WO2019066469A1

WO2019066469A1 - Use of febuxostat or topiroxostat as agent for prevention and treatment of cancer metastasis

Info

Publication number: WO2019066469A1
Application number: PCT/KR2018/011386
Authority: WO
Inventors: 김용림; 최순연; 오세현
Original assignee: 경북대학교 산학협력단; 경북대학교병원
Priority date: 2017-09-27
Filing date: 2018-09-27
Publication date: 2019-04-04

Abstract

The present invention relates to a novel use of febuxostat or topiroxostat and, more specifically, to a pharmaceutical composition for suppression of cancer metastasis and prevention and treatment of cancer, the pharmaceutical composition containing, as an active ingredient, at least one selected from the group consisting of febuxostat, topiroxostat, and pharmaceutically acceptable salts thereof. The febuxostat or topiroxostat has a remarkable effect of specifically suppressing cancer metastasis, thereby providing a novel means for prevention and treatment of cancer.

Description

【Specification】

Title: Prophylactic and therapeutic use of cancer metastasis of Pemuksostat or Topical Roxostat

TECHNICAL FIELD This application claims the benefit of Korean Patent Application No. 10-2017-A filed on September 27,

0125443S. And Korean Patent Application No. 10-2018-0005667 filed on January 16, 2018, which are incorporated herein by reference in their entirety.

The present invention relates to novel uses of febuxostat or topiroxostat and more particularly to the use of a compound selected from the group consisting of peroxostart, topiroxorstart and pharmaceutically acceptable salts thereof, Which one _. And a pharmaceutical composition for prevention and treatment of cancer, which inhibits cancer metastasis and contains at least one effective ingredient.

BACKGROUND ART Cancer metastasis is the spread of cancer cells from primary cancer to other organs to form new cancers. Because metastasis is a major threat to life in a variety of cancer patients, preventing or controlling metastasis is an important goal in cancer research. When cancer is metastasized, the effectiveness of known chemotherapy methods is reduced. Clinically, the entire process of cancer metastasis has not yet been fully understood, but Epi thelial-Mesenchymal Transmission (EMT) has been recognized as an important concept in cancer metastasis (Sarah Heerboth et al ., EMT and tumor metastasis, Cl in Trans 1 Med. 2015; 4: 6.). Also, Wnt signaling pathway factors involved in cancer metastasis and their roles have been identified.

On the other hand, existing anticancer drugs have been mainly focused on inhibiting the growth of primary cancer (tumor). However, recent studies on tumor microenvironment (TME) cell-tumor cell interactions, Studies have shown that the treatment of target cancer drugs promotes the metastasis of cancer rather than cancer, thereby contributing to the outbreak of metastatic cancer. Ji-Sun Lee et a. According to 2015, when treated with a mouse model of cancer cells such as breast cancer, cixutumumab, an IGF-1R anticancer drug, was found to inhibit the growth of transplanted tumors, but metastasize to other organs (Ji-Sun Lee et al., STAT3-mediated IGF-2 secretion ion in the tumor microenvironment, in vitro resistance to anti-IGF-1R antisubstance, Nat Commun. 2015 Oct 14; 6: 8499, PMID: 26465273) . Therefore, there is a need for a new concept drug that can inhibit the mobility of cancer cells and inhibit metastasis, differently from anticancer drugs, which have been mainly focused on the elimination and growth inhibition of primary cancers.

SUMMARY OF THE INVENTION The inventors of the present invention conducted studies on cancer metastasis-inhibiting compounds, and confirmed that Pebuksotast or Topiroxastat specifically inhibited cancer cell migration and cancer metastasis, Completed.

It is therefore an object of the present invention to provide the use of phevaxostat topicals isostatic and their pharmaceutically acceptable salts for the prevention and treatment of cancer by inhibiting cancer metastasis.

