KR102355610B1 - Anticancer composition comprising cancer metabolism regulator - Google Patents

Abstract

The present invention relates to (1) an ASCT2 inhibitor; (2) a biguanide compound or a pharmaceutically acceptable salt thereof; And (3) to a pharmaceutical composition for the prevention or treatment of cancer comprising 2-deoxy-D-glucose (2-deoxy-D-glucose) as an active ingredient. The composition according to the present invention exhibits a synergistic anticancer effect by appropriately combining specific drugs having a problem that must be used in excess, thereby killing cancer cells and effectively treating cancer with a small amount. Moreover, the composition of the present invention can be usefully used as an anticancer agent and a composition for preventing or improving cancer because it can kill only cancer cells without side effects by exhibiting a cancer cell-specific toxic effect without being toxic in normal cells.

Description

Anticancer composition comprising cancer metabolism regulator

The present invention relates to an ASCT2 inhibitor; biguanide-based compounds; And 2-deoxy-D- relates to an anticancer composition comprising a glucose, more specifically, ASCT2 inhibitor; biguanide-based compounds; It relates to an anticancer composition comprising 2-deoxy-D-glucose and optionally an inositol-based compound and an immune checkpoint inhibitor.

The Warburg effect is an energy metabolism phenomenon that judges cancer-like tissues. As the metabolic pathway of glucose works abnormally, the glycolysis process, which is a metabolic reaction of glucose, does not properly lead to the normal flow to the citric acid cycle or electron transport system. In addition to that, pyruvic acid, a product of glycolysis, is fermented into lactic acid and released outside the cell. The first scientist to mention this was Otto Heinrich Warburg.

The Warburg effect in oncology indicates that, under aerobic conditions, cancer cells tend to favor metabolism via glycolysis over the much more efficient oxidative phosphorylation pathway favored by most other cells in the body (Alfarouk et al., Oncoscience 2014;12). :777?802). In tumor cells, the final product of glycolysis, pyruvic acid, is converted to lactic acid (Alfarouk et al., J ENZYM INHIB MED CH. 2016;31:859?866).

Recently, there is a lot of interest in the development of anticancer therapies that target cell signaling pathways that are important for the metabolism and growth of cancer cells. Metformin) and 2-deoxy-D-glucose (Wokoun et al., Oncol Rep. 2017;37:2418-2424).

As an antihyperglycemic agent, metformin has been used as the first-line treatment for type 2 diabetes for decades. Despite the widespread use of metformin as an antidiabetic drug, its potential anticancer effects were first reported in mammals in 2001. Additionally, the first reports of a reduced cancer risk in people with type 2 diabetes treated with metformin were published only 10 years ago. Since then, in many papers, metformin has shown consistent antiproliferative action in several cancer cell lines, including ovarian cancer, and in xenografts or transgenic mice. With respect to metabolism, metformin has been identified as a new class of complex I and ATP synthase inhibitors, acting directly on mitochondria, restricting respiration, making energy inefficient and reducing glucose metabolism through citric acid circulation (Andrzejewski et al., 2014; 2:12-25).

2-deoxy-D-glucose has been considered as a potential anticancer agent because of the dependence of tumor cells on glycolysis. 2-deoxy-D-glucose is a glucose analogue, which can be readily taken up by glucose transporters, and acts as a competitive inhibitor of glycolysis, reducing ATP production, thereby preventing cell death through activation of caspase-3 in solid tumors. inducing (Zhang et al., Cancer Lett. 2014;355:176-183).

The commonly used doses of metformin and 2-deoxy-D-glucose are insufficient to sufficiently treat cancer, and have limitations in that adverse reactions may occur during high-dose treatment (Raez et al., Cancer Chemother Pharmacol. 2013). ;71:523?530). The combined treatment of metformin and 2-deoxy-D-glucose studied by Chung et al. showed that it was effective in breast cancer cell lines, but this was higher than the tolerable concentration in the human body or the administrable concentration in plasma. (Cheong et al., Mol Cancer Ther. 2011;10:2350?2362). In another paper, a combination of metformin and 2-deoxy-D-glucose was successfully tested in prostate cancer cells using concentrations of metformin higher than those available in human plasma (Ben Sahra et al., Cancer Res. 2010; 70:2465?2475). This suggests that it is desirable to lower the therapeutic concentrations of metformin and 2-deoxy-D-glucose, which are clinically effective anticancer drugs, within a range that can be reasonably achieved in vivo. This suggests the need to develop combination therapies as well as strategies for tumor selective delivery (He et al., J CONTROL RELEASE. 2015;219:224-236).

Meanwhile, in addition to glucose, a new study shows an important role for glutamine in energy production, biosynthesis and cellular homeostasis in cancer cells (Altman et al., Nat Rev Cancer. 2016;16:619-634). Glutamine is transported into cells via ASCT2 (alanine-serine-cysteine transporter, type-2) (Geldermalsen et al., Oncogene. 2016;35:3201-3208).

After being transported into cells, glutamine itself can contribute to nucleotide biosynthesis. In addition, it may be involved in protein folding by contributing to the synthesis of uridine diphosphate N-acetylglucosamine, and may be converted into glutamate by mitochondrial glutaminase.

Alteration of glutamine requirements is also known as "glutamine poisoning," in which cancer cells consume high amounts of glutamine to maintain survival or proliferation compared to normal cells. Based on this feature, several compounds have been developed to target the aberrant dependence of cancer cells on glutamine (Choi et al., Biomolecules & therapeutics. 2018;75:19-28).

There are documents that study anticancer effects using binding molecules specific for ASCT2 (WO 2017/083451, WO 2018/107173, Toxicology and Applied Pharmacology 265 (2012) 93-102). For example, CB-839 is a glutaminase inhibitor in phase II clinical trials (Harding et al., J. CLIN. ONCOL. 2015;33:2512-2512). In addition, the recently reported inhibitor of the glutamine transporter ASCT2, V-9302, showed a promising antitumor response by inhibiting glutamine uptake in preclinical studies (Schulte et al., Nat Med. 2018;24:194-202). However, similar to the enhanced glutamine metabolism upon inhibition of glycolysis, interference with glutamic acid metabolism results in upregulation of glucose metabolism.

On the other hand, inositol hexaphosphate and inositol are natural organophosphorus compounds that are contained in large amounts in most grains, seeds, and legumes, and also exist in mammalian cells, and are present together with a phosphate form with low phosphate (IP1-5). Inositol hexaphosphate plays an important role in regulating important cellular functions such as signal transduction, cell proliferation and differentiation of various cells, and is recognized as a natural antioxidant (Shamsuddin et al., J Nutr. 2003;133:3778S-3784S). ).

Recently, inositol hexaphosphate has been reported to have some inhibitory effects on cancer prevention and experimental tumor growth, progression and metastasis (Vucenik et al., Nutr Cancer. 2006;55:109-125).

In a preliminary clinical study, it was reported that inositol hexaphosphate and inositol co-administered with chemotherapy reduced the side effects of chemotherapy and improved the quality of life of breast or colorectal cancer patients with liver metastases. and inositol, it is difficult to effectively inhibit cancer cell growth only with a combination preparation.

On the other hand, suppression of the anticancer immune response has been shown to be an important mechanism of tumor resistance to treatment, and the immune checkpoint receptors CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) and PD-1 (programmed death-1) or Through the development of monoclonal antibodies that block its ligand PD-L1 (programmed death-ligand 1), it has become possible to stimulate and/or expand the patient's endogenous anticancer immune response.

These pathways may play distinct roles in immune regulation, eg, CTLA-4 primarily regulates T cell proliferation in lymph nodes, whereas PD-1 primarily inhibits T cells in the tumor microenvironment. These immune checkpoint inhibitors have recently demonstrated excellent efficacy against a wide variety of tumor types, particularly melanoma and non-small cell lung cancer, and have quickly become the standard treatment regimen for patients.

However, immune checkpoint inhibitors usually have immune-related side effects that harm the gastrointestinal tract, endocrine glands, skin and liver. Most of these side effects are known to be related to adverse reactions of the immune system as a result of activated T lymphocytes.

In addition, immune checkpoint inhibitors are effective in only a small number of patients. In most advanced cancers, the response rate of anti-PD-1/PD-L1 monotherapy is about 20% and that of anti-CTLA-4 is about 12%, suggesting that there is a need for improvement (Borghaei et al., N Engl J Med. 2015; 373:1627-1639). This low potency may be due to a lack of pre-existing tumor-associated T cell immunity (Elizabeth et al., Am J Clin Oncol. 2016 Feb; 39(1): 98-106).

In order to maximize the therapeutic effect of these immune checkpoint inhibitors, clinical trials are being conducted in combination with other anticancer drugs. As an example, two immunotherapy drugs (nivolumab and ipilimumab combination treatment) for the treatment of advanced melanoma showed a greater improvement in survival rate than either monotherapy. However, treatment-related side effects were high enough to discontinue treatment in 4 out of 10 patients. When cancer is induced, the combination of two or more treatments has become the cornerstone of cancer treatment today.

Therefore, there is an urgent need for research to increase the therapeutic effect while minimizing the side effects caused by anticancer drugs.

It is an object of the present invention to provide a pharmaceutical composition for preventing or treating cancer, which can effectively kill cancer even with a low concentration of a drug, and has reduced side effects by showing toxicity specifically to cancer cells.

