained for 20 minutes with gentle mating with 0.2% crystal violet solution. The stained cells were washed with distilled water, and crystal violet dye was extracted with 1% SDS / PBS to color with a color counter, and the absorbance was measured with an EMax PLUS microplate reader (Molecular Device, USA) at 570 nm wavelength.
- Monolayer or spherical cultured SKOV3ip1 cells were treated with various concentrations of tyrosine kinase inhibitors and paclitaxel for 72 hours, and cell viability was confirmed using a crystal violet colorimetric clock, and the results are shown in FIG. 3.
- monolayer cultured SKOV3ip1 cell viability was dose-dependently reduced by paclitaxel and TAE648.
- cell viability of monolayer cultured SKOV3ip1 was not affected by BGJ398 and imatinib.
- the cells of spherical cultured SKOV3ip1 showed more resistance to paclitaxel than the distinctly monolayered cultured SKOV3ip1 cells, and TAE648 resistance was not confirmed in the spherical cultured SKOV3ip1.
- Imatinib also did not affect the survival rate of spherical cultured SKOV3ip1 cells.
- BGJ398 showed different effects on the survival rate of SKOV3ip1 cells according to monolayer culture and spherical culture. BGJ398 showed cell death effects even at very low concentrations of spherical cultured SKOV3ip1 cells, but also reduced dose-dependent cell viability. I was.
- BGJ398 monolayer cultured SKOV3ip1 cells showed no cytotoxicity even if the concentration was increased up to 5 uM. However, in 3D spherical cultured SKOV3ip1 cells, cytotoxicity was observed with only 1 uM treatment at 3 days. This increasing result was confirmed. That is, BGJ398 does not show anticancer activity in 2D monolayer cultured ovarian cancer cells that reflect adherent cancer, but exhibits high anticancer activity specifically for 3D spherical cultured ovarian cancer cells, that is, metastatic ovarian cancer cells.
- BGJ398 treated spherical cultured SKOV3ip1 cells did not maintain a normal aggregate state.
- spheroid degradation was not observed in TAE684 and imatinib treated spherical cultured SKOV3ip1 cells.
- Example 2 confirms that BJG398 exhibits a particularly good anticancer activity in spherical culture, which is a metastatic microenvironment, and therefore, to find out which cell signaling mechanism BJG398 specifically induces cytotoxicity in a spear culture environment.
- BJG398 exhibits a particularly good anticancer activity in spherical culture, which is a metastatic microenvironment, and therefore, to find out which cell signaling mechanism BJG398 specifically induces cytotoxicity in a spear culture environment.
- Western blot In order to confirm the expression and activity of various factors related to cell survival and proliferation was confirmed by Western blot.
- Example 1 Since it was confirmed in Example 1 that the cell survival signal molecules AKT and STAT3 are activated in spherical cultured SKOV3ip1 cells, in order to confirm whether BGJ398 can change the state of AKT and STAT3 in spherical cultured SKOV3ip1 cells.
- Single layer (MC) or spherical culture (SC) SKOV3ip1 cells were treated with 5 uM of BGJ398, and the change in phosphorylation level was confirmed.
- Spherical cultured SKOV3ip1 was also treated with 5 ⁇ M BGJ398 (BGJ), 3 ⁇ M TAE648 (TAE), and 5 ⁇ M imatinib (IMT) and after 72 hours, cell lysates were obtained and immunostaining was performed for AKT and STAT3. Activated cellular expression was analyzed with antibodies against it. In addition, the phosphorylation level of FGFR1 was shown as a positive control of the BGJ treatment group and actin was used as a loading control. The results are shown in FIG. The immunostaining assay was performed in the same manner as in Example 1.
- each cell line was divided into 2D monolayer culture and 3D spherical culture, and the change according to BGJ398 administration was analyzed by morphological analysis and crystal violet staining analysis. All cell lines were purchased from ATCC and used in this experiment, the details of which are shown in Table 3.
- results for the endometrial cancer cell line HEC1B are shown in FIGS. 9, 10 and 11, and results for the ovarian cancer cell line Hs578T are shown in FIGS. 12, 13 and 14.