Another object of the present invention to provide a page-start bukso 1511 ^ ₆₎ «)), toffee rokso start (topiroxostat) and their pharmaceutically acceptable salt thereof for the manufacture of a therapeutic preparation for the cancer.

Another object of the present invention is to provide an effective amount of a composition comprising, as an active ingredient, at least one selected from the group consisting of topoisomerase (topoisoxin), topiroxostat and pharmaceutically acceptable salts thereof And administering to a subject in need thereof a method for treating cancer. It is still another object of the present invention to provide the use of febuxostat, topi roxostat and pharmaceutically acceptable salts thereof for producing an agent for inhibiting cancer metastasis.

Another object of the present invention is to provide an effective amount of a composition comprising, as an active ingredient, at least one selected from the group consisting of febuxostat, topiroxostat and pharmaceutically acceptable salts thereof. To the object. Or a pharmaceutically acceptable salt thereof, and a method for inhibiting cancer metastasis.

[Technical Solution] In order to achieve the above object, the present invention provides a cancer metastasis comprising at least one member selected from the group consisting of Pebuksotast, Topi Roxostat and a pharmaceutically acceptable salt thereof as an active ingredient A pharmaceutical composition for prevention and treatment of cancer. The present invention also provides a pharmaceutical composition for the prevention and treatment of cancer, which inhibits cancer metastasis and is composed of at least one member selected from the group consisting of pemphigus starch, topiroxorstart, and pharmaceutically acceptable salts thereof. The present invention also provides a pharmaceutical composition for prevention and treatment of cancer, which is essentially composed of at least one member selected from the group consisting of pemphigus starch, topiary roxostat and pharmaceutically acceptable salts thereof. do.

In order to achieve another object of the present invention, the present invention provides a cancer-inhibiting food composition comprising at least one selected from the group consisting of Pebuksotsta, Topi Roxostat, and a pharmaceutically acceptable salt thereof as an active ingredient . The present invention also relates to a method for treating cancer, which comprises at least one member selected from the group consisting of pemphigus starch, topiroxorstart, and pharmaceutically acceptable salts thereof A food composition for inhibiting metastasis is provided. The present invention also provides a food composition for inhibiting cancer metastasis which is essentially composed of at least one member selected from the group consisting of pemphigus starch, topiroxstart, and pharmaceutically acceptable salts thereof.

In order to achieve still another object of the present invention, the present invention provides the use of febuxostat, topiroxostat and pharmaceutically acceptable salts thereof for preparing a therapeutic agent for cancer.

In accordance with still another aspect of the invention, the invention is Fe bukso start (febuxostat), toffee rokso start (topi roxostat) and those of the pharmaceutically acceptable than any ^one, selected from the group consisting of salts effective ingredient To a subject in need thereof an effective amount of a composition comprising the compound of the present invention.

In order to achieve still another object of the present invention, the present invention provides the use of febuxostat, topiroxostat and pharmaceutically acceptable salts thereof for producing an agent for inhibiting cancer metastasis.

In order to achieve still another object of the present invention, the present invention provides a pharmaceutical composition containing at least one selected from the group consisting of febuxostat, topiroxostat and pharmaceutically acceptable salts thereof as an active ingredient Which comprises administering an effective amount of the composition to a subject in need thereof.

Hereinafter, the present invention will be described in detail.

The present inventors have found that in vivo cancer metastasis models can be divided into two categories: It was confirmed that topiroxorstart specifically inhibited the metastasis of cancer cells and it was found that the behavior of the factors associated with the metastasis in the EMT and Wnt signaling systems was controlled normally at the molecular level. The use of such a pegylated starter and topiroxorstart for suppressing cancer metastasis is disclosed for the first time in the present invention. Accordingly, the present invention provides a method for inhibiting cancer metastasis of pemphigus starch, topiroxorstart, and pharmaceutically acceptable salts thereof; A composition for preventing, ameliorating or treating cancer.