Accordingly, the present invention is an ASCT2 inhibitor; biguanide compounds; a mixture of 2-deoxy-D-glucose; and optionally any one or more selected from the group consisting of inositol hexaphosphate, a pharmaceutically acceptable salt thereof, and inositol; And/or using an immune checkpoint inhibitor as a combination agent, it provides a pharmaceutical composition for anticancer that can effectively inhibit the growth of cancer cells.

Another object of the present invention is to provide a food composition for preventing or improving cancer.

As one aspect for achieving the above object, the present invention provides (1) an ASCT2 inhibitor; (2) a biguanide compound or a pharmaceutically acceptable salt thereof; and (3) 2-deoxy-D-glucose as an active ingredient. It provides a pharmaceutical composition for preventing or treating cancer.

In another aspect of the present invention, the pharmaceutical composition for preventing or treating cancer is an additional active ingredient (4) from the group consisting of inositol hexaphosphate, a pharmaceutically acceptable salt thereof, and inositol. It may further include one or more selected.

As another aspect of the present invention, the pharmaceutical composition for preventing or treating cancer may further include (5) an immune checkpoint inhibitor as another additional active ingredient.

As another aspect of the present invention, the pharmaceutical composition for preventing or treating cancer is composed of (4) inositol hexaphosphate, a pharmaceutically acceptable salt thereof, and inositol as another additional active ingredient. at least one selected from the group; and (5) an immune checkpoint inhibitor.

The above pharmaceutical compositions according to the present invention have an excellent effect of effectively treating cancer with few side effects, including individual small amounts of active ingredients. The pharmaceutical composition of the present invention can use a smaller amount of individual compounds included in the combination preparation than when treated with a single compound, thereby significantly lowering the risk and/or severity of side effects while significantly reducing the overall effect of treatment There are advantages to increasing it.

Hereinafter, the present invention will be described in detail.

In one aspect, the present invention provides a composition comprising: (1) an ASCT2 inhibitor; (2) a biguanide compound or a pharmaceutically acceptable salt thereof; And (3) to a pharmaceutical composition for the prevention or treatment of cancer comprising 2-deoxy-D-glucose (2-deoxy-D-glucose) as an active ingredient.

In the present invention, the ASCT2 inhibitor may be any one or more selected from a synthetic compound and an antibody, and the synthetic compound is V-9302, L-γ-glutamyl-p-nitroanilide (GPNA), 1,2,3-dithia It may be any one selected from the group consisting of sol-based compounds or a pharmaceutically acceptable salt thereof, and the antibody may be any one or more antibodies selected from the group consisting of KM4008, KM4012, KM4018, KM8094 and MEDI7247. The antibody may be purchased and used from, for example, a conventional antibody manufacturer, or may be prepared and used according to a known method for preparing an antibody.

According to the present invention, the antibody may be purchased from Creativebiolabs. KM4008 (CAT#: TAB-1006CLV), KM4012 (CAT#: TAB-1007CLV), KM4018 (CAT#: TAB-1008CLV-F(E)).

According to the present invention, V-9302 is a compound having the structural formula of the following formula (1).

[Formula 1]

`

According to the present invention, L-γ-glutamyl-p-nitroanilide (GPNA) is a compound having the structural formula of Formula 2 below.

[Formula 2]

According to the present invention, the 1,2,3-dithiazole-based compound is a compound having the structural formula of Formula 3 below.

[Formula 3]

In the formula,

R ₁ is halogen,

,

,

,

,

및

중에서 선택되고, R ₂ is

,

,

,

,

and

is selected from

R ₃ is hydrogen or C _{1- 6} alkyl,

R ₄ is any one selected from the group consisting of hydrogen, C _{1- 6} alkyl and -NH _2,

R ₅ is selected from —NH(CH ₂ ) _n C ₆ H ₆ and morpholinyl, n is an integer from 0 to 3,

,

및

로 이루어진 군으로부터 선택되는 1 내지 3개의 치환기로 치환되며, Z₁ 및 Z₂는 각각 독립적으로, C, O, N 및 S로 이루어진 군으로부터 선택되고; 상기 헤테로아릴은 피리딜, 피리미딜, 퀴놀리닐,

,

및

로 이루어진 군으로부터 선택되고, 여기서 Z₃은 수소, 산소 및 황 중에서 선택되고; R₆은 수소 또는 할로겐이다. Ar is aryl or heteroaryl; Here, the aryl is phenyl or naphthyl, the aryl is unsubstituted or substituted with one or more groups selected from halo, cyano, -OCF _3, phenyloxy, nitro, C _1-6 alkyl, C _{1- 6} alkyloxy, hydroxy,

,

and

substituted with 1 to 3 substituents selected from the group consisting of, Z ₁ and Z ₂ are each independently selected from the group consisting of C, O, N and S; The heteroaryl is pyridyl, pyrimidyl, quinolinyl,

,

and

is selected from the group consisting of, wherein Z ₃ is selected from hydrogen, oxygen and sulfur; R ₆ is hydrogen or halogen.

The halogen may be any one selected from chloro, bromo and iodo, and preferably chloro.

ASCT2 (alanine-serine-cysteine transporter 2; also known as SLC1A5) inhibitors are substances that can inhibit the metabolism of cancer cells. When the ASCT2 inhibitor is applied in combination with a biguanide compound and 2-deoxy-D-glucose according to the present invention, glucose in cancer cells that can be generated by the combination of the biguanide compound and 2-deoxy-D-glucose It is possible to solve the problem of a low level of metabolic inhibition.

Glutamine is one of the most abundant non-essential amino acids in the body, but is essential for cancer cells. Glutamine metabolism is very important for energy metabolism for the growth and proliferation of tumor cells. Tumor cells appear to consume the most glutamine compared to other amino acids, and absorb glutamine through various glutamine transporters. Glutamine starvation can interfere with tumor metabolism and inhibit tumor proliferation and survival. Glutamine is important for the synthesis of TCA cycle metabolites, nucleotides, splenic acid, antioxidants and ATP energy.

Glutamine enters cancer cells by amino acid transporters belonging to the SLC family, and ASCT2, a Na ⁺ -dependent neutral amino acid transporter encoded by the SLC1A5 gene, is mainly located in the cell membrane and is an important amino acid for the uptake of glutamine by rapidly growing tumor cells. mediates the exchange of substrates; Compared to healthy tissues, ASCT2 is significantly upregulated in many cancer cells. That is, many tumors show high glucose uptake and glutamine intoxication. An ASCT2 inhibitor according to the present invention, such as V-9302, inhibited glutamine uptake and exhibited an antitumor response in preclinical studies.

The composition according to the present invention prevents the breakdown of glucose in the tumor and reduces energy use by using a biguanide-based compound such as metformin in combination with 2-deoxy-D-glucose and an ASCT2 inhibitor that inhibits glutamine absorption. Not only can it effectively block the process, but it also exhibits a synergistic effect on anticancer through combined treatment. That is, the composition according to the present invention is preferable because the combination of the biguanide compound and 2-deoxy-D-glucose and the anticancer effect of the ASCT2 inhibitor are not simply added, but significantly improved.

In the present invention, the biguanide-based compound is, for example, metformin (Metformin) or phenformin (Phenformin). Specifically, metformin has the structural formula of Formula 4 below.

[Formula 4]

Specifically, phenformin has the structural formula of Formula 5 below.

[Formula 5]

Biguanide-based drugs are not limited thereto, but may exhibit anticancer effects through a mechanism of action that activates an enzyme called AMPK (AMP-activated kinase), which plays a central role in regulating intracellular energy balance and nutrient metabolism.

When metformin is orally administered to rats, the LD50 is 1,450 mg/kg, and it can be seen that metformin is a very safe compound, but there is a problem that it must be used in a high dose. On the other hand, phenformin was developed in the late 1950s as an oral diabetes treatment and was intended to be used for the treatment of non-insulin-dependent diabetes mellitus (type 2 diabetes). was banned

In the present invention, the above-mentioned combination formulation exhibits a high anticancer effect even at a much lower concentration than a composition that is a single agent or a combination of two compounds, while improving the problems of high dose administration or side effects of metformin or phenformin. It was confirmed that it is possible.

The pharmaceutical composition of the present invention includes (3) 2-deoxy-D-glucose; as an active ingredient.

In the present invention, 2-deoxy-D-glucose has a structure represented by the formula (6).

[Formula 6]

The compound of Formula 6 has an effect as an inhibitor of glycolysis.

2-deoxy-D-glucose, as a derivative of glucose, has the effect of inhibiting glycolysis in the glucose metabolism process and inducing ER stress by inhibiting glycosylation of proteins in the ER. As such, the glucose degradation inhibitor, 2-deoxy-D-glucose, was not shown to kill cancer cells by itself, but exhibits excellent anticancer effects by forming the combination formulation of the present invention.

The pharmaceutical composition of the present invention may further include (4) inositol hexaphosphate or a pharmaceutically acceptable salt thereof, inositol, or a mixture thereof as an additional active ingredient.

Inositol hexaphosphate (inositol hexaphosphate) or a pharmaceutically acceptable salt thereof, inositol (inositol), or when further comprising a mixture thereof exhibits an excellent anticancer effect than.

In the present invention, inositol hexaphosphate and/or inositol can modulate several important pathways in cancer cells. In the present invention, inositol hexaphosphate specifically has the structure of formula (7).

