Use of norethisterone enanthate compound for preventing or treating cancer

Abstract

The present invention relates to the use of norethisterone enanthate, or a stereoisomer, hydrate, solvate, or salt thereof. Specifically, norethisterone enanthate, or stereoisomers, hydrates, solvates, or salts thereof can be advantageously used for preventing, alleviating, or treating cancer.

Description

Use of norethisterone enanthate compounds for the prevention or treatment of cancer

[0001] The present invention relates to the use of norethisterone enanthate compounds for the prevention or treatment of cancer.

[0002] Norethisterone enanthate, or norethindrone enanthate, is used as a contraceptive and is marketed as Noristerat (Tenhaeff, D., et al. "3 months contraception with norethisteronφnantate. Clinical and biochemical studies." Die Medizinische Welt40 (1971): 1551-1553).

[0003] Cancer refers to a group of abnormal cells, also known as a tumor or neoplasm, that develops due to a disruption in the balance between cell division and death caused by various factors, resulting in continuous division and proliferation. It typically affects over 100 different parts of the body, including organs, white blood cells, bones, and lymph nodes, and progresses to serious symptoms through invasion of surrounding tissues and metastasis to other organs. While various anticancer drugs are currently being developed, the development of anticancer drugs that can effectively suppress cancer cell proliferation remains a pressing need.

[0004] Accordingly, the inventors of the present invention have made great efforts to develop a novel anticancer agent and have confirmed that norethisterone enanthate has antiproliferative and apoptotic effects on various cancer cells, thereby completing the present invention.

[0005] One object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer comprising norethisterone enanthate, a stereoisomer, a hydrate, a solvate or a salt thereof.

[0006] Another object of the present invention is to provide a health functional food for preventing or improving cancer, comprising norethisterone enanthate, a stereoisomer, a hydrate, a solvate or a salt thereof.

[0007] Another object of the present invention is to provide a method for preventing or treating cancer, comprising administering to a subject in need thereof norethisterone enanthate, a stereoisomer, a hydrate, a solvate or a salt thereof.

[0008] Another object of the present invention is to provide a feed composition for preventing or improving cancer comprising norethisterone enanthate, a stereoisomer, a hydrate, a solvate or a salt thereof.

[0009] Another object of the present invention is to provide a use of norethisterone enanthate or a stereoisomer, hydrate, solvate or salt thereof for the prevention or treatment of cancer.

[0010] Another object of the present invention is to provide a use of norethisterone enanthate or a stereoisomer, hydrate, solvate or salt thereof for the manufacture of a medicament for the prevention or treatment of cancer.

[0011] Each description and embodiment disclosed herein may also be applied to other descriptions and embodiments. That is, all combinations of the various elements disclosed herein fall within the scope of the present invention. Furthermore, the scope of the present invention is not limited by the specific descriptions described below.

[0012]

[0013] One aspect of the present invention is a pharmaceutical composition for preventing or treating cancer comprising norethisterone enanthate, a stereoisomer, a hydrate, a solvate or a salt thereof.

[0014] The chemical formula of norethisterone enanthate is as shown in Figure 1.

[0015] Among the term "stereoisomers," "isomer" refers to compounds that have the same molecular formula but different connection methods or spatial arrangements of the constituent atoms within the molecule. Isomers include, for example, structural isomers and stereoisomers. The "stereoisomers" may be diastereomers or enantiomers. Enantiomers are isomers that do not overlap with their mirror images, like the relationship between left and right hands, and are also called optical isomers. Enantiomers are distinguished as R (Rectus: clockwise) and S (Sinister: counterclockwise) when four or more substituents are different on the chiral center carbon. Diastereoisomers are stereoisomers that are not mirror images, and can be divided into cis-trans isomers due to the different spatial arrangement of atoms.

[0016] A "solvate" is a compound that is solvated in an organic or inorganic solvent. An example of a solvate is a hydrate.