The present invention suppresses metastasis of tumor cells (cancer cells) and thus can be applied to various cancers. But are not limited to, breast cancer, colorectal cancer, lung cancer, liver cancer, esophageal cancer, pancreatic cancer, gallbladder cancer, kidney cancer, bladder cancer, prostate cancer testicular cancer, cervical cancer, endometrial cancer, choriocarcinoma, , Head and neck cancer, malignant melanoma, lymphoma, aplastic anemia, and the like.

The 'cancer prevention and treatment' in the composition of the present invention is carried out by inhibiting cancer cells.

In the present invention, 'febuxostat' refers to the IUPAC designation 2- [3-cyano-4- (2-methylpropoxy) henyl] -4-methy 1 -1,3-thi azo 1 e-5-carboxy 1 ic acid ', And has a structure represented by the following formula (1). In the present invention, the phenol starting material may be commercially available or may be prepared by a chemical synthesis method known in the art, and examples of the synthesis include, but are not limited to, the following documents: US2013 / 0245278A1, Korean Patent No. 10-1630819, and the like.

&Lt; Formula 1 >

In the present invention, 'topiroxostat' refers to the IUPAC name '4- (5-pyridin-4-y1-1H1,1,2,4-ri azo1-3-y1) -car bon itri 1 e 'and has the structure of the following formula (2). In the present invention, the topical antioxidant may be purchased commercially or may be prepared by a chemical synthesis method known in the art. Examples of the synthesis of the topical antioxidant include, but are not limited to, CN105348264A, CN105566301A etc.

(2)

In the present invention, Pebusartot or topiroxorstant compound can be used as such or in the form of a salt, preferably a pharmaceutically acceptable salt. The term " pharmaceutically acceptable " as used herein means physiologically acceptable and does not generally cause an allergic reaction or a similar reaction when administered to a human. Examples of the salt include a pharmaceutically acceptable free acid ) Are preferred. As the free acid, an organic acid and an inorganic acid can be used. The organic acids include, but are not limited to, citric, acetic, lactic, tartaric, maleic, fumaric, formic, propionic, oxalic, tripleurooacetic, benzoic, gluconic, methosulfonic, glycolic, , Glutamic acid and aspartic acid. Such inorganic acids include, but are not limited to, hydrochloric acid, bricic acid, sulfuric acid, and phosphoric acid. In addition, pharmaceutically non-toxic salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, But are not limited to, but are not limited to, but are not limited to, but are not limited to, but are not limited to, halides, halides, halides, halides, halides, halides, But are not limited to, lactose, sebacate, fumarate, maleate, butyne-1,4-dioate, nucleic acid-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, Methoxybenzoate, phthalate, terephthalate Wight, Benzene sulfonate, tetraene sulfonate, chlorobenzene sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate lactate, hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate , Propane sulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate or mandelate, but are not limited thereto.

The pharmaceutically acceptable carrier may further include, for example, a carrier for oral administration or a carrier for parenteral administration. Carriers for oral administration may include lactose, starch, salicylose derivatives, magnesium stearate, stearic acid, and the like. In addition, the carrier for parenteral administration may contain water, a suitable oil, a saline solution, an aqueous glucose and a glycol, and may further contain a stabilizer and a preservative. Suitable stabilizers include antioxidants such as sodium hydrogen sulfite, sodium sulfite or ascorbic acid. Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. Other pharmaceutically acceptable carriers can be found in the following references (Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, PA, 1995).