[Formula 7]

In the present invention, inositol specifically has the structure of formula (8).

[Formula 8]

In the present invention, inositol hexaphosphate or a pharmaceutically acceptable salt thereof, inositol, or a mixture thereof is used as an ASCT2 inhibitor, a biguanide-based compound or a pharmaceutically acceptable salt thereof, and 2-deoxy By combining with -D-glucose, it was confirmed that a high anticancer effect was exhibited even at a low concentration.

In the present invention, the biguanide-based compound, such as metformin or phenformin, may exist in the form of a pharmaceutically acceptable salt. In addition, in the present invention, inositol hexaphosphate may exist in the form of a pharmaceutically acceptable salt. As the salt, an acid addition salt formed with a pharmaceutically acceptable free acid is useful. As used herein, "pharmaceutically acceptable salt" refers to a concentration having an effective action that is relatively non-toxic and harmless to a patient. means any and all organic or inorganic addition salts other than

In this case, as the addition salt, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. can be used as inorganic acids, and as organic acids, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, Benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid and the like may be used, but are not limited thereto.

In addition, a pharmaceutically acceptable metal salt can be prepared using a base. The alkali metal salt or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate. In this case, it is pharmaceutically suitable to prepare a sodium, potassium, calcium, magnesium salt or a mixed salt thereof as the metal salt, but is not limited thereto.

A pharmaceutically acceptable salt of each of the biguanide compound (metformin or phenformin) and inositol hexaphosphate may be present in each of the biguanide compound (metformin or phenformin) and inositol hexaphosphate, unless otherwise indicated. salts of acidic or basic groups. For example, pharmaceutically acceptable salts may include sodium, potassium, calcium or magnesium salts of a hydroxyl group, and other pharmaceutically acceptable salts of an amino group include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts; It can be prepared through a method for preparing a known salt.

The salt of the biguanide compound (metformin or phenformin) of the present invention is a pharmaceutically acceptable salt, and any salt of metformin or phenformin that exhibits an anticancer effect equivalent to that of metformin or phenformin can be used, preferably For example, metformin hydrochloride, metformin succinate, metformin citrate or phenformin hydrochloride, phenformin succinate, phenformin citrate, etc. are possible, but are not limited thereto.

The inositol hexaphosphate salt of the present invention is a pharmaceutically acceptable salt, and any inositol hexaphosphate salt exhibiting an anticancer effect equivalent to that of inositol hexaphosphate can be used. Preferably, inositol hexaphosphate sodium, inositol hexaphosphate potassium, inositol Calcium hexaphosphate, inositol hexaphosphate ammonium, inositol hexaphosphate magnesium, inositol hexaphosphate calcium magnesium, and the like are possible, but not limited thereto.

The biguanide compound, 2-deoxy-D-glucose, and inositol hexaphosphate of the present invention also include derivatives thereof, respectively. The "derivative" refers to a compound prepared by chemically changing a part of the compound, for example, introducing, replacing, or deleting a functional group within the limit in which the anticancer activity of the compound does not change, and the present invention is not limited thereto. may be included.

In the present invention, inositol may exist in the form of various isomers. Isomers include both enantiomers and diastereomers. Any inositol that has an anticancer effect pharmaceutically can be used, preferably D-chiro-inositol, L-chiro-inositol, myo-inositol, and scyllo Any one or more selected from the group consisting of inositol (scyllo-inositol) is possible, but is not limited thereto.

Even if two or more drugs with known anticancer effects are combined, it cannot be expected that the combined drugs exhibit a synergistic effect (synergistic effect) with each other. It is very difficult to find a combination of drugs. In the present invention, an anticancer complex formulation that can maximize the anticancer effect while minimizing side effects by using the minimum concentration of the anticancer agent was developed.

The pharmaceutical composition of the present invention may further include (5) an immune checkpoint inhibitor as an additional active ingredient.

Immune checkpoint inhibitors can treat cancer by inhibiting immune evasion of cancer by blocking immune checkpoints that block the progression of immune responses in cancers with high immune suppression power. Immune checkpoint inhibitors (immune checkpoint inhibitors) are a new tumor treatment developed as a result of a lot of understanding of the human immune system due to the development of the field of immunology, and are widely used in anticancer strategies. Exemplary mechanisms for exhibiting anticancer effects using immune checkpoint inhibitors include a mechanism of T lymphocyte suppression by CTLA-4 and a mechanism of PD-1/PD-L1 suppressing previously activated T lymphocytes. However, treatment using only immune checkpoint inhibitors has been reported to have limitations such as low therapeutic efficiency and insufficient effect.

However, the pharmaceutical composition of the present invention comprises (1) an ASCT2 inhibitor; (2) a biguanide compound or a pharmaceutically acceptable salt thereof; (3) 2-deoxy-D-glucose (4) inositol hexaphosphate or a pharmaceutically acceptable salt thereof (5) co-administered with an immune checkpoint inhibitor for synergistic complementary effect Therefore, it is possible to improve the prevention and treatment of cancer.

The immune checkpoint inhibitor according to the present invention may be an antibody, a fusion protein, an aptamer or an immune checkpoint protein-binding fragment thereof. For example, the immune checkpoint inhibitor is an anti-immune checkpoint protein antibody or antigen-binding fragment thereof.

Immune checkpoint inhibitors of the present invention include an anti-CTLA-4 antibody, derivative or antigen-binding fragment thereof; anti-PD-L1 antibody, derivative or antigen-binding fragment thereof; anti-LAG-3 antibody, derivative or antigen-binding fragment thereof; anti-OX40 antibody, derivative or antigen-binding fragment thereof; anti-TIM3 antibody, derivative or antigen-binding fragment thereof; And it may be any one or more selected from the group consisting of an anti-PD-1 antibody, a derivative thereof, or an antigen-binding fragment thereof, preferably an anti-CTLA-4 antibody, an anti-PD-1 antibody, and an anti-PD-L1 It may be any one or more selected from the group consisting of. The antibody may be purchased and used from, for example, a conventional antibody manufacturer, or may be prepared and used according to a known method for preparing an antibody.

For example, the immune checkpoint inhibitor is Ipilimumab, a derivative or antigen-binding fragment thereof; Tremelimumab, a derivative or antigen-binding fragment thereof; Nivolumab, a derivative or antigen-binding fragment thereof; pembrolizumab, a derivative or antigen-binding fragment thereof; Pidilizumab, a derivative or antigen-binding fragment thereof; Atezolizumab, a derivative or antigen-binding fragment thereof; Durvalumab, a derivative or antigen-binding fragment thereof; Avelumab, a derivative or antigen-binding fragment thereof; BMS-936559, a derivative or antigen-binding fragment thereof; BMS-986016, a derivative or antigen-binding fragment thereof; GSK3174998, a derivative or antigen-binding fragment thereof; TSR-022, a derivative or antigen-binding fragment thereof; MBG453, a derivative or antigen-binding fragment thereof; LY3321367, a derivative or antigen-binding fragment thereof; And it may be any one or more selected from the group consisting of IMP321 recombinant fusion protein, and any antibody or other type of immune checkpoint inhibitor that can be used as an immune checkpoint inhibitor may be used without limitation.

The immune checkpoint inhibitor may be a small molecule compound that has an effect as the above-mentioned immune checkpoint inhibitor or is involved in its inhibitory mechanism. These small molecule compounds may be, for example, small molecule compounds that bind to immune checkpoint proteins or are involved in mechanisms related to immune checkpoint inhibition.

Specifically, the low molecular weight compounds are BMS-202 (source: BMS), BMS-8 (source: BMS), CA170 (source: Curis/Aurigene), CA327 (source: Curis/Aurigene), Epacadostat, GDC-0919, BMS- 986205 and the like. Any small-molecule compound used as an immune checkpoint inhibitor or having a related effect may be used without limitation.

Aspects of the pharmaceutical composition for preventing or treating cancer preferred in the present invention are,

ASCT2 inhibitors; a biguanide-based compound or a pharmaceutically acceptable salt thereof; and 2-deoxy-D-glucose;

a composition comprising an ASCT2 inhibitor, a biguanide compound or a pharmaceutically acceptable salt thereof, 2-deoxy-D-glucose, and inositol hexaphosphate or a pharmaceutically acceptable salt thereof;

a composition comprising an ASCT2 inhibitor, a biguanide compound or a pharmaceutically acceptable salt thereof, 2-deoxy-D-glucose, and inositol;

a composition comprising an ASCT2 inhibitor, a biguanide compound or a pharmaceutically acceptable salt thereof, 2-deoxy-D-glucose, inositol hexaphosphate or a pharmaceutically acceptable salt thereof, and inositol; or

a composition comprising an ASCT2 inhibitor, a biguanide compound or a pharmaceutically acceptable salt thereof, 2-deoxy-D-glucose, inositol hexaphosphate or a pharmaceutically acceptable salt, and an immune checkpoint inhibitor;

a composition comprising an ASCT2 inhibitor, a biguanide compound or a pharmaceutically acceptable salt thereof, 2-deoxy-D-glucose, inositol, and an immune checkpoint inhibitor; and

A composition comprising an ASCT2 inhibitor, a biguanide compound or a pharmaceutically acceptable salt thereof, 2-deoxy-D-glucose, inositol hexaphosphate or a pharmaceutically acceptable salt thereof, inositol, and an immune checkpoint inhibitor can

In the present invention, the ASCT2 inhibitor is, for example, V-9302, L-γ-glutamyl-p-nitroanilide (GPNA), a 1,2,3-dithiazole-based compound, antibody KM4008, antibody KM4012, antibody KM4018, antibody KM8094 and antibody It may be any one or more selected from the group consisting of MEDI7247. More preferably, at least one compound selected from the group consisting of V-9302, L-γ-glutamyl-p-nitroanilide (GPNA), 1,2,3-dithiazole compounds, or KM4008, KM4012, KM4018, KM8094 And it may be any one or more antibodies selected from the group consisting of MEDI7247, preferably V-9302.