[0017] The term "salt" may be prepared in the same reaction system during the final separation, purification and synthesis of the compound according to one embodiment of the present invention, or may be prepared separately by reacting with an inorganic base or organic base. The salt may be a salt that can form a salt with a base when the compound of the present invention contains an acidic group, and such salts may include, but are not limited to, salts with alkali metals such as lithium salts, sodium salts or potassium salts; salts with alkaline earth metals such as barium or calcium; salts with other metals such as magnesium salts; organic base salts such as salts with dicyclohexylamine; and salts with basic amino acids such as lysine or arginine. In addition, when the compound of the present invention contains a basic group in the molecule, it can form an acid addition salt, and examples of such acid addition salts include, but are not limited to, salts with inorganic acids, particularly hydrohalic acids (e.g., hydrofluoric acid, hydrobromic acid, hydroiodic acid or hydrochloric acid), nitric acid, carbonic acid, sulfuric acid or phosphoric acid; salts with lower alkyl sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid or ethanesulfonic acid; salts with benzenesulfonic acid or p-toluenesulfonic acid; salts with organic carboxylic acids such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid or citric acid; and salts with amino acids such as glutamic acid or aspartic acid.

[0018] The term "cancer" refers to a class of diseases characterized by the development of abnormal cells that multiply uncontrollably and have the ability to invade and destroy normal body tissues.

[0019] In one specific example, the cancer may be a solid tumor or a blood cancer. Specifically, the solid cancer is breast cancer, lung cancer, prostate cancer, ovarian cancer, brain cancer, liver cancer, cervical cancer, endometrial cancer, uterine cancer, colon cancer, large intestine cancer, colorectal cancer, rectal cancer, kidney cancer, nephroblastoma, skin cancer, oral squamous cell carcinoma, epidermoid cancer, nasopharyngeal cancer, head and neck cancer, bone cancer, esophageal cancer, bladder cancer, lymphatic cancer, stomach cancer, pancreatic cancer, testicular cancer, thyroid cancer, thyroid follicular carcinoma, melanoma, myeloma, multiple myeloma, mesothelioma, osteosarcoma, myelodysplastic syndrome, tumor of mesenchymal origin, soft tissue sarcoma, liposarcoma, gastrointestinal stromal sarcoma, malignant peripheral nerve sheath tumor, Ewing sarcoma, leiomyosarcoma, mesenchymal chondrosarcoma, lymphosarcoma, fibrosarcoma, rhabdomyosarcoma, teratocarcinoma, neuroblastoma, medulloblastoma, glioma, benign tumor of the skin, The cancer may be at least one selected from the group consisting of leukemia, brain tumor, benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, brain lymphoma, oligodendroglioma, ependymoma, brainstem tumor, laryngeal cancer, oropharyngeal cancer, nasal cavity / paranasal sinus cancer, nasopharyngeal cancer, salivary gland cancer, hypopharyngeal cancer, thyroid cancer, oral cancer, thoracic tumor, small cell lung cancer, non-small cell lung cancer, thymic cancer, mediastinal tumor, esophageal cancer, male breast cancer, abdominal tumor, gallbladder cancer, biliary tract cancer, small intestine cancer, colon cancer, anal cancer, male genital tumor, penile cancer, female genital tumor, ovarian cancer, uterine sarcoma, vaginal cancer, female external genital cancer, female urethral cancer, bone tumor, duodenal cancer, and fibrosarcoma, but is not limited thereto. The above blood cancer may be at least one selected from the group consisting of acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, acute monocytic leukemia, multiple myeloma, Hodgkin's lymphoma, and non-Hodgkin's lymphoma, but is not limited thereto.

[0020] The term "prevention" may mean any act of inhibiting or delaying the onset of cancer in an individual by administration of a pharmaceutical composition according to one aspect.

[0021] The term "treatment" may mean any action by which the symptoms of cancer in an individual are improved or beneficially altered by administration of a pharmaceutical composition according to one aspect.

[0022] In one specific example, the pharmaceutical composition may not cause the side effect of weight gain or loss, but is not limited thereto.

[0023] When the above pharmaceutical composition is formulated, it can be prepared using diluents or excipients such as lubricants, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, fillers, bulking agents, binders, wetting agents, disintegrating agents, and surfactants that are commonly used.