The pharmaceutical composition of the present invention can be administered to mammals including humans by any method. For example, it can be administered orally or parenterally. Parenteral administration methods include, but are not limited to, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual or rectal administration Lt; / RTI >

In addition, the pharmaceutical composition may be formulated into oral or parenteral formulations according to the route of administration as described above. In the case of preparations for oral administration, the composition of the present invention may be formulated using methods known in the art such as powders, granules, tablets, pills, sugar tablets, capsules, liquids, gels, syrups, slurries, suspensions, . For example, the oral preparation may be prepared by mixing the active ingredient (in the present invention, at least one selected from the group consisting of Pebuksotst, Topi Roxostat, and a pharmaceutically acceptable salt thereof) with a solid excipient, Tablets or tablets of the sugar can be obtained by milling and processing with a granular blend after adding suitable auxiliaries have. Examples of suitable excipients include sugars such as lactose, dextrose, sucrose, sorbic, mannitol, xyli, erythritol and maltitol and corn starch, wheat starch, rice starch and potato starch Cells comprising rosin, gelatin, polyvinylpyrrolidone, and the like can be included in the cell, including cells, roots, methyl sal rosin, sodium carboxymethyl salicylose and hydroxypropyl methyl-sal rose. In addition, crosslinked polyvinylpyrrolidone, agar, alginic acid or sodium alginate may optionally be added as a disintegrant. Further, the pharmaceutical composition of the present invention may further comprise an anti-aging agent, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent and an antiseptic agent. The preparation for parenteral administration may be formulated by a method known in the art in the form of injections, creams, lotions, external ointments, oil agents, moisturizers, gels, aerosols and nasal inhalers. These formulations are described in Remington's Pharmaceutical Science, 15th Edition, 1975. Mack Publishing Company, East on, Pennsylvania 18042, Chapter 87: Blaug, Seymour), a commonly known formulary for all pharmaceutical chemistries. A preferable example of the preparation for parenteral administration may be an injecting agent. Examples of suitable carriers for injections include, but are not limited to, solvents or dispersion media containing water, ethanol, polyols (such as glycerol, propylene glycol and liquid polyethylene glycol, etc.), mixtures thereof and / or vegetable oils . More preferred examples of suitable carriers include Hank's solution, Ringer's solution, phosphate buffered saline (PBS) containing triethanolamine or isotonic solutions such as sterilized water for injection, 10% ethanol, 40% propylene glycol and 5% Can be used. In order to protect the injection from microbial contamination, various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like may be further included. Further, the injections may contain most of the ^weight, the horizontal isotonic agents such as sugars or sodium chloride cases.

The total effective amount of the compounds in the compositions of the present invention may be administered to a patient in a single dose and may be administered by a fractionated treatment protocol administered over a prolonged period of time in multiple doses have. The pharmaceutical composition of the present invention may vary in the content of the active ingredient depending on the severity of the disease. Preferably, the preferred total dose of the compounds in the composition of the present invention is about 0.01 to 1,000 mg daily dose, 0.1 to 100 mg is known. However, the dose of the compounds is not limited to the route of administration and the number of treatments of the pharmaceutical composition Considering various factors such as the patient's age, body weight, health condition, sex, severity of disease, diet and excretion rate, the effective dose for the patient is determined. Therefore, It will be possible to determine the appropriate effective dose depending on the specific use as inhibiting cancer metastasis of these compounds, preventing or treating cancer (tumor). The pharmaceutical composition according to the present invention is not particularly limited to its formulation, administration route and administration method as long as the effect of the present invention is exhibited.

The food composition of the present invention includes all forms such as functional foods, nutritional supplements, health foods, and food additives. Food compositions of this type may be prepared in a variety of forms according to conventional methods known in the art. For example, the health food may be prepared in the form of tea, juice and drink containing the above compounds, and liquefied, capped and powdered for ingestion. In addition, the above compounds can be administered in combination with anticancer (ant

Tumor growth inhibition), or a known substance or active ingredient known to have an inhibitory effect on cancer metastasis.

Functional foods also include but are not limited to beverages (including alcoholic beverages), fruits and processed foods (e.g., canned fruits, jams, maamarade, etc.), fish, meat and processed foods (Eg butter, chewing), edible vegetable oil, margarine (for example, sausage, noodles, etc.), breads and noodles (eg udon, buckwheat noodles, ramen noodles, spaghetti, macaroni, , Vegetable protein retort foods, roasted foods, various seasonings (e.g., soybean paste, soy sauce, sauces, etc.). Further, in order to use the above-mentioned compounds in the form of food additives, they may be used in the form of powders or concentrates.

