阅读说明：本技术 癌细胞增殖抑制剂及癌细胞增殖抑制用组合物 (Cancer cell growth inhibitor and composition for inhibiting cancer cell growth ) 是由 中上夕子 深田豪 加藤咏子 于 2020-05-08 设计创作，主要内容包括：本发明涉及一种癌细胞增殖抑制剂,其含有糖结合于肌醇而成的肌醇衍生物作为有效成分。另外,涉及一种癌细胞增殖抑制用组合物,其含有上述癌细胞增殖抑制剂及药学上可接受的载体。(The present invention relates to a cancer cell growth inhibitor containing, as an active ingredient, an inositol derivative in which a sugar is bonded to inositol. Also disclosed is a composition for inhibiting cancer cell growth, which contains the cancer cell growth inhibitor and a pharmaceutically acceptable carrier.)

1. A cancer cell proliferation inhibitor contains an inositol derivative obtained by binding a sugar to inositol as an active ingredient.

2. The cancer cell proliferation inhibitor according to claim 1, wherein the sugar is glucose or an oligosaccharide containing glucose as a structural unit.

3. The inhibitor for cancer cell proliferation according to claim 1 or 2, wherein the inositol is myoinositol.

4. The inhibitor of cancer cell proliferation according to any one of claims 1 to 3, which inhibits the expression of CYP1A1 gene and CYP1B1 gene.

5. The cancer cell proliferation inhibitor according to any one of claims 1 to 4, which inhibits the expression of ARNT gene.

6. The cancer cell proliferation inhibitor according to any one of claims 1 to 5, which inhibits the production of active oxygen.

7. A cancer cell growth inhibitory composition comprising the cancer cell growth inhibitor according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier.

8. The composition for inhibiting cancer cell growth according to claim 7, wherein the total content of the inositol derivatives is 0.1 to 2% by mass.

9. The composition for inhibiting cancer cell proliferation according to claim 7 or 8, further comprising tocopherol phosphate or a salt thereof.

10. The composition for inhibiting cancer cell proliferation according to claim 9, wherein the tocopherol phosphate is α -tocopherol phosphate.

11. The composition for inhibiting cancer cell proliferation according to claim 9 or 10, wherein the salt of tocopherol phosphoric acid ester is a sodium salt of tocopherol phosphoric acid ester.

12. The composition for inhibiting cancer cell proliferation according to any one of claims 9 to 11, wherein the total content of the tocopherol phosphates or salts thereof is 0.1 to 2% by mass.

Technical Field

The present invention relates to a cancer cell growth inhibitor and a composition for inhibiting cancer cell growth.

This application claims priority based on Japanese application No. 2019-090846, 5, 13, 2019, the contents of which are incorporated herein.

Background

In the atmosphere, aromatic hydrocarbons such as dioxin and PCB, chemical substances such as Polycyclic Aromatic Hydrocarbons (PAH), and oxidized substances obtained by oxidizing these chemical substances by the action of ultraviolet rays and the like exist. These substances have various effects on the human body. It is known that inhalation of these harmful substances into the human body through exhalation or absorption of these harmful substances from mucous membranes causes various inflammations in respiratory organs such as lungs, skin mucous membranes, and internal organs, and further causes canceration of cells. As a mechanism of carcinogenesis caused by harmful substances such as PAH and its oxide contained in the atmospheric dust, it has been reported that these harmful substances bind to an aromatic hydrocarbon receptor (AhR) present in cells and migrate into the nucleus of the cell, thereby inducing the expression of CYP1a1 gene and CYP1B1 gene to generate Reactive Oxygen Species (ROS) in the cell, and as a result, inflammation, canceration of the cell, and infiltration of cancer cells are caused (non-patent documents 1 and 2).

As a defense agent against air pollutants, a protective agent, and an inhibitor against air pollution-related symptoms, substances having an antioxidant effect, plant-derived extracts, and the like have been reported for the purpose of inhibiting ROS produced in cells (patent documents 1 to 3). In addition, substances that competitively bind to AhR and inhibit the influence of harmful substances, and the like have been reported (non-patent document 3). However, the effect is not yet sufficient.

As a protective agent for physically preventing an air contaminant from coming close to the air contaminant, a preparation in which an oily coating agent is mixed to coat the surface, a reagent for capturing an irritant substance contained in the air contaminant, a reagent for suppressing oxidation, and the like have been proposed. However, these protective agents are effective in the sense that they do not bring the stimulating substance into close proximity, but do not protect cells from carcinogenic effects in vivo that may be caused.

Documents of the prior art

Patent document

Patent document 1: japanese patent laid-open publication No. 2016-88928

Patent document 2: japanese patent laid-open publication No. 2017-186276

Patent document 3: japanese patent No. 6456815

Non-patent document

Non-patent document 1: moorthy B et al, multicyclic aromatic hydrocarbons from metabolism to lung cancer. Toxicol Sci.2015May; 145(1):5-15.

Non-patent document 2: nebert DW et al, Role of aryl hydrocarbon receptor-mediated indication of the CYP1 enzymes in environmental sensitivity and cancer.J Biol chem.2004Jun 4; 279(23):23847-50.

Non-patent document 3: fungal M et al, analytical Phytochemicals Accelperate epidemic temporal Differentiation via the AHR-OVOL1 Pathway, immunity for atmospheric Dermatitis, acta farm Venereol.2018 Nov 5; 98(10):918-923.

Disclosure of Invention

Problems to be solved by the invention

As described above, it is considered that PAH and its oxidizing substances in the atmosphere are involved in carcinogenesis, and agents capable of suppressing the action of these atmospheric pollutants are required. However, the substances described in patent documents 1 to 3 and non-patent document 3 do not demonstrate an effect of inhibiting the growth of cancer cells caused by these air pollutants.

Accordingly, an object of the present invention is to provide a cancer cell growth inhibitor capable of inhibiting the growth and infiltration of cancer cells accelerated by atmospheric pollutants, and a cancer cell growth inhibiting composition containing the cancer cell growth inhibitor.