[0024] Solid preparations for oral administration may include tablets, pills, powders, granules, capsules, etc., and these solid preparations may be prepared by mixing one or more excipients, such as starch, calcium carbonate, sucrose, lactose, gelatin, etc., with the above composition. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid preparations for oral administration include suspensions, oral solutions, emulsions, syrups, etc., and in addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included.

[0025] Formulations for parenteral administration may include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, injections, suppositories, etc. Non-aqueous solutions and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases may include witepsol, macrogol, Tween 61, cacao butter, laurin butter, glycerogelatin, etc. When manufacturing in the form of eye drops, known diluents or excipients may be used. Injections may include subcutaneous injections, intradermal injections, intravenous injections, intramuscular injections, intraperitoneal injections, or drip injections. Injectables can be prepared using aqueous solvents such as saline solution, Ringer's solution, vegetable oils, high-fatty acid esters (e.g., ethyl oleate), or alcohols (e.g., ethanol, benzyl alcohol, propylene glycol, glycerin, etc.). Injectables can contain pharmaceutical carriers such as biocompatible materials for sustained release of the drug (e.g., hyaluronic acid, collagen, PLGA, chitosan, etc.), stabilizers for preventing deterioration (e.g., ascorbic acid, sodium bisulfite, sodium pyrosulfite, BHA, tocopherol, EDTA, etc.), emulsifiers, buffers for pH adjustment, or preservatives for inhibiting the growth of microorganisms (e.g., phenylmercuric nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.).

[0026] The above pharmaceutical composition may be provided in a mixture with a conventionally known composition for preventing or treating cancer or another existing anticancer agent, and the other anticancer agent may be a conventionally known composition for preventing or treating cancer, an existing anticancer agent, or a newly developed anticancer agent.

[0027] When the above pharmaceutical composition includes another anticancer agent having a preventive or therapeutic effect on cancer, it is important to mix an amount that can achieve the maximum effect with the minimum amount without causing side effects, and this can be easily determined by a person skilled in the art.

[0028] When the above pharmaceutical composition further includes another anticancer agent, a synergistic effect may be produced in which the anticancer effect, i.e., the effect of tumor growth inhibition, immune activation, etc., becomes more pronounced.

[0029] In one embodiment, the route of administration of the pharmaceutical composition includes, but is not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, or rectal.

[0030] The above composition can be administered orally or parenterally, and when administered parenterally, the method of injection can be selected from external application to the skin or intraperitoneal injection, intrarectal injection, subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.

[0031] The above pharmaceutical composition is administered in a pharmaceutically effective amount. The term "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment. The effective dosage level may be determined based on the type and severity of the patient's disease, the activity and sensitivity of the drug, the time of administration, the route of administration, and the excretion rate, the duration of treatment, concomitant medications, and other factors well known in the medical field.

[0032] Specifically, the effective amount of the pharmaceutical composition may vary depending on the patient's age, sex, condition, body weight, absorption rate of the active ingredient in the body, inactivation rate, excretion rate, type of disease, and concomitantly administered drugs, and may increase or decrease depending on the route of administration, severity of obesity, sex, body weight, age, etc.

[0033]

[0034] Another aspect of the present invention is a method for preventing or treating cancer, comprising administering to a subject in need thereof norethisterone enanthate, a stereoisomer, hydrate, solvate or salt thereof; or a composition comprising the same.

[0035] The above “stereoisomer”, “hydrate”, “solvate”, “salt”, “cancer”, “prevention”, “treatment”, etc. may be within the aforementioned scope.

[0036] The term "subject" means a subject to which the composition of the present invention can be applied (prescribed), and may be a subject suffering from or likely to suffer from cancer.

[0037] Additionally, the above “subject” may be, but is not limited to, mammals such as rats, mice, and livestock, including humans.

[0038]

[0039] Another aspect of the present invention is a health functional food for preventing or improving cancer, comprising norethisterone enanthate, a stereoisomer, a hydrate, a solvate or a salt thereof.

[0040] The above “stereoisomer”, “hydrate”, “solvate”, “salt”, “cancer”, “prevention”, etc. may be within the aforementioned range.

[0041] The term "improvement" can refer to any action that at least reduces a parameter associated with the condition being treated, such as the severity of symptoms. In this case, the health functional food can be used before or after the onset of the condition, concurrently with or separately from a therapeutic agent, to prevent or improve cancer.