For example, looking at a composition centered on metformin as a biguanide-based compound as an aspect for achieving the above object, the composition for preventing or treating cancer of the present invention is V-9302/metformin/2-deoxy -D-glucose combination formulation, V-9302/metformin/2-deoxy-D-glucose/inositol hexaphosphate combination formulation, V-9302/metformin/2-deoxy-D-glucose/inositol combination formulation, Combination formulation of V-9302/metformin/2-deoxy-D-glucose/inositol hexaphosphate/inositol, V-9302/metformin/2-deoxy-D-glucose/inositol hexaphosphate/inositol/anti-CTLA-4 Combination formulation of antibody, V-9302/metformin/2-deoxy-D-glucose/inositol hexaphosphate/inositol combination formulation, V-9302/metformin/2-deoxy-D-glucose/inositol hexaphosphate/inositol/ Combination formulation of anti-PD-1 antibody, and V-9302/metformin/2-deoxy-D-glucose/inositol hexaphosphate/inositol combination formulation, V-9302/metformin/2-deoxy-D-glucose/ It may be a combination formulation of inositol hexaphosphate/inositol/anti-PD-L1 antibody, and the metformin may be in the form of a pharmaceutically acceptable salt.

For example, as another aspect for achieving the above object, looking at a composition centered on phenformin as a biguanide-based compound, the composition for preventing or treating cancer of the present invention is V-9302/phenformin Combination formulation of /2-deoxy-D-glucose, V-9302/phenformin/2-deoxy-D-glucose/inositol hexaphosphate combination formulation, V-9302/phenformin/2-deoxy- Combination formulation of D-glucose/inositol, V-9302/phenformin/2-deoxy-D-glucose/inositol hexaphosphate/inositol combination formulation, V-9302/phenformin/2-deoxy-D- Combination formulation of glucose/inositol hexaphosphate/inositol/anti-CTLA-4 antibody, V-9302/phenformin/2-deoxy-D-glucose/inositol hexaphosphate/inositol combination formulation, V-9302/phenfort Combination formulation of min/2-deoxy-D-glucose/inositol hexaphosphate/inositol/anti-PD-1 antibody, and V-9302/phenformin/2-deoxy-D-glucose/inositol hexaphosphate/inositol It may be a combination formulation of V-9302/phenformin/2-deoxy-D-glucose/inositol hexaphosphate/inositol/anti-PD-L1 antibody, and the phenformin is a pharmaceutically acceptable salt of may be in the form

As one aspect for achieving the above object,

The combination formulation of V-9302/metformin/2-deoxy-D-glucose showed a very high effect in reducing tumor size than a single formulation of each compound or a combination formulation containing two compounds.

As one aspect for achieving the above object,

Combination formulation of V-9302/metformin/2-deoxy-D-glucose/inositol hexaphosphate,

Combination formulation of V-9302/metformin/2-deoxy-D-glucose/inositol, and

The combination formulation of V-9302/metformin/2-deoxy-D-glucose/inositol hexaphosphate/inositol is more effective in reducing tumor size than a single formulation of each compound or a combination formulation containing 2-3 types of compounds. appeared high.

As another aspect for achieving the above object,

Combination formulation of V-9302/metformin/2-deoxy-D-glucose/inositol hexaphosphate/anti-CTLA-4 antibody,

Combination formulation of V-9302/metformin/2-deoxy-D-glucose/inositol/anti-CTLA-4 antibody, and

The combination formulation of V-9302/metformin/2-deoxy-D-glucose/inositol hexaphosphate/inositol/anti-CTLA-4 antibody has more tumors than a single formulation of each compound or a combination formulation containing 2 to 4 compounds. The effect of reducing the size was very high.

As another aspect for achieving the above object,

Combination formulation of V-9302/metformin/2-deoxy-D-glucose/inositol hexaphosphate/anti-PD-1 antibody,

Combination formulation of V-9302/metformin/2-deoxy-D-glucose/inositol/anti-PD-1 antibody, and

The combination formulation of V-9302/metformin/2-deoxy-D-glucose/inositol hexaphosphate/inositol/anti-PD-1 antibody has more tumors than a single formulation of each compound or a combination formulation containing 2 to 4 compounds. The effect of reducing the size was very high.

As another aspect for achieving the above object,

Combination formulation of V-9302/metformin/2-deoxy-D-glucose/inositol hexaphosphate/anti-PD-L1 antibody,

Combination formulation of V-9302/metformin/2-deoxy-D-glucose/inositol/anti-PD-L1 antibody, and

The combination formulation of V-9302/metformin/2-deoxy-D-glucose/inositol hexaphosphate/inositol/anti-PD-L1 antibody has more tumors than a single formulation of each compound or a combination formulation containing 2 to 4 compounds. The effect of reducing the size was very high.

In one embodiment of the present invention, it was confirmed that the pharmaceutical composition according to the present invention can inhibit cancer with a remarkably excellent effect in a cancer animal model. That is, according to the present invention, an ASCT2 inhibitor; Each of the biguanide compounds, 2-deoxy-D-glucose, inositol hexaphosphate, inositol, and immune checkpoint inhibitors, when used alone, has insufficient anticancer effect and must be used in excess, but used as a combination preparation combining the above compounds It was confirmed that even a small amount can effectively kill cancer cells.

In each pharmaceutical composition according to the present invention, the weight ratio of the combination of each compound is not particularly limited.

For example, ASCT2 inhibitors such as V-9302, L-γ-glutamyl-p-nitroanilide (GPNA), 1,2,3-dithiazole compounds, antibody KM4008, antibody KM4012, antibody KM4018, antibody KM8094 and Any one or more selected from the group consisting of antibody MEDI7247 may be used in a single dose within the range of 1-200 mg/kg.

Components other than the ASCT2 inhibitor may be used in the following ranges depending on the type of cancer to be treated.

For example, the weight ratio of metformin or a pharmaceutically acceptable salt thereof to 2-deoxy-D-glucose may be in the range of 1:0.2 to 1:5, and the relative amount of the combination may vary depending on the type of cancer being treated. .

For example, the weight ratio of phenformin or a pharmaceutically acceptable salt thereof to 2-deoxy-D-glucose may range from 1:1 to 1:50, and the relative amount of the combination may vary depending on the type of cancer being treated. can

As another example, the weight ratio of metformin or a pharmaceutically acceptable salt thereof: 2-deoxy-D-glucose: inositol hexaphosphate or a pharmaceutically acceptable salt thereof is in the range of 1:0.2:0.5 to 1:5:20. Also, the relative amount of the combination may vary depending on the type of cancer to be treated.

As another example, the weight ratio of phenformin or a pharmaceutically acceptable salt thereof: 2-deoxy-D-glucose: inositol hexaphosphate or a pharmaceutically acceptable salt thereof is 1:1:1 to 1:50:200 may be in the range of, and the relative amount of the combination may vary depending on the type of cancer to be treated.

As another example, the weight ratio of metformin or a pharmaceutically acceptable salt thereof: 2-deoxy-D-glucose: inositol may be in the range of 1:0.2:0.5 to 1:5:20, depending on the type of cancer to be treated. Depending on the combination, the relative amount may vary.

As another example, the weight ratio of phenformin or a pharmaceutically acceptable salt thereof: 2-deoxy-D-glucose: inositol may be in the range of 1:1:1 to 1:50:200, and the cancer to be treated The relative amount of the combination may vary depending on the type of .

As another example, the weight ratio of metformin or a pharmaceutically acceptable salt thereof: 2-deoxy-D-glucose: inositol hexaphosphate or a pharmaceutically acceptable salt thereof: inositol is 1:0.2:0.5:0.5 to 1: It may be in the range of 5:20:20, and the relative amount of the combination may vary depending on the type of cancer being treated.

As another example, the weight ratio of phenformin or a pharmaceutically acceptable salt thereof: 2-deoxy-D-glucose: inositol hexaphosphate or a pharmaceutically acceptable salt thereof: inositol is 1:1:1:1 to It may be in the range of 1:50:200:200, and the relative amount of the combination may vary depending on the type of cancer being treated.

As another example, an immune checkpoint inhibitor as a monoclonal antibody such as an anti-CTLA4 antibody, an anti-PD-1 antibody, an anti-LAG-3 antibody, an anti-OX40 antibody, an anti-TIM3 antibody, an anti-PD-1 antibody And any one or more selected from the group consisting of an anti-PD-L1 antibody may be used in a single dose within the range of 0.01-25 mg/kg.