Means for solving the problems

The present invention includes the following aspects.

(1) A cancer cell proliferation inhibitor contains an inositol derivative obtained by binding a sugar to inositol as an active ingredient.

(2) The cancer cell growth inhibitor according to (1), wherein the sugar is glucose or an oligosaccharide containing glucose as a structural unit.

(3) The inhibitor of cancer cell proliferation according to (1) or (2), wherein the inositol is myoinositol.

(4) The cancer cell growth inhibitor according to any one of (1) to (3), which inhibits the expression of CYP1A1 gene and CYP1B1 gene.

(5) The cancer cell growth inhibitor according to any one of (1) to (4), which inhibits the expression of the ARNT gene.

(6) The cancer cell growth inhibitor according to any one of (1) to (5), which inhibits the production of active oxygen.

(7) A cancer cell growth inhibitory composition comprising the cancer cell growth inhibitory agent according to any one of (1) to (6) and a pharmaceutically acceptable carrier.

(8) The composition for inhibiting cancer cell growth according to (7), wherein the total content of the inositol derivatives is 0.1 to 2% by mass.

(9) The composition for inhibiting cancer cell proliferation according to (7) or (8), which further comprises a tocopherol phosphate or a salt thereof.

(10) The composition for inhibiting cancer cell growth according to (9), wherein the tocopherol phosphate is α -tocopherol phosphate.

(11) The composition for inhibiting cancer cell growth according to (9) or (10), wherein the salt of tocopherol phosphoric acid ester is a sodium salt of tocopherol phosphoric acid ester.

(12) The composition for inhibiting cancer cell growth according to any one of (9) to (11), wherein the total content of the tocopherol phosphates or salts thereof is 0.1 to 2% by mass.

Effects of the invention

The present invention can provide a cancer cell growth inhibitor capable of inhibiting the growth and infiltration of cancer cells that are accelerated by atmospheric pollutants, and a cancer cell growth inhibitor composition containing the cancer cell growth inhibitor.

Detailed Description

[ cancer cell proliferation inhibitor ]

In one embodiment, the present invention provides a cancer cell growth inhibitor containing, as an active ingredient, an inositol derivative in which a sugar is bonded to inositol.

The cancer cell growth inhibitor of the present embodiment can be suitably used for inhibiting the cell growth of cancer cells that are accelerated by air pollutants. In the present specification, the term "air-polluting substance" refers to a substance present in the atmosphere and having a harmful effect on the human body, and particularly refers to a substance involved in the occurrence, progression, etc. of cancer. Examples of the harmful effects of the air pollutants include carcinogenesis, cancer cell proliferation promoting effect, and cancer cell infiltration promoting effect.

Examples of the air pollutants include substances contained in Standard Reference Material 1648a supplied by the National Institute of Standards and Technology (NIST). Specific examples thereof include Polycyclic Aromatic Hydrocarbons (PAHs), nitro-polycyclic aromatic hydrocarbons (nitro-PAHs), polychlorinated biphenyls (PCBs), chlorine insecticides, and the like.

Examples of polycyclic aromatic hydrocarbons include naphthalene, acenaphthene, phenanthrene, methylphenylene, anthracene, benzanthracene, dibenzoanthracene, fluoranthene, benzofluoranthene, dibenzofluoranthene, pyrene, benzopyrene, dibenzopyrene, perylene, benzoperylene, indenoperylene, perylene, and aromatic hydrocarbon,Benzo (b) isTriphenylene, picene, coronene, biphenyl, and the like, but are not limited to theseThese are described.

Examples of the nitro polycyclic aromatic hydrocarbons include those obtained by substituting a part of hydrogen atoms of the polycyclic aromatic hydrocarbons exemplified above with a nitro group. Specific examples thereof include 1-nitronaphthalene, 2-nitronaphthalene, 3-nitroacenaphthylene, 4-nitrophenanthrene, 9-nitroanthracene, 1-nitropyrene, 2-nitropyrene, 4-nitropyrene, 2-nitrofluoranthene, 3-nitrofluoranthene, 8-nitrofluoranthene, 7-nitrobenzanthrene, and 6-nitrobenzoacryleneAnd the like, but are not limited thereto.

Examples of the polychlorinated biphenyls include, but are not limited to, dichlorobiphenyl, trichlorobiphenyl, tetrachlorobiphenyl, pentachlorodiphenyl, hexachlorobiphenyl, heptachlorobiphenyl, octachlorobiphenyl, nonachlorobiphenyl, and decachlorobiphenyl.

Examples of the chlorine-based pesticide include, but are not limited to, hexachlorocyclohexane (benzzene hexachloride), hexachlorobenzene, chlordane, mirex, dichlorodiphenyltrichloroethane (DDT), and the like.

The air pollutants are not limited to substances having a harmful action (carcinogenesis, cancer proliferation, cancer infiltration, etc.) alone, and may be substances exhibiting a harmful action by a composite action of a plurality of substances.

As shown in examples described later, the presence of air pollutants promotes the proliferation of cancer cells. The cancer cell growth inhibitor of the present embodiment can effectively inhibit the cell growth of cancer cells promoted by such air pollutants. That is, the cancer cell growth inhibitor of the present embodiment can inhibit the cell growth of cancer cells in the presence of an air contaminant, as compared with the case where the cancer cell growth inhibitor is not administered.

When the polycyclic aromatic Hydrocarbon invades into the cell, it binds to AhR and is transported into the nucleus by ARNT (Aryl Hydrocarbon Receptor Nuclear Translocator), thereby inducing the expression of drug metabolism genes such as CYP1a1 and CYP1B 1. ROS are produced in cells by drug metabolism caused by CYP1a1, CYP1B1, and the like. Carcinogenesis has been reported to be induced by ROS causing DNA variation and/or disruption of gene expression profiles (Moorthy B et al, Toxicol Sci.2015May; 145(1): 5-15.; Nebert DW et al, J Biol chem.2004Jun 4; 279(23): 23847-50.).