[0042] In the above health functional food, the active ingredient can be added directly to the food or used in combination with other foods or food ingredients, and can be used appropriately according to conventional methods. The amount of active ingredient mixed can be appropriately determined depending on the intended use (prevention or improvement).

[0043] The above health functional food may be formulated into one selected from the group consisting of tablets, pills, powders, granules, powders, capsules, and liquid formulations, further comprising one or more of a carrier, diluent, excipient, and additive. Foods to which compounds according to one aspect may be added include various foods, powders, granules, tablets, capsules, syrups, beverages, gum, tea, vitamin complexes, and health functional foods.

[0044] Specific examples of the carrier, excipient, diluent and additive may include at least one selected from the group consisting of lactose, dextrose, sucrose, sorbitol, mannitol, erythritol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium phosphate, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, polyvinylpyrrolidone, methylcellulose, water, sugar syrup, methylcellulose, methyl hydroxy benzoate, propyl hydroxy benzoate, talc, magnesium stearate and mineral oil.

[0045] In addition to containing the above-mentioned effective ingredient, the above-mentioned health functional food may contain other ingredients as essential ingredients without special restrictions. For example, it may contain various flavoring agents or natural carbohydrates as additional ingredients, as in conventional beverages. Examples of the above-mentioned natural carbohydrates may include conventional sugars such as monosaccharides, such as glucose, fructose, etc.; disaccharides, such as maltose, sucrose, etc.; and polysaccharides, such as dextrin, cyclodextrin, etc.; and sugar alcohols, such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (thaumatin, stevia extracts (e.g., rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.) may be advantageously used. The proportion of the above-mentioned natural carbohydrates may be appropriately determined by a person skilled in the art.

[0046] In addition to the above, health functional foods according to the aspect may contain various nutrients, vitamins, minerals (electrolytes), flavorings such as synthetic flavorings and natural flavorings, coloring agents and thickening agents (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. These ingredients may be used independently or in combination, and the ratio of these additives may also be appropriately selected by those skilled in the art.

[0047]

[0048] Another aspect of the present invention is a feed composition for preventing or improving cancer comprising norethisterone enanthate, a stereoisomer, a hydrate, a solvate or a salt thereof.

[0049] The above “stereoisomer”, “hydrate”, “solvate”, “salt”, “cancer”, “prevention”, “improvement”, etc. may be within the above-mentioned range.

[0050] The term "feed" refers to any natural or artificial diet, meal, etc., or ingredients of such meal, intended for or suitable for consumption, ingestion, and digestion by an animal. Specifically, the feed composition for preventing or improving cancer according to the present invention can be manufactured using various types of feed known in the art, and preferably includes concentrate feed, roughage, and / or special feed.

[0051] Concentrated feed includes, but is not limited to, seed products including grains such as wheat, oats, and corn; bran including rice bran, wheat bran, and barley bran as by-products obtained by refining grains; sesame cakes which are by-products obtained by extracting soybeans, sesame seeds, linseeds, and coconut oil; residual starch which is the main component of starch residue left after removing starch from sweet potatoes, potatoes, etc.; animal feed such as fish meal, fish waste, fish soluble which is concentrated fresh liquid obtained from fish; meat meal, blood meal, feather meal, skim milk powder, dried whey which is the residue when manufacturing cheese from milk or casein from skim milk; yeast, chlorella, and seaweed.

[0052] Forage includes, but is not limited to, raw forage such as wild grass, grasses, and green grasses; root vegetables such as forage turnips, forage beets, and a type of turnip called luterberger; silage, which is stored forage made by filling a silo with raw grasses, green grasses, and grains and fermenting them with lactic acid; hay made by cutting and drying wild grasses and grasses; straw from crops for breeding stock; and leaves of legumes. Special feed includes, but is not limited to, mineral feed such as oyster shells and rock salt; urea feed such as urea or its derivative diuretic isobutane; feed additives and dietary supplements, which are substances added in small amounts to compound feed to supplement ingredients that are likely to be lacking when only natural feed ingredients are mixed or to increase the storability of feed.