As used herein, the term “cancer” is a disease related to the regulation of cell death, and refers to a disease caused by excessive cell proliferation when the normal balance of apoptosis is disrupted. In some cases, these abnormal hyperproliferative cells invade surrounding tissues and organs, form a mass, and destroy or modify the normal structure of the body. This condition is called cancer. In general, a tumor refers to an abnormally grown mass due to autonomous overgrowth of body tissues, and can be divided into benign tumors and malignant tumors. Malignant tumors grow very rapidly compared to benign tumors, and metastasis occurs while infiltrating surrounding tissues, threatening life. Such malignant tumors are commonly called 'cancer', and the types of cancer include cerebrospinal tumors, brain cancer, head and neck cancer, lung cancer, breast cancer, such as triple negative breast cancer, thymoma, esophageal cancer, stomach cancer, colorectal cancer, liver cancer, and pancreatic cancer. , biliary tract cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, germ cell tumor, ovarian cancer, cervical cancer, endometrial cancer, lymphoma, leukemia such as acute or chronic leukemia, osteosarcoma, multiple myeloma, sarcoma, melanoma, malignant melanoma and skin cancer. The anticancer composition of the present invention may be used without limitation on the type of cancer, but for the purpose of the present invention, liver cancer, lung cancer, stomach cancer, pancreatic cancer, colorectal cancer, cervical cancer, breast cancer, prostate cancer, ovarian cancer, brain cancer, osteosarcoma, bladder cancer, It can be usefully used for the prevention or treatment of any one or more cancers selected from the group consisting of head and neck cancer, kidney cancer, melanoma, leukemia, and lymphoma.

The term "prevention or treatment" as used in the present invention refers to any action that suppresses or delays the onset of cancer by using the pharmaceutical composition or combination preparation according to the present invention, and in particular, 'treatment' means cancer using the composition. It means any action that improves or changes to the advantage.

Accordingly, the present invention provides a subject in need of prevention or treatment of cancer (1) an ASCT2 inhibitor; (2) a biguanide compound or a pharmaceutically acceptable salt thereof; And (3) 2-deoxy-D- glucose (2-deoxy-D-glucose) provides a method for preventing or treating cancer, comprising administering a therapeutically effective amount.

The method may further comprise (4) administering inositol hexaphosphate or a pharmaceutically acceptable salt thereof, inositol, or a mixture thereof in a therapeutically effective amount.

The method further comprises administering (4) inositol hexaphosphate or a pharmaceutically acceptable salt thereof, inositol, or a mixture thereof, and (5) an immune checkpoint inhibitor in a therapeutically effective amount. may include

The pharmaceutical composition for preventing or treating cancer of the present invention may additionally include a chemotherapeutic agent for cancer treatment, if necessary, in addition to the above-mentioned active ingredients.

In addition, the pharmaceutical composition for preventing or treating cancer of the present invention may additionally include a pharmaceutically acceptable carrier. The composition of the present invention is suitable for each purpose of use, and oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., in the form of sterile injection solutions, external preparations such as ointments, It may be formulated and used as a suppository, and carriers, excipients and diluents that may be included in the composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, and the like.

Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations contain at least one excipient, for example, starch, calcium carbonate, sucrose, lactose, gelatin, etc. in the composition. Mix and formulate. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid formulations for oral administration include suspensions, internal solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. have.

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. The base for injection may include conventional additives such as solubilizing agents, isotonic agents, suspending agents, emulsifying agents, stabilizing agents and preservatives.

The composition of the present invention may be administered using various methods such as oral, intravenous, subcutaneous, intradermal, intranasal, intraperitoneal, intramuscular, and transdermal, and the dosage may vary depending on the age, sex, and weight of the patient. It can be readily determined by one of ordinary skill in the art. The dosage of the composition according to the present invention may be increased or decreased depending on the route of administration, the type of cancer, the degree of disease, sex, weight, age, etc. For example, in the case of a combination preparation of five compounds, V-9302 as an ASCT2 inhibitor 1 to 200 mg/kg (body weight), 1 to 50 mg/kg (body weight) per day when using metformin as a biguanide compound, 0.1 per day when using phenformin to 10 mg/kg (body weight), 2-deoxy-D-glucose is 1 to 100 mg/kg (body weight) per day, inositol hexaphosphate is 1 to 150 mg/kg (body weight) per day, and inositol is 1 1 to 150 mg/kg (body weight) per day, when using the monoclonal antibody anti-PD-1 as an immune checkpoint inhibitor, a single dose is 0.01 to 10 mg/kg (body weight). However, the scope of the present invention is not limited by the dosage.

In another aspect, the present invention provides (1) an ASCT2 inhibitor; (2) a biguanide compound or a pharmaceutically acceptable salt thereof; And (3) to a method for preventing or treating cancer by administering 2-deoxy-D-glucose (2-deoxy-D-glucose) to a subject.

In another aspect, the present invention provides (1) an ASCT2 inhibitor; (2) a biguanide compound or a pharmaceutically acceptable salt thereof; (3) 2-deoxy-D-glucose; And (4) inositol hexaphosphate (inositol hexaphosphate) or a pharmaceutically acceptable salt thereof, inositol (inositol), or a mixture thereof is administered to a subject to a method for preventing or treating cancer.

In another aspect, the present invention provides (1) an ASCT2 inhibitor; (2) a biguanide compound or a pharmaceutically acceptable salt thereof; (3) 2-deoxy-D-glucose; (4) inositol hexaphosphate or a pharmaceutically acceptable salt thereof, inositol, or a mixture thereof, and (5) in a method for preventing or treating cancer by administering an immune checkpoint inhibitor to a subject it's about

In another aspect, the present invention provides (1) an SCT2 inhibitor; (2) a biguanide compound or a pharmaceutically acceptable salt thereof; And (3) to a composition for use in the prevention or treatment of cancer comprising 2-deoxy-D-glucose (2-deoxy-D-glucose).

In another aspect, the present invention provides (1) an SCT2 inhibitor; (2) a biguanide compound or a pharmaceutically acceptable salt thereof; (3) 2-deoxy-D-glucose; and (4) inositol hexaphosphate or a pharmaceutically acceptable salt thereof, inositol, or a mixture thereof, for use in the prevention or treatment of cancer.

In another aspect, the present invention provides (1) an ASCT2 inhibitor; (2) a biguanide compound or a pharmaceutically acceptable salt thereof; (3) 2-deoxy-D-glucose; (4) inositol hexaphosphate (inositol hexaphosphate) or a pharmaceutically acceptable salt thereof, inositol (inositol), or a mixture thereof, and (5) a composition for use in the prevention or treatment of cancer comprising an immune checkpoint inhibitor is about

In another aspect, the present invention provides a pharmaceutical composition comprising: (1) an SCT2 inhibitor; (2) a biguanide compound or a pharmaceutically acceptable salt thereof; and (3) 2-deoxy-D-glucose.

As another aspect, the present invention relates to (1) an SCT2 inhibitor for manufacturing a medicament for the prevention or treatment of cancer; (2) a biguanide compound or a pharmaceutically acceptable salt thereof; (3) 2-deoxy-D-glucose; and (4) inositol hexaphosphate or a pharmaceutically acceptable salt thereof, inositol, or a mixture thereof.

As another aspect, the present invention is for the manufacture of a medicament for the prevention or treatment of cancer (1) an ASCT2 inhibitor; (2) a biguanide compound or a pharmaceutically acceptable salt thereof; (3) 2-deoxy-D-glucose; (4) inositol hexaphosphate or a pharmaceutically acceptable salt thereof, inositol, or a mixture thereof, and (5) the use of an immune checkpoint inhibitor.

In another aspect, the present invention provides (1) an ASCT2 inhibitor; (2) a biguanide compound or a pharmaceutically acceptable salt thereof; And (3) to a food composition for preventing or improving cancer comprising 2-deoxy-D-glucose as an active ingredient.

In another aspect, the present invention provides (1) an SCT2 inhibitor; (2) a biguanide compound or a pharmaceutically acceptable salt thereof; (3) 2-deoxy-D-glucose; And (4) inositol hexaphosphate (inositol hexaphosphate) or a pharmaceutically acceptable salt thereof, inositol (inositol), or a mixture thereof relates to a food composition for preventing or improving cancer comprising a mixture as an active ingredient.

In another aspect, the present invention provides (1) an SCT2 inhibitor; (2) a biguanide compound or a pharmaceutically acceptable salt thereof; (3) 2-deoxy-D-glucose; (4) inositol hexaphosphate (inositol hexaphosphate) or a pharmaceutically acceptable salt thereof, inositol (inositol), or a mixture thereof, and (5) to a food composition for the prevention or improvement of cancer comprising an immune checkpoint inhibitor will be.

In addition to the active ingredient, the composition may include a food additive that is pharmaceutically acceptable.

As used in the present invention, the term "food supplement additive" refers to a component that can be supplementally added to food, and is added to manufacture health functional food of each formulation, and those skilled in the art can appropriately select and use it. Examples of food supplement additives include various nutrients, vitamins, minerals (electrolytes), synthetic flavoring agents and flavoring agents such as natural flavoring agents, coloring agents and fillers, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonation agents used in carbonated beverages, etc. are included, but the types of food supplement additives of the present invention are not limited by the above examples.