As shown in examples described later, the cancer cell growth inhibitor of the present embodiment can inhibit the expression of the CYP1a1 gene and the CYP1B1 gene induced by atmospheric pollutants. Therefore, the cancer cell growth inhibitor of the present embodiment may also be referred to as an expression inhibitor of the CYP1a1 gene and the CYP1B1 gene. That is, the cancer cell growth inhibitor of the present embodiment can inhibit the expression of the CYP1a1 gene and the CYP1B1 gene in the presence of an air pollutant, as compared to the case where the cancer cell growth inhibitor is not administered.

CYP1A1(NCBI gene ID: 1543) is 1 of cytochrome P450 superfamily of enzymes as monooxygenases catalyzing reactions associated with drug metabolism. CYP1a1 is localized in the endoplasmic reticulum, and is induced by polycyclic aromatic hydrocarbons, which are metabolized to form carcinogenic substances. Examples of the nucleotide sequence of the human CYP1A1 gene include NM _ 000499.5, NM _ 001319216.2, and NM _ 001319217.2, which are registered in the NCBI reference sequence database. The CYP1A1 gene is not limited to the genes having the above-mentioned sequences, and includes homologs thereof.

CYP1B1(NCBI gene ID: 1545) is 1 of cytochrome P450 superfamily of enzymes as monooxygenases catalyzing reactions associated with drug metabolism. CYP1B1 is localized in the endoplasmic reticulum, and is induced by polycyclic aromatic hydrocarbons, which are metabolized to form carcinogenic substances. Examples of the nucleotide sequence of the human CYP1B1 gene include NM-000104.3 registered in the NCBI reference sequence database. The CYP1B1 gene is not limited to the genes having the above-mentioned sequences, and includes homologs thereof.

As shown in the examples described below, the cancer cell growth inhibitor of the present embodiment can inhibit the expression of the ARNT gene induced by an atmospheric pollutant. Therefore, the cancer cell growth inhibitor of the present embodiment may also be referred to as an expression inhibitor of ARNT gene. That is, the cancer cell growth inhibitor of the present embodiment can inhibit the expression of the ARNT gene in the presence of an air pollutant, as compared to the case where the cancer cell growth inhibitor is not administered.

ARNT (NCBI gene ID: 405) is a protein which binds to AhR to which a ligand such as polycyclic aromatic hydrocarbon is bound and transports the ligand-AhR complex to the nucleus. Examples of the nucleotide sequence of the human ARNT gene include NM _ 001197325.1, 2.NM _ 001286035.1, 3.NM _ 001286036.1, 4.NM _ 001350224.1, 5.NM _ 001350225.1, 6.NM _ 001350226.1, 7.NM _ 001668.4, and 8.NM _ 178427.2, which are registered in the NCBI reference sequence database. The ARNT gene is not limited to the genes having the above sequences, and includes homologs thereof.

As shown in examples described later, the cancer cell growth inhibitor of the present embodiment can inhibit the generation of ROS induced by air pollutants. Therefore, the cancer cell proliferation inhibitor of the present embodiment may also be referred to as an ROS production inhibitor. That is, the cancer cell growth inhibitor of the present embodiment can inhibit the generation of ROS in the presence of an air pollutant, as compared with the case where the cancer cell growth inhibitor is not administered.

As shown in examples described later, the cancer cell growth inhibitor of the present embodiment can inhibit infiltration of cancer cells promoted by air pollutants. Therefore, the cancer cell growth inhibitor of the present embodiment may also be referred to as a cancer cell infiltration inhibitor. That is, the cancer cell growth inhibitor of the present embodiment can inhibit infiltration of cancer cells in the presence of an air contaminant, as compared with the case where the cancer cell growth inhibitor is not administered.

(inositol derivative)

The cancer cell growth inhibitor of the present embodiment contains, as an active ingredient, an inositol derivative in which a sugar is bonded to inositol.

Inositol is C₆H₆(OH)₆Cyclic hexahydric alcohols are shown. Among the myo-inositol, cis-inositol (cis-inositol), epi-inositol (epi-inositol), allo-inositol (allo-inositol), myo-inositol (myo-inositol), mucoinositol (muco-inositol), neo-inositol (neo-inositol), chiro-inositol (chiro-inositol) (both in D-form and in L-form), scyllo-inositol, and allo-inositol are presentAlcohol (scyllo-inositol) these 9 stereoisomers.

In the cancer cell growth inhibitor of the present embodiment, the inositol constituting the inositol derivative is preferably myoinositol having a physiological activity among the isomers. Inositol can be synthesized by a method of extraction from rice bran, a chemical synthesis method, a fermentation method, or the like.

In the cancer cell growth inhibitor of the present embodiment, the inositol derivative is a compound in which a sugar is bonded to a hydroxyl group of inositol. The sugar may be bonded to any 1 of 6 hydroxyl groups present in the inositol molecule, or may be bonded to any 2 or more.

The inositol-binding sugar may be a monosaccharide or an oligosaccharide. For example, 1 or more monosaccharides may be bound to 1 molecule of inositol, 1 or more oligosaccharides may be bound to 1 molecule of inositol, and 1 or more monosaccharides and 1 or more oligosaccharides may be bound to 1 molecule of inositol. In the inositol derivative, the total of the monosaccharide or oligosaccharide bound to 1 molecule of inositol is 1 or more, for example, 2 or more, for example, 3 or more, for example, 4 or more, in terms of monosaccharide unit.