The preferred content of the compounds in the food composition of the present invention is not particularly limited, but is preferably 0.01 to 50% by weight in the finally prepared food. The present invention provides the use of febuxostat, topiroxostat and pharmaceutically acceptable salts thereof for preparing a therapeutic agent for cancer.

The present invention relates to a pharmaceutical composition comprising an effective amount of a composition comprising, as an active ingredient, at least one selected from the group consisting of febuxostat, topiroxostat and pharmaceutically acceptable salts thereof, Or a pharmaceutically acceptable salt thereof.

The present invention provides the use of febuxostat, topiroxostat and pharmaceutically acceptable salts thereof for producing an agent for inhibiting cancer metastasis.

The present invention relates to a method of treating an effective amount of a composition comprising, as an active ingredient, at least one selected from the group consisting of febuxostat, topiroxostat and pharmaceutically acceptable salts thereof, Or a pharmaceutically acceptable salt thereof.

The "effective amount" of the present invention refers to an amount that, when administered to an individual, is indicative of improvement, treatment, prevention, detection, diagnosis, or inhibition of cancer or metastasis of cancer, , Particularly an animal including a human, and may be an animal-derived cell, tissue, organ, and the like. The subject may be a patient requiring the effect. The term " treatment " of the present invention broadly refers to ameliorating the symptoms of cancer or cancer, which may include curing, substantially preventing, or ameliorating the condition, But is not limited to, relieving, curing or preventing symptoms or most symptoms. The term " compri sing " of the present invention is used in the same way as " containing " or " characterized ", and does not exclude any additional component elements or method steps Do not. The term " consisting of " means excluding any additional elements, steps or components not otherwise mentioned. The term " essential consent of " as used herein is intended to encompass, in the scope of the invention, a component element or step as well as component elements or steps which do not materially affect its basic properties, .

[Effect of the Invention] [61] [61] 11) 31) and topi roxostat have a remarkable effect of specifically inhibiting the metastasis of cancer, thus providing new means for cancer prevention and treatment do.

ADVANTAGEOUS EFFECTS OF THE INVENTION Figures la to Id show the results of observing the changes in the metastasis pattern according to the oral administration of phevasostat for the normal diet (ND) or the ghoulcoleste diet (HCD) breast cancer mouse model. FIG. 1A shows the in vivo luminescence image changes (lesion sites) in the order of time in each experimental group, FIG. 1B shows the result of comparative evaluation of the degree of cancer metastasis after excision of organs in each experimental group after the experiment , Degree. lc indicates the extent of cancer metastasis to other organs in each experimental group _. Id shows the results of H & E staining for cancer metastasis in lung and liver tissues in each experimental group.

FIGS. 2A to 2C show the expression pattern of EMT-related factors f ibronectin (FIG. 2A), E-cadherin (FIG. 2B) and vimentin (FIG. 2C) for cancer metastasis in each experimental group.

FIGS. 3A and 3B show the expression pattern of AQP5 (FIG. 3A) and MMP9 (FIG. 3B), which are factors involved in cancer cell migration, comparatively for each experimental group. FIGS. 4A and 4B show the expression pattern of Wnt signal pathway-related factors Wnt7a (FIG. 4A) and β-catenin (FIG. 4B) for cancer metastasis relative to each experimental group.

FIG. 5 shows the results of evaluation of cancer cell survival rate by using MTT assay for breast cancer cells induced to metastasize to LDL (as a positive control, PE isostatic or LDL alone treatment group is used).

FIGS. 6A and 6B show the results of evaluating the cancer cell mobility of breast cancer cells induced by metastatic status into LDL using the Wound healing assay method (IncuCyte® Scratch found cell migration system) (Fig. 6A) and the final quantitative result (Fig. 6B) with time.