The food composition of the present invention may include a health functional food. The term "health functional food" used in the present invention refers to food manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, etc. using raw materials or ingredients useful in the human body. Here, 'functionality' refers to obtaining useful effects for health purposes, such as regulating nutrients or physiological effects on the structure and function of the human body. The health functional food of the present invention can be manufactured by a method commonly used in the art, and at the time of manufacture, it can be prepared by adding raw materials and components commonly added in the art. In addition, if the formulation of the health functional food is also recognized as a health functional food, it may be manufactured without limitation. The composition for food of the present invention can be prepared in various forms, and unlike general drugs, it has the advantage that there are no side effects that may occur during long-term administration of the drug using food as a raw material, and it is excellent in portability, and the present invention health functional food can be taken as an adjuvant to enhance the effect of anticancer drugs.

The composition according to the present invention exhibits broad and improved indications for various carcinomas by using a metabolizing anticancer agent with limited indications in combination. Therefore, compared to single use, it is possible to effectively kill cancer even with a much smaller amount of the drug, thereby solving the problem of excessive use and selectively treating cancer while minimizing side effects. In addition, the composition according to the present invention can exhibit a more remarkable synergistic effect by additional combination of an inositol-based compound and an immune checkpoint inhibitor, as well as expand the indications to various anti-carcinomas, so that it is possible to use anticancer agents for various types of cancer and cancer It can be usefully used as a combination preparation for the prevention or improvement of

1 is a cancer cell derived from human liver HepG2 cell line metformin (MET), 2-deoxy-D-glucose (2DG), V-9302, and inositol hexaphosphate (IP6) alone and combined treatment of cells It is a graph showing the survival rate as a percentage. The drug was treated at a low concentration usable in human plasma, and after 48 hours, it was confirmed by MTT assay. The vertical bar of each bar represents the standard deviation. Statistical analysis was performed by one-way ANOVA test using Tukey's multiple comparisons post hoc analysis using GraphPad Prism 6.0 software. ****p<0.0001.
Figure 2 is a cancer cell derived from human lung A549 cell line metformin (MET), 2-deoxy-D-glucose (2DG), V-9302, and inositol hexaphosphate (IP6) alone and combined treatment of cells It is a graph showing the survival rate as a percentage. ****p<0.0001.
3 is a cancer cell line derived from the human stomach, metformin (MET), 2-deoxy-D-glucose (2DG), V-9302, and inositol hexaphosphate (IP6) alone and cell viability by combined treatment is a graph expressed as a percentage. ****p<0.0001.
4 is a cancer cell derived from human pancreas, metformin (MET), 2-deoxy-D-glucose (2DG), V-9302, and inositol hexaphosphate (IP6) alone and in combination treatment for the PANC-1 cell line. It is a graph showing the cell viability by percentage. ****p<0.0001.
Figure 5 shows the treatment of metformin (MET), 2-deoxy-D-glucose (2DG), V-9302, and inositol hexaphosphate (IP6) alone and in combination with respect to the DLD-1 cell line, a cancer cell derived from the human colon. It is a graph showing the cell viability by percentage. ****p<0.0001.
6 is a cancer cell line derived from human cervix, metformin (MET), 2-deoxy-D-glucose (2DG), V-9302, and inositol hexaphosphate (IP6) alone and in combination treatment by It is a graph showing the cell viability as a percentage. ****p<0.0001.
7 shows metformin (MET), 2-deoxy-D-glucose (2DG), V-9302, and inositol hexaphosphate (IP6) alone and in combination against the human breast-derived cancer cell line MDA-MB-231. It is a graph showing the cell viability by treatment as a percentage. ****p<0.0001.
Figure 8 shows the treatment of metformin (MET), 2-deoxy-D-glucose (2DG), V-9302, and inositol hexaphosphate (IP6) alone and in combination with respect to the PC-3 cell line, a cancer cell derived from the human prostate. It is a graph showing the cell viability by percentage. ****p<0.0001.
9 shows metformin (MET), 2-deoxy-D-glucose (2DG), V-9302, and inositol hexaphosphate (IP6) alone and in combination against the SK-OV-3 cell line, which is a cancer cell derived from human ovary. It is a graph showing the cell viability by treatment as a percentage. ****p<0.0001.
Figure 10 shows cells by treatment alone and in combination with metformin (MET), 2-deoxy-D-glucose (2DG), V-9302, and inositol hexaphosphate (IP6) for T24 cell line, a cancer cell derived from human bladder. It is a graph showing the survival rate as a percentage. ****p<0.0001.
Figure 11 is a human cancer cell line glioblastoma (U-87 MG) metformin (MET), 2-deoxy-D-glucose (2DG), V-9302, and inositol hexaphosphate (IP6) alone and in combination treatment It is a graph showing the cell viability by percentage. ****p<0.0001.
Figure 12 shows the treatment of metformin (MET), 2-deoxy-D-glucose (2DG), V-9302, and inositol hexaphosphate (IP6) alone and in combination with respect to the Saos-2 cell line, a cancer cell derived from human bone meat. It is a graph showing the cell viability by percentage. ****p<0.0001.
13 is a graph measuring the change in tumor volume following administration of MET, 2DG, V-9302, IP6+Ins, and anti-PD-1 antibody alone and in combination in an animal model at 3-day intervals. Statistical analysis was performed by two-way ANOVA testing using Tukey's multiple comparisons post hoc analysis using GraphPad Prism 6.0 software. **p<0.01, ****p<0.0001.
14 is a graph measuring the change in tumor volume following administration of MET, 2DG, V-9302, IP6+Ins, and anti-PD-L1 antibody alone and in combination in an animal model at 3-day intervals. Statistical analysis was performed by two-way ANOVA testing using Tukey's multiple comparisons post hoc analysis using GraphPad Prism 6.0 software. **p<0.01, ****p<0.0001.
15 is a graph measuring tumor volume changes according to administration of MET, 2DG, V-9302, IP6+Ins, and anti-CTLA-4 antibodies alone and in combination in an animal model at 3-day intervals. Statistical analysis was performed by two-way ANOVA testing using Tukey's multiple comparisons post hoc analysis using GraphPad Prism 6.0 software. **p<0.01, ****p<0.0001.

Advantages and features of the present invention, and methods for achieving them, will become apparent with reference to the embodiments described below in detail. However, the present invention is not limited to the embodiments disclosed below, but will be implemented in a variety of different forms, and only these embodiments allow the disclosure of the present invention to be complete, and common knowledge in the technical field to which the present invention belongs It is provided to fully inform the possessor of the scope of the invention, and the present invention is only defined by the scope of the claims.

In the following examples, V-9302 was used as an ASCT2 inhibitor. Also, as a biguanide-based compound, metformin hydrochloride (Metformin HCl) was used among various pharmaceutically acceptable salts of metformin or phenformin. The form of these salts is not limited by the Examples. In addition, inositol hexaphosphate (Phytic acid) was used in the form of several pharmaceutically acceptable salts of inositol hexaphosphate. These shapes are not limited by the examples. Also, myo-inositol was used among the isomers of inositol. These isomers are not limited by the examples. As immune checkpoint inhibitors, monoclonal antibodies anti-mouse PD-1 mAb (RMP1-14), anti-mouse PD-L1 mAb (10F. 9G2), and anti-mouse CTLA-4 mAb (UC10-4F10-11) were administered. was used.

cell culture

The cells used in this test were tumor cells, including liver cancer (HepG2), lung cancer (A549), stomach cancer (AGS), pancreatic cancer (PANC-1), colorectal cancer (DLD-1), cervical cancer (HeLa), and breast cancer (MDA-MB). -231), prostate cancer (PC-3), ovarian cancer (SK-OV-3), bladder cancer (T24), glioblastoma (U-87 MG), osteosarcoma (Saos-2), and mouse-derived breast cancer (4T1). Prostate (PZ-HPV-7), colon (CCD-18Co), and lung (MRC5) cell lines were used as non-tumor cells. All cell lines were Korean Cell Line Bank or ATCC (American Type Culture). Collection, Rockville, MD) was purchased and used.

The cells were prepared by adding 10% fetal bovine serum (FBS, Hyclone) and 1% penicillin/streptomycin (P/S, Hyclone) to Roswell Park Memorial Institute 1640 Medium (RPMI1640, Hyclone, Logan, UT, USA). was used, and maintained and cultured in an incubator at 37° C. (5% CO ₂ /95% air). When the cells were filled to about 80% of the culture dish, the monolayer of cells was washed with phosphate-buffered saline (PBS, Hyclone) and subcultured with 0.25% trypsin-2.65 mM EDTA (Hyclone), and the medium was changed every 2 days.

drug used

V9302, an inhibitor of ASCT2, was purchased from MedKoo Biosciences and stored and handled according to the manufacturer's instructions. Metformin hydrochloride (Metformin HCl, hereinafter MET), 2-deoxy-D-glucose (2-deoxy-D-glucose, hereinafter 2DG), inositol hexaphosphate (Phytic acid, hereinafter IP6), myo-inositol (myo-inositol, hereinafter) Ins) was purchased from Sigma (St. Louis, USA). As monoclonal antibodies, anti-mouse PD-1 mAb (RMP1-14), anti-mouse PD-L1 mAb (10F.9G2), and anti-mouse CTLA-4 mAb (UC10-4F10-11) were purchased from BioXcell. Stored and handled as directed by the manufacturer.

All drugs used in the tables and drawings summarizing the results obtained through the experiments in the present invention are indicated as abbreviations.