In the present specification, the monosaccharide refers to a saccharide that cannot be further hydrolyzed, and refers to a compound that becomes a constituent element in forming the polysaccharide. Monosaccharides may also be referred to as the smallest building blocks of carbohydrates. In the present specification, the term "monosaccharide unit" refers to a chemical structure corresponding to a monosaccharide. "monosaccharide units" may also be referred to as chemical structures derived from monosaccharides. For example, disaccharide is 2 in terms of monosaccharide units, and trisaccharide is 3 in terms of monosaccharide units. More specifically, for example, mannitol, sorbitol, xylitol, erythritol, pentaerythritol, glucose, fructose, xylose, and the like are converted to a monosaccharide unit to be 1. When maltitol, sucrose, lactose, maltose, trehalose, and the like are converted into monosaccharide units, they are 2. For example, α -cyclodextrin is 6 in terms of monosaccharide units, β -cyclodextrin is 7 in terms of monosaccharide units, and γ -cyclodextrin is 8 in terms of monosaccharide units.

The inositol derivative may also be a mixture of inositol derivatives combined with a different number of sugars converted to monosaccharide units. For example, the inositol derivative may be a mixture of an inositol derivative having a saccharide having 1 monosaccharide unit bonded to 1 molecule of inositol, an inositol derivative having a saccharide having 2 monosaccharide units bonded to 1 molecule of inositol, an inositol derivative having a saccharide having 3 monosaccharide units bonded to a saccharide, an inositol derivative having a saccharide having 4 monosaccharide units bonded to a saccharide, and an inositol derivative having a saccharide having 5 or more monosaccharide units bonded to a saccharide. For example, the inositol derivative may contain 10 to 100% by mass of a sugar having 2 or more monosaccharide units bonded to 1 molecule of inositol, based on the total mass (100% by mass) of the inositol derivative. The ratio of the inositol derivative having a saccharide in which 2 or more monosaccharide units are bonded to 1 molecule of inositol to the total mass (100 mass%) of the inositol derivative may be, for example, 20 mass% or more, 30 mass% or more, 40 mass% or more, 50 mass% or more, 60 mass% or more, 70 mass% or more, or 80 mass% or more.

The sugar constituting the inositol derivative is not particularly limited, and examples thereof include mannitol, sorbitol, xylitol, maltitol, erythritol, pentaerythritol, glucose, sucrose, fructose, lactose, maltose, xylose, trehalose, α -cyclodextrin, β -cyclodextrin, and γ -cyclodextrin.

The sugar constituting the inositol derivative may be glucose, or may be an oligosaccharide containing glucose as a structural unit. The oligosaccharide may contain only glucose as a structural unit. Alternatively, the oligosaccharide may contain at least 1 molecule of glucose, and a sugar other than glucose as a structural unit. The molecular weight of the oligosaccharide may be, for example, about 300 to 3000. More specific examples of the oligosaccharide include disaccharides such as sucrose, lactose, maltose, trehalose and cellobiose, trisaccharides such as raffinose, melezitose and maltotriose, and tetrasaccharides such as stachyose.

The inositol derivative may be a mixture of an inositol derivative with a monosaccharide as the sugar and an inositol derivative with an oligosaccharide as the sugar. In addition, the inositol derivative may be a mixture of inositol derivatives combined with different kinds of sugars.

From the viewpoint of easily obtaining an inositol derivative with a high degree of purification, it is preferable to use β -cyclodextrin which is industrially inexpensive and can be stably supplied as a raw material for the inositol derivative. In this case, the sugar constituting the inositol derivative contains glucose as a structural unit. On the other hand, when cheaper starch or the like is used as a raw material for an inositol derivative, various sugars are transferred to various places during synthesis of the inositol derivative, and thus the degree of purification of the obtained inositol derivative tends to be unstable.

The inositol derivative may be in the form of a pharmaceutically acceptable salt. In the present specification, the term "pharmaceutically acceptable salt" refers to a salt form which does not impair the effect of inositol derivatives on inhibiting the proliferation of cancer cells caused by air pollutants. The pharmaceutically acceptable salt of the inositol derivative is not particularly limited, and examples thereof include a salt with an alkali metal (sodium, potassium, etc.); salts with alkaline earth metals (magnesium, calcium, etc.); salts with organic bases (such as pyridine and triethylamine), salts with amines, salts with organic acids (such as acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, and methanesulfonic acid), and salts with inorganic acids (such as hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, and nitric acid).

The inositol derivative may be in the form of a solvate. The inositol derivative may be in the form of a solvate of a salt of the inositol derivative. The solvate is not particularly limited, and examples thereof include a hydrate and an ethanol solvate.

(method for synthesizing inositol derivative)

The method for synthesizing the inositol derivative is not particularly limited, and the inositol derivative can be appropriately synthesized by a conventionally known method. For example, inositol and cyclodextrin, which is 1 kind of oligosaccharide, can be reacted in the presence of cyclodextrin glycosyltransferase to synthesize an inositol derivative (see, for example, Japanese patent application laid-open No. Sho 63-196596). Alternatively, an inositol derivative can be synthesized by a method of obtaining a sugar substrate using a glycosyl phosphite as a sugar donor (see, for example, Japanese patent application laid-open No. 6-298783).

In the cancer cell growth inhibitor of the present embodiment, the inositol derivative may contain 1 kind of compound selected from the group consisting of the inositol derivative, the salt of the inositol derivative, and the solvate of the inositol derivative, or 2 or more kinds of compounds in combination.

The cancer cell growth inhibitor of the present embodiment can be used by itself being administered to a patient for the purpose of inhibiting the growth of cancer cells induced by an atmospheric pollutant. The cancer cell growth inhibitor of the present embodiment may be used by being mixed in a pharmaceutical or cosmetic for the purpose of providing a function of inhibiting the growth of cancer cells induced by an air contaminant. The cancer cell growth inhibitor of the present embodiment may be used by being mixed with a cancer cell growth inhibiting composition described later.

The cancer cell growth inhibitor of the present embodiment can be administered to a patient before cancer onset, and is used for preventing cancer from occurring due to the growth of cells that have become cancerous. The cancer cell growth inhibitor of the present embodiment may be administered to a cancer patient to inhibit the growth of cancer cells induced by an atmospheric pollutant.