- cell death can be confirmed upon administration of BGJ398 as in the SKOV (ovarian cancer) cell line in the cultured endometrial cancer cell line and breast cancer cell line.
- BGJ398 has been shown to be an effective anticancer agent for three-dimensional spherical cultured ovarian cancer cells, when administered with paclitaxel used as a primary anticancer agent for ovarian cancer, it overcomes the resistance of spherical cultured cells to paclitaxel. It was confirmed whether the resistance could be improved. In other words, in order to confirm whether the combination of BGJ398 and paclitaxel showed synergistic effect on the death of spherical cultured SKOV3ip1 cells, the combination of serially diluted paclitaxel and BGJ398 with different doses of 0, 1.25 and 5 ⁇ M were spherically cultured SKOV3ip1. 72 hours after the treatment, crystal violet colorimetric analysis was performed and the results are shown in FIG. 8.
- spherical cultured SKOV3ip1 cells treated with paclitaxel and BGJ398 were found to have high cell death compared to cells treated with paclitaxel alone. More specifically, when comparing the group treated with paclitaxel only and the two groups treated with BGJ398 at 1.25 and 5 uM in the three-dimensional culture SKOV3ip1, the sensitivity to paclitaxel was higher than that in the group treated with BGJ398. It was confirmed that the increase dependently.
- spherical cultured SKOV3ip1 ovarian cancer cells could be effectively killed, which is the activity of fibroblast proliferation factor using BGJ398 in three-dimensional spherical culture, a metastatic microenvironment of ovarian cancer. Inhibition is very effective in inhibiting the proliferation of metastatic ovarian cancer. That is, BGJ398 can exhibit an effective anticancer effect in spherical cultured ovarian cancer cells that can reflect metastatic ovarian cancer status.
- each cell line was divided into 2D monolayer cultures and 3D spherical cultures, and morphologically analyzed by BGJ398 alone or in combination with paclitaxel.
- 3D spherical cultures of endometrial cancer cell line HEC1B and breast cancer cell line Hs578T cell line cell spheres were collapsed and cytotoxicity was induced. As shown in FIGS.
- pan-FGFR inhibitor BGJ398 may be a very effective treatment for metastatic ovarian cancer, endometrial edema, and breast cancer.
- FGFR plays a role in promoting survival of spheroids in ovarian cancer cells. It can be seen that the target is to promote the spheroid decomposition of metastatic ovarian cancer, thereby killing metastatic ovarian cancer.
- SKOV3-TR (Taxol Resistant) is a paclitaxel-resistant ovarian cancer cell line that has been cultured for a long time by gradual increase in concentration of paclitaxel as a parent cell of SKOV3 ovarian cancer cell line.
- SKOV3-TR cell line was used from Sook AK of MD-Anderson Cancer Center (USA).
- the resistance of SKOV3 and SKOV3-TR to paclitaxel was confirmed by measuring cell viability by crystal violet colorimetric analysis by the method described above. The experiment was performed three times and the difference was calculated by student's t-test.
- the resistance to paclitaxel of the SKOV3-TR cell line is significantly higher than that of the SKOV3 cell line.
- each cell line was divided into 2D monolayer culture and 3D spherical culture, and the change according to paclitaxel alone, BGJ398 alone or in combination with paclitaxel was analyzed by morphological analysis and crystal violet staining analysis.
- FIG. 16 is a combination of paclitaxel (PTX) alone or BGJ398, TAE684 and AG490 in SKOV3-TR ovarian cancer cells, and the viability of the cells is visualized.
- PTX paclitaxel
- BGJ398, TAE684 and AG490 a combination of paclitaxel alone or BGJ398, TAE684 and AG490 in SKOV3-TR ovarian cancer cells
- Figure 17 shows the survival rate of the cells according to paclitaxel alone, BGJ398 alone or in combination with paclitaxel to ovarian cancer cells divided into 2D monolayer culture and 3D spherical culture of paclitaxel resistant cell line SKOV3-TR. All of the culture methods can confirm further improved anticancer activity when combined with paclitaxel of BGJ398.