Reference Example 1: In vitro cell growth inhibition assay

The cytotoxicity of V-9302, MET, 2DG and IP6 was confirmed by MTT assay [3-(4,5-dimethyl thiazolyl-2)-2,5-diphenyltetrazolium bromide assay]. The cells (3~4×10 ⁵ cells/well) are dispensed in a 96-well culture plate and stabilized for more than 12 hours, then the medium from each well is removed, and MET, 2DG, and IP6 for each cell are mixed by concentration or by mixing. Treated with serum-free medium. For control cells, PBS was added into the medium. _{After incubation at 37 ° C. containing CO 2} for 48 hours, the medium including the control and mixture was removed, and MTT (Sigma Aldrich, St. Louis, MO, USA) reagent (0.5 mg/ml) was used at 37 ° C. incubated for hours. After that, the medium containing the MTT reagent was removed, and the MTT formazan crystals formed by the living cells were dissolved by adding DMSO (Sigma) and leaving it at room temperature for more than 15 min. Absorbance was measured at a wavelength of 560 nm using a microplate reader (BioTek ^{® Instruments, Inc., Winooski, VT, USA).}

Reference Example 2: Experimental method of single formulation and combination formulation

The cells (3-4 × 10 ⁵ cells/well) were seeded in a 96-well plate, and the cell proliferation inhibition rate was confirmed by treating each concentration of V-9302, MET, 2DG and IP6 as a single agent drug.

As the combination drug, it was treated with a drug concentration corresponding to _{IC 50} of the combination formulation consisting of two or more compounds selected from the group consisting of V-9302, MET, 2DG and IP6. All cell lines were cultured for 48 hours at the concentration of single or combined preparations, and the growth inhibitory effect was measured by MTT assay.

Reference Example 3: Experimental animals

Five-week-old, female BALB/c mice without specific pathogen free were purchased from Dooyeol Biotech Co., Ltd. and used. After one week of quarantine and adaptation, healthy animals without weight loss were selected and used for the experiment.

Experimental animals were raised in a breeding environment set at 23 ± 3℃, 50 ± 10% relative humidity, 10-15 ventilation times/hour, 12 hours illumination (08:00 - 20:00), and 150 - 300 Lux illumination. did During the entire period of the test, the experimental animals were allowed to freely ingest solid feed for laboratory animals (Cargill Agripurina, Co., Ltd.) and drinking water.

Reference Example 4: Tumor cell transplantation and test substance administration

After the BALB/c mouse had an adaptation period of 1 week, 4T1 cells (1×10 ⁵ cells/mouse), which are breast cancer cells, were injected into the left breast adipose tissue of the experimental animal, and tumor tissue was observed with the naked eye. . The size of the experimental animal tumor tissue on experimental method 10 test groups (control, V-9302 group (70 mg / kg V-9302 ), MET group (MET 500 mg / kg on the basis of when ³ about 50 mm), 2DG group (2DG 1000 mg/kg), IP6(+Ins) group (IP6 800 mg/kg + Ins 200 mg/kg), mAb group (monoclonal antibody (anti-PD1 antibody or anti-PD-L1 antibody or anti -CTLA-4 antibody) as 150 μg/mouse), 2DG+V-9302 group (2DG 1000 mg/kg + V-9302 70 mg/kg), MET+2DG group (MET 500 mg/kg + 2DG 1000 mg/kg) kg), MET+2DG+V-9302 group (MET 500 mg/kg + 2DG 1000 mg/kg + V-9302 70 mg/kg), MET+2DG+V-9302+IP6(+Ins) group (MET 500 mg/kg + 2DG 1000 mg/kg + V-9302 70 mg/kg + IP6 800 mg/kg + Ins 200 mg/kg), MET+2DG+V-9302+IP6(+Ins)+mAb group (MET 500 mg/kg + 2DG 1000 mg/kg + V-9302 70 mg/kg + IP6 800 mg/kg + Ins 200 mg/kg + mAb 150 μg/mouse).

Five experimental animals were used in each test group. The test substance monoclonal antibody was intraperitoneally administered every 4 days with the test group separation time of day 1, and the test substance V-9302 was intraperitoneally administered daily with the test group separation time of day 1, and the test substances MET, 2DG, IP6(+Ins ) was dissolved in distilled water until the end of the test with the test group separation time of day 1 and administered orally for 3 weeks at a certain time.

Reference example 5: Measurement of body weight and tumor volume of experimental animals

During the test period, the body weight of the experimental animals was measured at a fixed time once a week from the day of administration of the test substance. The tumor volume was measured using a digital caliper at 3-day intervals, and the length and width of the tumor were measured, and the tumor volume was calculated by substituting the following formulas.

Tumor volume (mm ³ ) = (width ² × length) / 2

Reference example 6: Statistical processing

All assay values are presented as mean±SD. In order to compare the difference between the control group and the test substance administration group, the significance was assessed by one-way ANOVA or two-way ANOVA test using Tukey's multiple comparison post-hoc analysis using GraphPad Prism 6.0 software. verified. It was judged to be statistically significant only when p < 0.05 or more.

Example 1: V-9302, MET, 2DG and cell viability after administration of IP6 alone and in combination

The cell proliferation inhibitory effects of V-9302, MET, 2DG, and IP6 single and combined formulations were compared using 12 cancer cells.

1 to 12 are human cancer cell lines, respectively, liver cancer (HepG2), lung cancer (A549), stomach cancer (AGS), pancreatic cancer (PANC-1), colorectal cancer (DLD-1), cervical cancer (HeLa), breast cancer (MDA-MB) -231), prostate cancer (PC-3), ovarian cancer (SK-OV-3), bladder cancer (T24), glioblastoma (U-87 MG), osteosarcoma (Saos-2), MET, 2DG and IP6 This is the result of evaluating the cell viability (% cell viability) after administration alone and in combination.

1 shows the viability in liver cancer (HepG2) cell lines treated alone and in combination with MET at a concentration of 4 mM, 2DG at a concentration of 1 mM, V-9302 at a concentration of 6 μM, and IP6 at a concentration of 1 mM. In the triple combination formulation (MET + 2DG + V-9302) group, the viability was significantly reduced (P <0.0001) than those treated with the single and double combination formulations including the control group. In the quadruple combination preparation (MET + 2DG + V-9302 + IP6) group, viability was significantly reduced (P <0.0001) compared to treatment with single, double, and triple combination preparations including the control group.

Figure 2 shows the survival rate in lung cancer (A549) cell lines treated alone and in combination with MET at a concentration of 4 mM, 2DG at a concentration of 1 mM, V-9302 at a concentration of 6 μM, and IP6 at a concentration of 1 mM. In the triple combination formulation (MET + 2DG + V-9302) group, the viability was significantly reduced (P <0.0001) than those treated with the single and double combination formulations including the control group. In the quadruple combination preparation (MET + 2DG + V-9302 + IP6) group, viability was significantly reduced (P <0.0001) compared to treatment with single, double, and triple combination preparations including the control group.

3 shows viability in gastric cancer (AGS) cell lines treated alone and in combination with MET at a concentration of 2 mM, 2DG at a concentration of 0.7 mM, V-9302 at a concentration of 6 μM, and IP6 at a concentration of 1 mM. In the triple combination formulation (MET + 2DG + V-9302) group, the viability was significantly reduced (P <0.0001) than those treated with the single and double combination formulations including the control group. In the quadruple combination preparation (MET + 2DG + V-9302 + IP6) group, viability was significantly reduced (P <0.0001) compared to treatment with single, double, and triple combination preparations including the control group.

Figure 4 shows the survival rate in pancreatic cancer (PANC-1) cell lines treated alone and in combination with MET at a concentration of 5 mM, 2DG at a concentration of 0.7 mM, V-9302 at a concentration of 6 μM, and IP6 at a concentration of 1 mM. In the triple combination formulation (MET + 2DG + V-9302) group, the viability was significantly reduced (P <0.0001) than those treated with the single and double combination formulations including the control group. In the quadruple combination preparation (MET + 2DG + V-9302 + IP6) group, viability was significantly reduced (P <0.0001) compared to treatment with single, double, and triple combination preparations including the control group.

5 shows the survival rate in colorectal cancer (DLD-1) cell lines treated alone and in combination with MET at a concentration of 5 mM, 2DG at a concentration of 0.4 mM, V-9302 at a concentration of 6 μM, and IP6 at a concentration of 1 mM. In the triple combination formulation (MET + 2DG + V-9302) group, the viability was significantly reduced (P <0.0001) than those treated with the single and double combination formulations including the control group. In the quadruple combination preparation (MET + 2DG + V-9302 + IP6) group, viability was significantly reduced (P <0.0001) compared to treatment with single, double, and triple combination preparations including the control group.

6 shows viability in cervical cancer (HeLa) cell lines treated alone and in combination with MET at a concentration of 6 mM, 2DG at a concentration of 0.5 mM, V-9302 at a concentration of 6 μM, and IP6 at a concentration of 1 mM. In the triple combination formulation (MET + 2DG + V-9302) group, the viability was significantly reduced (P <0.0001) than those treated with the single and double combination formulations including the control group. In the quadruple combination preparation (MET + 2DG + V-9302 + IP6) group, viability was significantly reduced (P <0.0001) compared to treatment with single, double, and triple combination preparations including the control group.