Examples of the cancer cells to which the cancer cell growth inhibitor of the present embodiment is applied include, but are not limited to, cancer cells such as lung cancer, pancreatic cancer, stomach cancer, head and neck cancer, mesothelioma, Neuroblastoma (Neuroblastoma), liver cancer, malignant melanoma, uterine cancer, bladder cancer, bile duct cancer, esophageal cancer, osteosarcoma, testicular tumor, thyroid cancer, acute myelogenous leukemia, brain tumor, prostate cancer, head and neck squamous cell carcinoma, colon cancer, kidney cancer, ovarian cancer, and breast cancer. The cancer cell growth inhibitor of the present embodiment is suitably used for inhibiting cell growth of lung cancer cells.

The cancer cell growth inhibitor of the present embodiment can be administered to a patient by the same method as the composition for inhibiting cancer cell growth described later, and is preferably administered transdermally.

[ composition for inhibiting cancer cell proliferation ]

In one embodiment, the present invention provides a cancer cell growth inhibitory composition comprising the cancer cell growth inhibitory agent and a pharmaceutically acceptable carrier.

The cancer cell growth inhibition composition of the present embodiment can be produced by: the cancer cell growth inhibitor, the pharmaceutically acceptable carrier, and optionally other components are mixed and formulated according to a conventional method (for example, a method described in the japanese pharmacopoeia).

In the present specification, the term "pharmaceutically acceptable carrier" refers to a carrier which does not impair the physiological activity of an active ingredient and does not substantially exhibit toxicity when administered to a subject. The phrase "not showing substantial toxicity" means that the administration subject does not show toxicity in an amount of the component generally used. The pharmaceutically acceptable carrier is not particularly limited, and examples thereof include excipients, binders, disintegrants, lubricants, emulsifiers, stabilizers, diluents, solvents for injection, oily bases, moisturizers, feel improvers, surfactants, polymers, thickeners, gelling agents, solvents, propellants, antioxidants, reducing agents, oxidizing agents, chelating agents, acids, bases, powders, inorganic salts, water, metal-containing compounds, unsaturated monomers, polyhydric alcohols, polymer additives, adjuvants, wetting agents, thickening substances, oily raw materials, liquid bases, fat-soluble substances, and polymer carboxylates. Specific examples of these components include those described in International publication No. 2016/076310. Specific examples of the polymer, thickener and gelling agent include methacryloyloxyethyl phosphorylcholine, butyl methacrylate, and polymers thereof. The pharmaceutically acceptable carriers can be used alone in 1 kind, or can be used in combination with more than 2 kinds.

The other ingredients are not particularly limited, and examples thereof include antiseptics, antibacterial agents, ultraviolet absorbers, whitening agents, vitamins and derivatives thereof, anti-inflammatory agents, hair growth agents, blood circulation promoters, stimulants, hormones, anti-wrinkle agents, anti-aging agents, firming agents, cold-feeling agents, temperature-feeling agents, wound healing promoters, irritation-mitigating agents, analgesics, cell activators, plant extracts, animal extracts, microbial extracts, seed oils, antipruritics, keratolytic/lytic agents, antiperspirants, cooling agents, astringents, enzymes, nucleic acids, perfumes, pigments, colorants, dyes, pigments, anti-inflammatory analgesics, antifungal agents, antihistamines, hypnotic agents, psychotropic agents, antihypertensive diuretics, antibiotics, anesthetics, antibacterial agents, antiepileptics, coronary vasodilators, anti-inflammatory agents, anti-allergic agents, skin-itch agents, anti-inflammatory agents, skin-inflammatory drugs, skin external drugs, skin external drugs, skin external drugs, and skin external drugs, and the like, Crude drug, antipruritic, cutin softening and peeling agent, ultraviolet blocker, antiseptic, antioxidant, pH regulator, additive, and metal soap. Specific examples of these components include those described in International publication No. 2016/076310. Specific examples of the plant extract include common plant (Lapsana communis) flowers/leaves/stems, tea leaves, and the like. Specific examples of the seed oil include moringa seed oil. Specific examples of the flavorant include perillaldehyde. The other components may be used alone in 1 kind, or may be used in combination in 2 or more kinds.

The cancer cell growth inhibitory composition of the present embodiment may contain a therapeutically effective amount of the cancer cell growth inhibitory agent. By "therapeutically effective amount" is meant an amount of an agent effective to treat or prevent a disease in a patient. The therapeutically effective amount may vary depending on the state of the disease, age, sex, and body weight of the subject to which it is administered. In the cancer cell growth inhibitory composition of the present embodiment, the therapeutically effective amount of the cancer cell growth inhibitor may be an amount at which the inositol derivative in the cancer cell growth inhibitor can inhibit the growth of cancer cells promoted by an air contaminant. For example, the therapeutically effective amount of the cancer cell growth inhibitor in the cancer cell growth inhibition composition of the present embodiment may be, for example, 0.01 to 20% by mass, for example, 0.1 to 10% by mass, for example, 0.1 to 5% by mass, for example, 0.1 to 3% by mass, for example, 0.1 to 2% by mass, for example, 0.3 to 2% by mass, for example, 0.6 to 1.5% by mass, based on the total content of the inositol derivative in the composition.

The content of the inositol derivative in the cancer cell growth inhibitory composition is the content of the inositol derivative when 1 kind of inositol derivative is contained alone, and the total content of the inositol derivatives when 2 or more kinds of inositol derivatives are contained in combination.

(Tocopherol phosphate)

The cancer cell growth inhibitory composition of the present embodiment may contain tocopherol phosphate or a salt thereof as another component.

The inositol derivative inhibits the AhR-mediated expression of CYP1A1 gene, CYP1B1 gene, and ARNT gene. Tocopherol phosphates inhibit the production of ROS induced by atmospheric pollutants by their antioxidant effect. Inositol derivatives and tocopherol phosphates each hinder different parts of the process of canceration. Therefore, it is presumed that the canceration-inhibiting effect is synergistically improved by using these compounds in combination.