- Figure 18 was examined whether there is a concentration-dependent anticancer effect of BGJ398 according to paclitaxel treatment in SKOV3-TR ovarian cancer cells.
- the survival rate of the cells according to paclitaxel alone, BGJ398 alone or in combination with paclitaxel is shown.Referring to this, anti-cancer activity is minimal when paclitaxel alone is treated, but when BGJ398 is used in combination, resistance is blocked to increase the treatment concentration of BGJ398. It can be confirmed that the more showing anti-cancer activity.
- FIG. 20 microscopically analyzed cell morphological changes according to the administration of paclitaxel alone, BGJ398 alone or in combination with paclitaxel to SKOV3-TR ovarian cancer cells.
- the treatment of 2.5 ⁇ M BGJ398 and 50 nM paclitaxel in SKOV3-TR cells showed minimal cytotoxicity and no morphological changes. Can be.
- Figure 21 is a paclitaxel resistant ovarian cancer cell line prepared in our laboratory according to the gradual increase in paclitaxel concentration from SKOV3ip1 cell line.
- the morphological changes of the cells according to paclitaxel alone, BGJ398 alone, or in combination with paclitaxel in SKOV3ip1-TR ovarian cancer cells were shown.
- BGJ398 is used in combination, paclitaxel resistance is blocked and anticancer activity is increased.
- Figure 22 shows the cytotoxicity of paclitaxel alone, BGJ398 alone or in combination with paclitaxel to SKOV3-TR ovarian cancer cells by FACS analysis, and the intracellular DNA content as propidium iodide (PI). Staining and FACS confirm the degree of cell death.
- PI propidium iodide
- Figure 23 is a graph showing the results of FACS in each cell cycle in the same experiment above.
- the combination treatment of 2.5 ⁇ M of BGJ398 and 50 nM of paclitaxel in SKOV3-TR cells showed an increase in anti-cancer activity by showing a 2.5-fold increase in Sub-G1 cells compared to 50 nM of paclitaxel alone. Confirmed.
- Figures 24 and 25 confirm the expression of cleaved PARP and Actin according to paclitaxel alone, BGJ398 alone or in combination with paclitaxel to SKOV3-TR ovarian cancer cells by immunostaining as described above.
- the expression of cleaved PARP and Actin was increased in concentration and time dependent manner.
- Fig. 26 shows the inhibition of AKT phosphorylation and induction of PARP cleavage by paclitaxel alone or in combination with paclitaxel of BGJ398 to SKOV3-TR ovarian cancer cells with PathScan Intracellular Signaling Array Kit (Cell Signaling Technology).
- the phosphorylation of AKT to serine 473 decreased and cleaved PARP increased.
- FIG. 27 shows AKT, phosphorylated AKT, BAD, phosphorylated BAD, XIAP to confirm AKT downstream signaling mechanisms related to cell survival and death in cells upon administration of paclitaxel alone or BGJ398 paclitaxel to SKOV3-TR ovarian cancer cells.
- Expression of CASP9, p42 / 44, phosphorylated p42 / 44 was confirmed. Referring to this, it was confirmed that the level of intracellular phosphorylated AKT was very inhibited by the treatment of BGJ398 in SKOV3-TR cells, and specifically, the expression of XIAP was reduced. This is believed to inhibit paclitaxel sensitivity by inhibiting the expression level of XIAP in cells.
- FIG. 28 shows that the anticancer effect of paclitaxel is increased by treating wortmannin, known as an inhibitor of PI3K / AKT, to SKOV3-TR cells at different concentrations.
- wortmannin known as an inhibitor of PI3K / AKT
- each cell line was cultured in 2D monolayers, and the change according to cisplatin alone, BGJ398 alone or in combination with cisplatin was analyzed by crystal violet staining assay.
- both SKOV3ip1 and SKOV3-TR exhibit cisplatin sensitivity.
- anticancer activity is improved when BGJ398 is used in combination with cisplatin.