7 shows the survival rate in breast cancer (MDA-MB-231) cell lines treated alone and in combination with MET at a concentration of 6 mM, 2DG at a concentration of 1 mM, V-9302 at a concentration of 6 μM, and IP6 at a concentration of 1 mM. In the triple combination formulation (MET + 2DG + V-9302) group, the viability was significantly reduced (P <0.0001) than those treated with the single and double combination formulations including the control group. In the quadruple combination preparation (MET + 2DG + V-9302 + IP6) group, viability was significantly reduced (P <0.0001) compared to treatment with single, double, and triple combination preparations including the control group.

8 shows the viability in prostate cancer (PC-3) cell lines treated alone and in combination with MET at a concentration of 5 mM, 2DG at a concentration of 1 mM, V-9302 at a concentration of 6 μM, and IP6 at a concentration of 1 mM. In the triple combination formulation (MET + 2DG + V-9302) group, the viability was significantly reduced (P <0.0001) than those treated with the single and double combination formulations including the control group. In the quadruple combination preparation (MET + 2DG + V-9302 + IP6) group, viability was significantly reduced (P <0.0001) compared to treatment with single, double, and triple combination preparations including the control group.

9 shows the viability in ovarian cancer (SK-OV-3) cell lines treated alone and in combination with MET at a concentration of 5 mM, 2DG at a concentration of 0.5 mM, V-9302 at a concentration of 6 μM, and IP6 at a concentration of 1 mM. In the triple combination formulation (MET + 2DG + V-9302) group, the viability was significantly reduced (P <0.0001) than those treated with the single and double combination formulations including the control group. In the quadruple combination preparation (MET + 2DG + V-9302 + IP6) group, viability was significantly reduced (P <0.0001) compared to treatment with single, double, and triple combination preparations including the control group.

Figure 10 shows the survival rate in bladder cancer (T24) cell lines treated alone and in combination with MET at a concentration of 4 mM, 2DG at a concentration of 1 mM, V-9302 at a concentration of 6 μM, and IP6 at a concentration of 1 mM. In the triple combination formulation (MET + 2DG + V-9302) group, the viability was significantly reduced (P <0.0001) than those treated with the single and double combination formulations including the control group. In the quadruple combination preparation (MET + 2DG + V-9302 + IP6) group, viability was significantly reduced (P <0.0001) compared to treatment with single, double, and triple combination preparations including the control group.

11 shows viability in glioblastoma (U-87 MG) cell lines treated alone and in combination with MET at a concentration of 5 mM, 2DG at a concentration of 0.4 mM, V-9302 at a concentration of 6 μM, and IP6 at a concentration of 1 mM. In the triple combination formulation (MET + 2DG + V-9302) group, the viability was significantly reduced (P <0.0001) than those treated with the single and double combination formulations including the control group. In the quadruple combination preparation (MET + 2DG + V-9302 + IP6) group, viability was significantly reduced (P <0.0001) compared to treatment with single, double, and triple combination preparations including the control group.

12 shows the viability in osteosarcoma (Saos-2) cell lines treated alone and in combination with MET at a concentration of 5 mM, 2DG at a concentration of 0.7 mM, V-9302 at a concentration of 6 μM, and IP6 at a concentration of 1 mM. In the triple combination formulation (MET + 2DG + V-9302) group, the viability was significantly reduced (P <0.0001) than those treated with the single and double combination formulations including the control group. In the quadruple combination preparation (MET + 2DG + V-9302 + IP6) group, viability was significantly reduced (P <0.0001) compared to treatment with single, double, and triple combination preparations including the control group.

From the above results, it was confirmed that triple or more combination formulations of MET, 2DG, V-9302, and IP6 exhibit superior cancer cell proliferation inhibitory effects than single or double combination formulations.

Example 2. Effect of Addition of Immune Checkpoint Inhibitors on Tumor Volume Change

Example 2.1. V-9302, MET, 2DG , IP6, Ins and anti-PD-1 alone and combination formulation Effect on tumor volume change

When the size of the tumor tissue was about 50 mm ³ , the test group was classified and the test substance administration was started, and the tumor volume was measured every 3 days from the start date of the test substance administration. As shown in FIG. 13 , from the 3rd day of administration of the test substance, the tumor volume of the single and combination treatment groups showed a tendency to decrease compared to the control group.

On the 21st day of test substance administration, the group (MET + 2DG + V-9302) showed a significant difference from the single and double combination preparation groups including the control group (P <0.001). In addition, in the (MET + 2DG + V-9302 + IP6(+Ins)) group and (MET + 2DG + V-9302 + IP6(+Ins) + anti-PD-1) group among the combination formulations, single and There was also a high significant difference compared with the double combination preparation group (P <0.0001). In tumor volume, the (MET + 2DG + V-9302 + IP6(+Ins) + anti-PD-1) group showed the highest reduction in tumor volume, indicating a high tumor growth inhibitory effect.

Example 2.2. V-9302, MET, 2DG , IP6, Ins and anti-PD-L1 alone and Combination formulations effect on tumor volume change

When the size of the tumor tissue was about 50 mm ³ , the test group was classified and the test substance administration was started, and the tumor volume was measured every 3 days from the start date of the test substance administration. As shown in FIG. 14 , from the third day of administration of the test substance, the tumor volume of the group treated alone and in combination showed a tendency to decrease compared to the control group.

On the 21st day of test substance administration, the group (MET + 2DG + V-9302) showed a significant difference from the single and double combination preparation groups including the control group (P <0.01). In addition, in the (MET + 2DG + V-9302 + IP6(+Ins)) group and (MET + 2DG + V-9302 + IP6(+Ins) + anti-PD-L1) group, including the control group alone and There was also a high significant difference compared with the double combination preparation group (P <0.0001). In terms of tumor volume, the (MET + 2DG + V-9302 + IP6(+Ins) + anti-PD-L1) group showed the highest reduction in tumor volume, indicating a high tumor growth inhibitory effect.

Example 2.3. V-9302, MET, 2DG , IP6, Ins and anti- CTLA -4 alone and combination formulation Effect on tumor volume change

When the size of the tumor tissue was about 50 mm ³ , the test group was classified and the test substance administration was started, and the tumor volume was measured every 3 days from the start date of the test substance administration. As shown in FIG. 15 , from the 3rd day of administration of the test substance, the tumor volume of the single and combination treatment groups showed a tendency to decrease compared to the control group.

On the 21st day of test substance administration, the group (MET + 2DG + V-9302) showed a significant difference from the single and double combination preparation groups including the control group (P <0.01). In addition, in the (MET + 2DG + V-9302 + IP6(+Ins)) group and the (MET + 2DG + V-9302 + IP6(+Ins) + anti-CTLA-4) group among the combination formulations, single and There was also a high significant difference compared with the double combination preparation group (P <0.0001). In tumor volume, the (MET + 2DG + V-9302 + IP6(+Ins) + anti-CTLA-4) group showed the highest reduction in tumor volume, indicating a high tumor growth inhibitory effect.

Claims (16)

(1) an ASCT2 inhibitor of Formula 1;
[Formula 1]

(2) metformin or a pharmaceutically acceptable salt thereof;
(3) 2-deoxy-D-glucose; and
(4) inositol hexaphosphate or a pharmaceutically acceptable salt thereof; myo-inositol; and inositol hexaphosphate or a pharmaceutically acceptable salt thereof, and any one selected from the group consisting of a mixture of myoinositol; a pharmaceutical composition for preventing or treating cancer comprising as an active ingredient. delete delete The pharmaceutical composition for preventing or treating cancer according to claim 1, wherein the composition comprises inositol hexaphosphate or a pharmaceutically acceptable salt thereof. delete According to claim 1, wherein the composition is inositol hexaphosphate or a pharmaceutically acceptable salt thereof; And a pharmaceutical composition for the prevention or treatment of cancer comprising myo-inositol. delete delete delete delete delete According to claim 1, wherein the cancer is liver cancer, lung cancer, stomach cancer, pancreatic cancer, colorectal cancer, cervical cancer, breast cancer, prostate cancer, ovarian cancer, brain cancer, osteosarcoma, bladder cancer, head and neck cancer, kidney cancer, melanoma, consisting of leukemia and lymphoma. A pharmaceutical composition for preventing or treating cancer that is selected from the group. (1) an ASCT2 inhibitor of Formula 1;
[Formula 1]

(2) metformin or a pharmaceutically acceptable salt thereof;
(3) 2-deoxy-D-glucose; and
(4) inositol hexaphosphate or a pharmaceutically acceptable salt thereof; myo-inositol; and inositol hexaphosphate or a pharmaceutically acceptable salt thereof, and any one selected from the group consisting of a mixture of myoinositol; a food composition for preventing or improving cancer, comprising as an active ingredient. The food composition for preventing or improving cancer according to claim 13, wherein the composition comprises inositol hexaphosphate or a pharmaceutically acceptable salt thereof. 14. The method of claim 13, wherein the composition is inositol hexaphosphate (inositol hexaphosphate) or a pharmaceutically acceptable salt thereof; And myo-inositol (myo-inositol) for the prevention or improvement of cancer food composition comprising. The method of claim 13, wherein the cancer is liver cancer, lung cancer, stomach cancer, pancreatic cancer, colorectal cancer, cervical cancer, breast cancer, prostate cancer, ovarian cancer, brain cancer, osteosarcoma, bladder cancer, head and neck cancer, kidney cancer, melanoma, leukemia and lymphoma consisting of A food composition for preventing or improving cancer that is selected from the group.

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