As shown in examples described later, the use of an inositol derivative in combination with tocopherol phosphate or a salt thereof can synergistically inhibit the proliferation of cancer cells induced by an atmospheric pollutant. Therefore, in a preferred embodiment, the cancer cell growth inhibitory composition of the present embodiment includes an inositol derivative and tocopherol phosphate or a salt thereof.

As shown in examples described later, the use of an inositol derivative in combination with tocopherol phosphate or a salt thereof can synergistically inhibit the generation of ROS induced by atmospheric pollutants. Therefore, the cancer cell growth inhibition composition of the present embodiment can also be said to be a composition for inhibiting ROS production, which comprises an inositol derivative and tocopherol phosphate or a salt thereof.

Examples of the tocopherol phosphate include compounds represented by the following general formula (1).

[ chemical formula 1]

[ in the formula, R¹、R²And R³Independently of one another, represents a hydrogen atom or a methyl group.]

R in the tocopherol phosphoric acid ester according to the above-mentioned general formula (1)¹、R²And R³Of the kind in (1), the presence of alpha-tocopherol phosphate (R)¹、R²、R³＝CH₃) Beta-tocopherol phosphate (R)¹、R³＝CH₃，R²H), gamma-tocopherol phosphate (R)¹、R²＝CH₃，R³H), delta-tocopheryl phosphate (R)¹＝CH₃，R²、R³＝H)、ζ₂-tocopherol phosphoric acid ester (R)²、R³＝CH₃，R¹H), and η -tocopherol phosphate (R)²＝CH₃，R¹、R³H), etc.

The tocopherol phosphoric acid ester is not particularly limited, and any of these tocopherol phosphoric acid esters may be used. Among these tocopherol phosphates, α -tocopherol phosphate and γ -tocopherol phosphate are preferable, and α -tocopherol phosphate is more preferable.

The compound represented by the above general formula (1) has a chiral carbon atom at the 2-position of the chroman ring, and thus there are d-isomer, l-stereoisomer, and dl-isomer. The tocopherol phosphate may be any of these stereoisomers, but is preferably dl isomer.

Among the above, the tocopherol phosphates are preferably dl- α -tocopherol phosphate and dl- γ -tocopherol phosphate, and more preferably dl- α -tocopherol phosphate.

The salt of the tocopherol phosphoric acid ester is not particularly limited, and examples thereof include a salt with an inorganic base, a salt with an organic base, and the like.

Examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salts and magnesium salts; an aluminum salt; an ammonium salt; zinc salts, and the like.

Examples of the salt with an organic base include an alkylammonium salt and a salt with a basic amino acid.

Among the above, the salt of tocopherol phosphoric acid ester is preferably an alkali metal salt, and more preferably a sodium salt. The alkali metal salt, particularly the sodium salt of tocopherol phosphate has advantages of high solubility in water and easy handling because it is in the form of powder.

Preferred examples of the tocopherol phosphoric acid ester include an alkali metal salt (for example, sodium salt) of the compound represented by the above general formula (1), an alkali metal salt (for example, sodium salt) of α -tocopherol phosphoric acid ester, an alkali metal salt (for example, sodium salt) of γ -tocopherol phosphoric acid ester, an alkali metal salt (for example, sodium salt) of dl- α -tocopherol phosphoric acid ester, an alkali metal salt (for example, sodium salt) of dl- γ -tocopherol phosphoric acid ester, and the like.

The sodium salt of dl- α -tocopherol phosphate is commercially available from showa electrician under the product name of TPNa (registered trademark) (display name: tocopherol phosphate Na). The above-mentioned TPNa is exemplified as a preferable example of the tocopherol phosphoric acid ester.

The cancer cell growth inhibitory composition of the present embodiment may be used alone or in combination with 2 or more selected from tocopherol phosphate and salts thereof. The cancer cell growth inhibitory composition of the present embodiment preferably contains a salt of tocopherol phosphate, and more preferably an alkali metal salt (for example, sodium salt) of tocopherol phosphate is used alone.

The tocopherol phosphate or a salt thereof can be produced by a known production method, for example, a method described in Japanese patent laid-open Nos. 59-44375 and WO 97/14705. For example, tocopherol phosphate can be obtained by reacting tocopherol dissolved in a solvent with a phosphorylating agent such as phosphorus oxychloride and appropriately purifying the product after the reaction is completed. The obtained tocopherol phosphate may be neutralized with a metal oxide such as magnesium oxide, a metal hydroxide such as sodium hydroxide, ammonium hydroxide, alkylammonium hydroxide, or the like to obtain a salt of the tocopherol phosphate.

When the cancer cell growth inhibitory composition of the present embodiment contains tocopherol phosphate or a salt thereof, the content of tocopherol phosphate or a salt thereof is not particularly limited. The content of the tocopherol phosphate or the salt thereof in the cancer cell growth inhibition composition of the present embodiment is preferably an amount that can synergistically exhibit an inhibitory effect on cancer cell growth when used in combination with an inositol derivative. For example, the cancer cell growth inhibitory composition of the present embodiment may contain a therapeutically effective amount of tocopherol phosphate or a salt thereof. The therapeutically effective amount of the tocopherol phosphate or the salt thereof in the cancer cell growth inhibition composition of the present embodiment may be, for example, 0.01 to 20% by mass, for example, 0.1 to 10% by mass, for example, 0.1 to 5% by mass, for example, 0.1 to 3% by mass, for example, 0.1 to 2% by mass, for example, 0.3 to 2% by mass, for example, 0.6 to 1.5% by mass, based on the total content of the tocopherol phosphate or the salt thereof in the composition.

The content of the tocopherol phosphate or a salt thereof in the cancer cell growth inhibitory composition is the content of the compound when 1 kind of the tocopherol phosphate or a salt thereof is contained alone, and the total content of the compounds when 2 or more kinds of the tocopherol phosphates or salts thereof are contained in combination.

The ratio of the inositol derivative to the tocopherol phosphate or a salt thereof in the cancer cell growth inhibition composition of the present embodiment is not particularly limited, and may be, for example, an inositol derivative: tocopherol phosphate or a salt thereof ═ 1: 10-10: 1 (mass ratio), preferably 1: 5-5: 1 (mass ratio), more preferably 1: 3-3: 1 (mass ratio).