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Abstract
Description
Claims (33)
- 청구항 1에 있어서, 상기 전이성 난소암, 자궁내막암 또는 유방암은 그 암세포의 적어도 일부가 스페로이드 형태인, 약학적 조성물.
- 청구항 1에 있어서, 상기 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염은 암세포의 스페로이드(spheroid) 형태를 분해하는, 약학적 조성물.
- 청구항 1에 있어서, 상기 전이성 난소암은 난소암 3기 또는 4기인, 약학적 조성물.
- 청구항 1에 있어서, 상기 전이성 난소암, 자궁내막암 또는 유방암은 화학항암제 저항성암인, 약학적 조성물.
- 청구항 1에 있어서, 상기 약학적 조성물은 화학항암제와 병용 투여되는 것인, 약학적 조성물.
- 청구항 6에 있어서, 상기 화학항암제는 유사분열 저해제 또는 알킬화제인, 약학적 조성물.
- 청구항 6에 있어서, 상기 화학항암제는 파클리탁셀인, 약학적 조성물.
- 청구항 1에 있어서, 상기 약학적 조성물은 유사분열 저해제 또는 알킬화제인 화학항암제를 더 포함하는, 약학적 조성물.
- 청구항 1에 있어서, 상기 약학적 조성물은 파클리탁셀을 더 포함하는, 약학적 조성물.
- 청구항 11에 있어서, 상기 전이성 난소암, 자궁내막암 또는 유방암은 화학항암제 저항성암인, 항암 보조제.
- 청구항 11에 있어서, 상기 항암 보조제는 화학항암제와 병용 투여하는, 항암 보조제.
- 청구항 13에 있어서, 상기 화학항암제는 유사분열 저해제 또는 알킬화제인, 항암 보조제.
- 청구항 13에 있어서, 상기 화학항암제는 파클리탁셀인, 항암 보조제.
- 청구항 16에 있어서, 상기 전이성 난소암, 자궁내막암 또는 유방암은 그 암세포의 적어도 일부가 스페로이드 형태인, 건강기능식품.
- 청구항 16에 있어서, 상기 전이성 난소암은 난소암 3기 또는 4기인, 건강기능식품.
- 청구항 16에 있어서, 상기 화학식 1의 화합물 또는 이의 식품학적으로 허용가능한 염은 암세포의 스페로이드(spheroid) 형태를 분해하는, 건강기능식품.
- 청구항 20에 있어서, 상기 전이성 난소암, 자궁내막암 또는 유방암은 그 암세포의 적어도 일부가 스페로이드 형태인, 방법.
- 청구항 20에 있어서, 상기 전이성 난소암은 난소암 3기 또는 4기인, 방법.
- 청구항 20에 있어서, 상기 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염을 투여하여 암세포의 스페로이드(spheroid) 형태를 분해하는, 방법.
- 청구항 20에 있어서, 상기 전이성 난소암, 자궁내막암 또는 유방암은 화학항암제 저항성암인, 방법.
- 청구항 20에 있어서, 상기 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염을 화학항암제와 병용 투여하는, 방법.
- 청구항 25에 있어서, 상기 병용 투여 전에 상기 개체의 암의 화학항암제 저항성을 확인하고, 저항성 획득이 확인된 개체에 상기 화학항암제를 병용 투여하는 것인, 방법.
- 청구항 25에 있어서, 상기 화학항암제는 유사분열 저해제 또는 알킬화제인, 방법.
- 청구항 25에 있어서, 상기 화학항암제는 파클리탁셀인, 방법.
- 청구항 29에 있어서, 상기 전이성 난소암, 자궁내막암 또는 유방암은 그 암세포의 적어도 일부가 스페로이드 형태인, 용도.
- 청구항 29에 있어서, 상기 전이성 난소암은 난소암 3기 또는 4기인, 용도.
- 청구항 29에 있어서, 상기 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염은 암세포의 스페로이드(spheroid) 형태를 분해하는, 용도.
- 청구항 29에 있어서, 상기 전이성 난소암, 자궁내막암 또는 유방암은 화학항암제 저항성암인, 용도.
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