FIGS. 7A and 7B show the results of transwell migration assay of breast cancer cells induced by metastasis to LDL using the transwell migration assay. 7a) and final quantification results (Fig. 7b).

FIG. 8 shows the results of evaluating the cancer cell mobility according to the concentration of the starting cells in the breast cancer cells induced by the metastatic state to LDL using the Wound healing assay (IncuCyte® Scratch Wound Cell Migration System).

FIGS. 9A and 9B show the results of evaluating the cancer cell mobility after treatment with toxitosotrost in Wound healing assay (IncuCyte® Scratch Wound Cell Migration System) for breast cancer cells induced to metastatic state by LDL (FIG. 9A) and the final quantitative result (FIG. 9B) over time. BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail. However, the following examples are illustrative of the present invention, and the present invention is not limited to the following examples.

Experimental Method

1. In vivo cancer metastasis experiment

Four-week-old female BALB / c mice were obtained from SAMTACO bioscience CO., LTD, Korea. The mice were divided into two groups (normal diet D10001 control rodent diet, Research Diets Inc.) and gourcoleste diet group (gourcoleste for feed D12336, Research Diets Inc.), and gourcoleste was fed for 6 weeks. On the 4th week after the high cholesterol diet, Luc-4T1 breast cancer cell line (BW124087, PerkinElmer, lxi0 ⁶ cell suspended in 100 ^ RPMI) was injected into the mammary fat pad of BALB / Mouse model was constructed. In addition, Febuxost at (Catalog No. 14127, Cayman chemical, feed mixed with drinking water) was orally administered in an amount of 10 mg / kg / day. During the experimental period, cancer metastasis was observed with IVIS Lumina XRMS (PerkinElmer) in vivo. After 6 weeks, the mice of each experimental group were regenerated and the organs were observed.

2. H & E staining The tissues (lung, liver, and primary carcinoma) were fixed in paraffin formaldehyde (PFA), rinsed, dehydrated and clarified, embedded in paraffin after paraffin infiltration. And paraffin-embedded tissue ol-size. The scored tissue was stained on a slide, stained with Harris hematoxylin for 7 min, washed for 10 min, and eosin stained for 3 min.

3. In vitro cancer metastasis experiments

Incubation patterns were observed in vitro through the IncuCyte® Scratch Wound Cell Migration System. Briefly, a 4T1 breast cancer cell line (ATCC®, CRL2539 ™) was seeded on a 96-well plate at 1.2 × 10 ⁴ cells and then seeded at 96-pin A scratch was made using a WounderMaker (IncuCyte). The debris was removed with PBS, and real-time cells were measured at intervals of 4 hours while being treated with 50 μg / m LDL (Merk) and 50 μM Febuxostat (Calbiochem) or 50 μM Toporoxostat (Calbiochem) for 48 hours. The relative wound density was expressed as a percentage of the control.

4. Measurement of cancer cell survival rate

4T1 breast cancer cell lines (ATCC®, CRL2539 ™) were dispensed into 96-well plates at 7 × 10 ³ cells / well, and then treated with LDL (Merk) and 50 μM Febuxostat (Calbiochem) for 24 hours. After the reaction, the cells were repelled for 4 hours in 500/3 MTT (Amresco) solution, and the stained cells were dissolved using 200 // DMSO (Amersco) and then measured at 570 nm absorbance. The graphs are expressed as a percentage of the control.

5. Transwell cell migration analysis

The 4T1 breast cancer cell line reacted with 50 μg / n LDL (Merk) and 50 μM Febuxostat (Calbiochem) for 24 h was incubated with the Corning® Transwell system for 2 to ⁴ hours _well cell culture Inserts (Corning) were dispensed 10,000 wells per well. After 4 h, the bottom of the membrane was fixed in 3.7% formaldehyde for 10 min. After washing with PBS, the cells were stained with 0.1% crystal violet (Sigma-Aldrich). The stained cells were photographed 10 times at a resolution of 100 times in an optical microscope and then expressed as a percentage of the number of cells stained for the control group.