[0053] The feed composition for preventing or improving the above cancer can be manufactured by adding norethisterone enanthate or a stereoisomer, hydrate, solvate or salt thereof in an appropriate effective concentration range according to various feed manufacturing methods known in the art.

[0054]

[0055] Another aspect of the present invention is the use of norethisterone enanthate or a stereoisomer, hydrate, solvate or salt thereof; or a composition comprising them, for the prevention or treatment of cancer.

[0056]

[0057] Another aspect of the present invention is the use of norethisterone enanthate or a stereoisomer, hydrate, solvate or salt thereof; or a composition comprising them, for the manufacture of a medicament for the prevention or treatment of cancer.

[0058] The present invention establishes the effects of inhibiting cancer cell proliferation and increasing apoptosis by treating cancer cells with norethisterone enanthate. Norethisterone enanthate can be useful in the development of anticancer therapeutics that inhibit cancer cell growth and induce apoptosis.

[0059] Figure 1 is a diagram showing the structure of norethisterone enanthate.

[0060] Figure 2 is a diagram analyzing the viability of cells after treating HepG2 with norethisterone enanthate.

[0061] Figure 3 is a diagram analyzing the viability of cells after treatment with norethisterone enanthate in H1975.

[0062] Figure 4 is a diagram analyzing the viability of cells after treating PC-3 with norethisterone enanthate.

[0063] Figure 5 is a diagram analyzing the viability of cells after treating HCT116 with norethisterone enanthate.

[0064] Figure 6 is a diagram showing the analysis of changes in tumor volume following treatment with norethisterone enanthate in mice xenografted with HCT116.

[0065] Figure 7 is a diagram analyzing the change in body weight following treatment with norethisterone enanthate in mice xenografted with HCT116.

[0066] Figure 8 is a diagram showing the analysis of changes in tumor volume following treatment with norethisterone enanthate in HepG2 xenografted mice.

[0067] Figure 9 is a diagram analyzing the change in body weight in mice xenografted with HepG2 after treatment with norethisterone enanthate.

[0068] Figure 10 is a comparative analysis of the tumor volume growth in mice xenografted with HepG2 after treatment with norethisterone enanthate and the anticancer drug sorafenib.

[0069] Figure 11 is a diagram analyzing the change in body weight in mice xenografted with HepG2 after treatment with norethisterone enanthate and the anticancer drug sorafenib.

[0070]

[0071] The present invention will be described in more detail below through examples. However, these examples are intended to exemplify the present invention and the scope of the present invention is not limited to these examples.

[0072]

[0073] Example

[0074] Example 1. Cell culture and compound preparation

[0075] HepG2 cells (human liver cancer cell line), HCT116 cells (human colon cancer cell line), and PC-3 (human prostate cancer cell line) were purchased from the Korean Cell Line Bank (KCLB), and H1975 (human non-small cell lung cancer (NSCLC) cell line) was purchased from the American Type Culture Collection (ATCC, Virginia, USA).

[0076] HCT116 and HepG2 cells were cultured in RPMI1640 medium (Rosewell Park Memorial Institute) supplemented with 2 mM glutamine, 1% penicillin-streptomycin, and 10% fetal bovine serum (FBS) at 37°C and 5% CO2.

[0077] Norethisterone enanthate was purchased from MedChemExpress.

[0078]

[0079] Example 2. Confirmation of the effect of norethisterone enanthate on reducing cancer cell viability.

[0080] We tested whether norethisterone enanthate treatment had a viability-reducing effect on HepG2, H1975, PC-3, and HCT116 cells.

[0081] Specifically, cells were seeded at 2–5 × 10 in 96-well plates. 3 Cells were seeded at a density of 10 cells / well and cultured at 37°C for 24 h before treatment with norethisterone enanthate. Plates treated with various concentrations (0–20 μM) of norethisterone enanthate were incubated at 37°C in 5% CO2 for 72 h.

[0082] Afterwards, 100 μl of assay reagent (CellTiterGlo, Promega) was added to each well, and luminescence was measured using a plate reader (GloMax® Discover Microplate Reader; Promega), and cell viability (%) was calculated from this.