The cancer cell growth inhibition composition of the present embodiment may be a pharmaceutical composition or a cosmetic.

(pharmaceutical composition)

In one embodiment, the present invention provides a pharmaceutical composition for inhibiting cancer cell proliferation, which comprises the cancer cell proliferation inhibitor and a pharmaceutically acceptable carrier.

In the pharmaceutical composition of the present embodiment, the pharmaceutically acceptable carrier is not particularly limited, and a carrier generally used for pharmaceuticals may be used in addition to the above-mentioned carriers. For example, usual raw materials described in japanese pharmacopoeia, Pharmaceutical specifications outside japanese pharmacopoeia, Pharmaceutical additive specification 2013 (japanese newspaper agency, 2013), Pharmaceutical additive dictionary 2016 (edited by japanese Pharmaceutical additive society, japanese newspaper agency, 2016), Handbook of Pharmaceutical Excipients,7th edition (seventh edition of Pharmaceutical Excipients manual) (Pharmaceutical Press, 2012) and the like can be used. The pharmaceutically acceptable carriers can be used alone in 1 kind, or can be used in combination with more than 2 kinds.

The pharmaceutical composition of the present embodiment may contain other components in addition to the cancer cell growth inhibitor and the pharmaceutically acceptable carrier. The other components are not particularly limited, and a usual pharmaceutical additive may be used. In addition, as other components, active components other than the cancer cell growth inhibitors can be used. As the Pharmaceutical additives and active ingredients as other ingredients, in addition to the above-mentioned ingredients, general raw materials described in, for example, japanese pharmacopoeia, Pharmaceutical specifications outside japanese pharmacopoeia, Pharmaceutical additive specification 2013 (daikon, 2013), Pharmaceutical additive dictionary 2016 (editions of japan Pharmaceutical additives society, daikon, 2016), Handbook of Pharmaceutical Excipients,7th edition (seventh edition of Pharmaceutical Excipients manual) (Pharmaceutical Press, 2012) and the like can be used. The other components may be used alone in 1 kind, or may be used in combination in 2 or more kinds. As the other component, tocopherol phosphate or a salt thereof can be preferably exemplified.

The dosage form of the pharmaceutical composition of the present embodiment is not particularly limited, and may be a dosage form generally used as a pharmaceutical preparation. Examples of the dosage form include orally administered dosage forms such as tablets, coated tablets, pills, powders, granules, capsules, liquids, suspensions, and emulsions; and parenteral preparations such as injections, suppositories, external preparations for skin, and nasal drops. Pharmaceutical compositions of these dosage forms can be formulated by a general method (for example, a method described in the Japanese pharmacopoeia).

The pharmaceutical composition of the present embodiment is preferably an external preparation for skin or nasal drops. More specifically, the skin external preparation includes dosage forms such as creams, lotions, masks, foams, skin detergents, ointments, plasters, ointments, alcoholic preparations, suspensions, tinctures, patches, cataplasms, liniments, aerosols, sprays, gels, and the like.

The method of administering the pharmaceutical composition of the present embodiment is not particularly limited, and administration can be performed by a method generally used as a method of administering a pharmaceutical. For example, the composition may be administered orally in the form of tablets, coated tablets, pills, powders, granules, capsules, liquids, suspensions, emulsions, etc., may be administered alone or mixed with ordinary infusion solutions such as glucose solution, ringer's solution, etc., to intravenous, intra-arterial, intramuscular, intradermal, subcutaneous, intraperitoneal, etc., may be administered intrarectally in the form of suppositories, may be administered to the skin in the form of skin preparations for external use, or may be administered to the nasal cavity in the form of nasal drops. In a preferred embodiment, the pharmaceutical composition of the present embodiment is prepared as an external preparation for skin and applied, attached or sprayed to the affected part. Alternatively, it can be made into nasal drop for administration into nasal cavity.

The administered amount of the pharmaceutical composition of this embodiment can be a therapeutically effective amount. The therapeutically effective amount may be determined appropriately according to the symptoms, body weight, age, sex, etc. of the patient, the dosage form of the pharmaceutical composition, the administration method, etc. For example, the amount of the pharmaceutical composition of the present embodiment to be administered may be, for example, 0.01 to 500mg per unit administration form of an inositol derivative in the case of oral administration, 0.02 to 250mg per unit administration form of an inositol derivative in the case of injection, or 0.01 to 500mg per unit administration form of an inositol derivative in the case of suppository; and so on. The amount of the pharmaceutical composition of the present embodiment to be administered is, for example, 0.15 to 500mg, for example, 0.15 to 300mg, for example, 0.15 to 200mg, for example, 0.2 to 100mg per unit dosage form of inositol derivative in the case of an external preparation for skin or a nasal drop.

The administration interval of the pharmaceutical composition of the present embodiment may be determined as appropriate depending on the symptoms, body weight, age, sex, and the like of the patient, the dosage form of the pharmaceutical composition, the administration method, and the like. For example, the number of the administration may be 1 time per day or about 2 to 3 times per day.

The pharmaceutical composition of the present embodiment can be administered to, for example, a cancer patient, and is thus useful for inhibiting cancer cell proliferation. In addition, the pharmaceutical composition of the present embodiment can be administered to a cancer patient, and is useful for inhibiting infiltration and metastasis of cancer cells.

In towns, cancer patients are routinely exposed to the risk of cancer cell proliferation promoted by atmospheric pollutants in contact with these pollutants. Therefore, the risk of promoting the proliferation of cancer cells by air pollutants can be reduced by administering the pharmaceutical composition of the present embodiment to a cancer patient.

Alternatively, the pharmaceutical composition of the present embodiment may be administered to a patient prophylactically in a region where air pollutants are present, and used for inhibiting the proliferation of cells that have become cancerous and preventing the onset of cancer.