6. Real-time PCR Total RA was extracted from the primary tumor tissue using TRIzol (Invitrogen), and cDNA was synthesized using PrimeScript ™ 1 ^st strand cDNA synthesis kit (Takara). The synthesized cDNA was performed by qPCR using ^{Power SYBR® "Green PCR Master Mix (} Thermo) and the reaction, StepOne Plus Real-time PCR system (Appl ied Biosystems) was. Banung qPCR conditions were 30 seconds at 95 ^° C 40 cycles denaturation and annealing and polymerization for 1 min at 60 ^° C. The primer The sequence is shown in Table 1 below.

[Table 11

Statistical analysis All data were expressed as mean SEM and at least four experiments were performed. All statistical analyzes were performed using GraphPad prism 5.01 programs (GraphPad) of ^{one ¬ way ANOVA Tukey 's Post} hos analysis. P values less than 0,05 were statistically significant.

Example 1: In vivo inhibition of metastasis

1-1. Cancer metastatic mouse model Biomedical imaging and long-term metastasis confirmed As shown in Figs. La to Id, it was confirmed that breast cancer was significantly transferred in the mice that had undergone HCD (high cholesterol diet) than those in which the normal diet (ND) was performed after breast cancer cell transplantation. In particular, many metastases to the lungs have been identified, and some metastases to the liver and spleen have been observed. On the other hand, it was confirmed that cancer metastasis was significantly inhibited in the group administered with Pegasus start (see Figs. La to Id).

1-2. Confirmation of Expression Patterns of Cancer Metastasis-Related Factors The expression pattern of cancer metastasis-related factors was confirmed in the lesion tissues obtained from the experimental groups of Example 1-1. It is known that the epithelial mesenchymal transition (EMT) plays a very important role in the process of metastasis. In this regard, there is a decrease in E-cadherin, an increase in vimentin and fibronectin in cancer metastasis, In this study, we also confirmed that these factors have the same expression patterns in breast cancer transgenic mice (HCD + cancer). On the other hand, in the treatment group of the bevacizumab, the increase of E-cadherin (FIG. 2b), the decrease of vimentin (FIG. 2c) and the decrease of fibronectin (FIG. In addition, AQP5 and MMP9 were increased in relation to cancer cell migration, and it was confirmed that the expression of the factors was decreased by treatment with Pevasostat (FIGS. 3A and 3B). In addition, Wnt7 and β-catenin, which are related to the Wnt signal pathway, were found to be increased in breast cancer metastatic mice, but the expression of the factors was decreased by treatment with Pevasostat (FIGS. 4A and 4B).

Example 2: Confirmation of specific inhibitory effect on cancer cell metastasis (migration) in vitro In order to investigate whether phevocastat acts specifically to control the metastasis of cancer cells, 4wt. Breast cancer cell lines were treated with phenobarbstart alone or with LDL low density lipoprotein cholesterol) was treated to induce metastatic status, treated with Pevasostat and MTT assay, Wound healing assay and migration assay. As shown in the results of the evaluation of the cancer cell survival rate by the < RTI ID = 0.0 > mni assay, < / RTI > (Figs. 6A, 6B, 7A and 7B). In addition, the effect of inhibiting the migration of cancer cells by the pegasus starter was dose-dependent (Fig. 8).