[0083] As a result, it was confirmed that cell viability significantly decreased as the concentration of norethisterone enanthate increased in all HepG2, H1975, PC-3, and HCT116 cells (Figs. 2, 3, 4, and 5). Table 1 below shows the IC50 of each cancer cell.

[0084] TissueCell lineIC50(μM)LiverHepG20.54LungH19750.82ProstatePC30.82ColonHCT1160.98

[0085] From this, it was confirmed that norethisterone enanthate has an anticancer effect against various cancers.

[0086]

[0087] Example 3. Confirmation of the tumor growth inhibitory effect of norethisterone enanthate in a mouse xenograft model.

[0088] To determine the anticancer effects of norethisterone enanthate in a mouse xenograft model, we examined changes in tumor size. After injecting HCT116 and HepG2 cells into the mouse xenograft model, norethisterone enanthate was administered, and changes in tumor size were measured.

[0089] Specifically, HCT116 cells (1 Х 10 6 (Cells) were subcutaneously implanted into 6- to 8-week-old male BALB / c nude mice. After the average tumor volume reached 100-150 mm³, the mice were randomly divided into three groups (five mice per group). Norethisterone enanthate was administered intraperitoneally to two groups of mice at 10 mg / kg (mpk) and 20 mg / kg, respectively, every other day for 14 days. At this time, 100 μL of a solution containing DMSO, Tween-80, PEG300, and saline in a volume ratio of 5:5:20:70 was administered intraperitoneally to the remaining group of mice every other day for 14 days. Body weight and tumor diameter were measured every other day, and the tumor volume was evaluated using a caliper according to the following formula [Mathematical Formula 1]:

[0090] [Mathematical Formula 1]

[0091] .

[0092] P-values ​​were determined using Student's t-test.

[0093] HepG2 cells (1.5 Х 10 6 (Cells) were subcutaneously implanted into 6- to 8-week-old male BALB / c nude mice. After the average tumor volume reached 50 mm³, the mice were randomly divided into three groups (six mice in each group). Two groups of mice were intraperitoneally injected with norethisterone enanthate at 10 mg / kg and 20 mg / kg daily for 10 days. At this time, a solution containing DMSO, Tween-80, PEG300, and saline in a volume ratio of 5:5:20:70 was intraperitoneally injected at 100 μL daily for 10 days to the remaining group of mice. Body weight and tumor diameter were measured every other day, and tumor volume was evaluated using a caliper according to the formula in [Equation 1] above. P-values ​​were determined using Student's t-test. The animal experiment protocol was purchased from Ersteq Co., Ltd. It was performed in accordance with guidelines approved by the Animal Care and Use Committee.

[0094] As a result, experiments confirmed that norethisterone enanthate inhibited tumor growth in a concentration-dependent manner compared to the control group in both HCT116 cell and HepG2 cell mouse xenograft models (Figs. 6 and 8). In addition, it was confirmed that the body weights of HCT116 cell and HepG2 cell mouse xenograft models remained constant during the administration of norethisterone enanthate (Figs. 7 and 9).

[0095] From this, it was confirmed that norethisterone enanthate has an anticancer effect by inhibiting tumor growth in an animal model.

[0096]

[0097] Example 4. Confirmation of superior tumor growth inhibition effect compared to existing anticancer drugs.

[0098] To determine whether norethisterone enanthate possesses superior anticancer effects compared to existing anticancer drugs, we compared changes in tumor size. After injecting HepG2 cells into a mouse xenograft model, we treated the cells with norethisterone enanthate and measured changes in tumor size.

[0099] Specifically, HepG2 cells (3 Х 10 6 (cells) were subcutaneously implanted into 6- to 8-week-old female BALB / c nude mice. After the average tumor volume reached 50 to 100 mm³, the mice were randomly divided into four groups (six mice in each group). Two groups of mice were administered intraperitoneally 10 mg / kg and 20 mg / kg of norethisterone enanthate daily, respectively, and one group was administered intraperitoneally 20 mg / kg of sorafenib daily. The remaining group was administered intraperitoneally 100 μL of the same vehicle as in Example 3 daily for 14 days. Body weight and tumor diameter were measured every other day, and tumor volume was evaluated using a caliper according to the formula in [Equation 1] above. P-values ​​were determined using Student's t-test. The animal experiment protocol was performed in accordance with the guidelines approved by the Animal Care and Use Committee of Ersteq Co., Ltd.

[0100] As a result, the mouse xenograft model not treated with norethisterone enanthate showed a continuous increase in tumor size, whereas the mouse xenograft model treated with norethisterone enanthate showed a continuous decrease in tumor size (Fig. 10). In addition, norethisterone enanthate reduced tumor size in a dose-dependent manner and showed a better tumor size reduction than the existing anticancer drug sorafenib (Fig. 10). The body weight of the mouse xenograft model remained constant during the administration of norethisterone enanthate (Fig. 11).

[0101] From this, it was confirmed that norethisterone enanthate has a superior anticancer effect than the existing anticancer drug sorafenib.

[0102] The foregoing description of the present invention is provided for illustrative purposes only. Those skilled in the art will readily appreciate that the present invention can be readily modified into other specific forms without altering the technical spirit or essential characteristics of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive.

Claims

1. A pharmaceutical composition for preventing or treating cancer comprising norethisterone enanthate, a stereoisomer, a hydrate, a solvate or a salt thereof.

2. A pharmaceutical composition according to claim 1, which does not cause the side effect of weight increase or decrease.

3. A pharmaceutical composition according to claim 1, wherein the cancer is a solid cancer.

4. A pharmaceutical composition according to claim 1, wherein the cancer is a blood cancer.

5. In claim 3, the solid cancer is breast cancer, lung cancer, prostate cancer, ovarian cancer, brain cancer, liver cancer, cervical cancer, endometrial cancer, uterine cancer, colon cancer, large intestine cancer, colorectal cancer, rectal cancer, kidney cancer, nephroblastoma, skin cancer, oral squamous cell carcinoma, epidermoid cancer, nasopharyngeal cancer, head and neck cancer, bone cancer, esophageal cancer, bladder cancer, lymphatic cancer, stomach cancer, pancreatic cancer, testicular cancer, thyroid cancer, thyroid follicular carcinoma, melanoma, myeloma, multiple myeloma, mesothelioma, osteosarcoma, myelodysplastic syndrome, tumor of mesenchymal origin, soft tissue sarcoma, liposarcoma, gastrointestinal stromal sarcoma, malignant peripheral nerve sheath tumor, Ewing sarcoma, leiomyosarcoma, mesenchymal chondrosarcoma, lymphosarcoma, fibrosarcoma, rhabdomyosarcoma, teratocarcinoma, neuroblastoma, medulloblastoma, glioma, A pharmaceutical composition comprising at least one selected from the group consisting of benign skin tumors, leukemia, brain tumors, benign astrocytomas, malignant astrocytomas, pituitary adenomas, meningiomas, brain lymphomas, oligodendrogliomas, ependymomas, brainstem tumors, laryngeal cancer, oropharyngeal cancer, nasal / paranasal sinus cancer, nasopharyngeal cancer, salivary gland cancer, hypopharyngeal cancer, thyroid cancer, oral cancer, thoracic tumors, small cell lung cancer, non-small cell lung cancer, thymic cancer, mediastinal tumors, esophageal cancer, male breast cancer, abdominal tumors, gallbladder cancer, biliary tract cancer, small intestine cancer, colon cancer, anal cancer, male genital tumors, penile cancer, female genital tumors, ovarian cancer, uterine sarcoma, vaginal cancer, female external genital cancer, female urethral cancer, bone tumors, duodenal cancer, and fibrosarcoma.

6. A pharmaceutical composition according to claim 4, wherein the blood cancer is at least one selected from the group consisting of acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, acute monocytic leukemia, multiple myeloma, Hodgkin's lymphoma, and non-Hodgkin's lymphoma.

7. Health functional food for preventing or improving cancer, comprising norethisterone enanthate, a stereoisomer, hydrate, solvate or salt thereof.

8. A feed composition for preventing or improving cancer comprising norethisterone enanthate, a stereoisomer, a hydrate, a solvate or a salt thereof.

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