Example 3: In vitro cancer cell metastasis-specific inhibitory effect of topiroxlostat In order to examine whether topiroxlostat specifically acts to control the metastasis of cancer cells, the 4T1 breast cancer cell line was cultured in the same manner as in Example 2, Roxastat was treated alone or treated with low density lipoprotein cholesterol (LDL) to induce a metastatic state, followed by topical antioxidant treatment and Wound healing assay. As a result, as shown in FIGS. 9A and 9B, the relative wound density of the cells was low in the group treated with topical antioxidant in the group inducing the metastatic state to LDL (FIG. 9A). Also, when the relative wound densities of the cells were quantified, the relative wound densities decreased with concentration when treated with Topi Roxostat (Fig. 9b). It was confirmed that topiary risot. Specifically inhibited the migration (metastasis) of cancer cells, and it was confirmed that the inhibitory effect of topical risoxast on cancer cell migration was increased in a concentration dependent manner.

INDUSTRIAL APPLICABILITY As described above, the present invention relates to a novel use of febuxostat or topiroxostat, and more particularly, to a novel use of febuxostat or topiroxostat, A pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt thereof, as an active ingredient, to a pharmaceutical composition for prevention and treatment of cancer. Since febuxostat and topiroxostat have a remarkable effect of specifically inhibiting the metastasis of cancer, they provide a new means for cancer prevention and treatment, and thus are highly industrially applicable in the pharmaceutical industry and the like .

Claims

Claims:

Claims: What is claimed is: 1. A process for the production of topoisomerase 1 (0), topi roxostat and

A pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition for the prophylaxis and treatment of cancer comprising as an active ingredient.

2. The composition according to claim 1, wherein the prevention and treatment is carried out by inhibiting the metastasis of cancer cells.

3. The method according to claim 1, wherein the cancer is selected from the group consisting of breast cancer, colon cancer, lung cancer, liver cancer, gastric cancer, esophageal cancer, pancreatic cancer, gallbladder cancer, renal cancer, bladder cancer, prostate cancer, testicular cancer, cervical cancer, endometrial cancer, Ovarian cancer, thyroid cancer, brain cancer, head and neck cancer, malignant melanoma, lymphoma and aplastic anemia.

4. The method of claim 1, further comprising: ), Topi roxostat, and a pharmaceutically acceptable salt thereof, as an active ingredient.

5. A method for inhibiting cancer metastasis comprising, as an active ingredient, at least one member selected from the group consisting of Pemuksonstart ^ 61¾1} (0), topi roxostat and pharmaceutically acceptable salts thereof. Composition.

[Claim 6] Use of febuxostat, topiroxostat and pharmaceutically acceptable salts thereof for the preparation of a therapeutic agent for cancer.

7. A pharmaceutical composition comprising an effective amount of a composition comprising, as an active ingredient, at least one selected from the group consisting of febuxostat, topiroxostat and pharmaceutically acceptable salts thereof, Wherein said method comprises administering to said mammal a therapeutically effective amount of said compound.

8. The method of claim 7, wherein the cancer is selected from the group consisting of breast cancer, colon cancer, lung cancer, liver cancer, gastric cancer, esophageal cancer, pancreatic cancer, gallbladder cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, cervical cancer, Cancer, thyroid cancer, brain cancer, head and neck cancer, malignant melanoma, lymphoma, and aplastic anemia.

9. The use of febuxostat, topiroxostat and pharmaceutically acceptable salts thereof for producing an agent for inhibiting cancer metastasis.

10. A pharmaceutical composition comprising an effective amount of a composition comprising, as an active ingredient, at least one selected from the group consisting of febuxostat, topiroxostat and pharmaceutically acceptable salts thereof, &Lt; / RTI > or a pharmaceutically acceptable salt thereof.

Claim 111

11. The method of claim 10, wherein the cancer is selected from the group consisting of breast cancer, colon cancer, lung cancer, liver cancer, gastric cancer, esophageal cancer, pancreatic cancer, gallbladder cancer, renal cancer, bladder cancer, prostate cancer, testicular cancer, Wherein the composition is selected from the group consisting of choriocarcinoma, ovarian cancer, thyroid cancer, brain cancer, head and neck cancer, malignant melanoma, lymphoma and aplastic anemia.