(cosmetics)

In one embodiment, the present invention provides a cosmetic for inhibiting cancer cell proliferation, which contains the cancer cell proliferation inhibitor and a pharmaceutically acceptable carrier.

In the cosmetic of the present embodiment, the pharmaceutically acceptable carrier is not particularly limited, and carriers generally used in cosmetics other than the above-mentioned carriers can be used. For example, general materials described in the second Edition notes of Cosmetic raw material references (edited by the Japan national institute of public Specifications, journal of medicine, 1984), external component specifications of Cosmetic raw material references (examination and revision of the ministry of health and provincial pharmacy, journal of medicine, 1993), standards for Cosmetic type approval (examination and revision of the ministry of health and provincial pharmacy, journal of medicine, 1993), Dictionary of Cosmetic raw materials (Sun light ケミカルズ, 3 years), International Cosmetic Ingredient Dictionary and Handbook 2002Ninth Edition (International Dictionary of Cosmetic raw materials and Ninth 2002) Vol.1 to 4, by CTFA, and the like can be used. The pharmaceutically acceptable carriers can be used alone in 1 kind, or can be used in combination with more than 2 kinds.

The cosmetic of the present embodiment may contain other components in addition to the cancer cell growth inhibitor and the pharmaceutically acceptable carrier. The other components are not particularly limited, and usual cosmetic additives can be used. In addition, as other components, active components other than the cancer cell growth inhibitors can be used. As the Cosmetic additives and active ingredients as other ingredients, in addition to the above-mentioned ingredients, general raw materials described in, for example, second Edition notes of Cosmetic raw material standards (edited by Japan official gazette, Probeol. Proc., 1984), external component standards of Cosmetic raw material standards (examination and repair by Hough's Bureau of pharmacy, Probeol., 1993), additional external component standards of Cosmetic raw material standards (examination and repair by Hough's Bureau of pharmacy, Probeol. Proc., 1993), standards for Cosmetic variety approval (examination and repair by Hough's Bureau of pharmacy, Industy. Probeol. Proc., 1993), Dictionary of Cosmetic raw materials (ケミカルズ, High. 3 years), International Cosmetic Ingredient Dictionary and Handbook 2002Ninth Edition (Ninth Edition, International Cosmetic raw materials Dictionary and Handbook), Vol.1 to 4, and CTFA can be used. The other components may be used alone in 1 kind, or may be used in combination in 2 or more kinds. As the other component, tocopherol phosphate or a salt thereof can be preferably exemplified.

The form of the cosmetic according to the present embodiment is not particularly limited, and may be a form generally used as a cosmetic. Examples thereof include hair cosmetics such as shampoos, conditioners, hair conditioners, and hair conditioners; basic cosmetics such as face toilet, makeup remover, cosmetic water, lotion, toner, cream, gel, sunscreen cream, facial mask (pack), skin care mask (mask), and skin caring liquid; makeup cosmetics such as foundation make-up, makeup cream, lipstick, lip gloss, and blush; body cosmetics such as body wash, toilet powder, deodorant cosmetics, etc. These cosmetics can be produced by a general method. Among these cosmetics, the cosmetic of the present embodiment is preferably in the form of a skin preparation for external use, for example, to be applied to or applied to the skin. Examples of suitable lotions, toilet lotions, creams, gels, sunscreen creams, facial masks, skin care films, beauty lotions, foundations, and pre-creams are given.

The formulation of the cosmetic of the present embodiment is not particularly limited, and examples thereof include emulsion type such as oil-in-water (O/W) type, water-in-oil (W/O) type, W/O/W type, and O/W/O type, emulsion polymer type, oil type, solid type, liquid type, paste type, stick type, volatile oil type, powder type, gel type, paste type, cream type, sheet type, film type, mist type, spray type, multilayer type, foam type, and sheet type.

The amount of the cosmetic of the present embodiment is not particularly limited, and may be an amount effective for suppressing the proliferation of cancer cells caused by air pollutants. For example, the amount of the cosmetic according to the present embodiment may be 0.15 to 500mg, for example, 0.15 to 300mg, for example, 0.15 to 200mg, for example, 0.2 to 100mg per 1 time of the amount of the inositol derivative.

The interval between the use of the cosmetic of the present embodiment is not particularly limited, and may be, for example, 1 time per day or about 1 day and 2 to 3 times per day.

The cosmetic of the present embodiment can be used by cancer patients in order to reduce the risk of cancer cell proliferation promotion due to air pollutants in towns and the like where the concentration of air pollutants is high, for example. Alternatively, in a region or season where the distribution concentration of air pollutants is high, it is possible to use the cosmetic composition for daily skin care or color cosmetics in order to suppress the proliferation of cells that have become cancerous and prevent the onset of cancer.

[ other embodiments ]

In one embodiment, the present invention provides a method for inhibiting cancer cell proliferation, which comprises administering an inositol derivative obtained by binding a sugar (monosaccharide or oligosaccharide) to inositol to a mammal. The cancer cell proliferation is preferably cancer cell proliferation promoted by an air pollutant.

In one embodiment, the present invention provides a method for inhibiting cancer cell infiltration, which comprises administering an inositol derivative obtained by binding a sugar (monosaccharide or oligosaccharide) to inositol to a mammal. The cancer cell infiltration is preferably cancer cell infiltration promoted by an air pollutant.

In one embodiment, the present invention provides a method for inhibiting the expression of at least one gene selected from the group consisting of a CYP1a1 gene, a CYP1B1 gene, and an ARNT gene, comprising the step of administering an inositol derivative in which a sugar (monosaccharide or oligosaccharide) is bound to inositol to a mammal. The gene expression is preferably a gene expression promoted by an air pollutant.

In one embodiment, the present invention provides a method for inhibiting ROS production, which comprises administering an inositol derivative obtained by binding a sugar (monosaccharide or oligosaccharide) to inositol to a mammal. The above ROS production is preferably ROS production promoted by atmospheric pollutants.

In one embodiment, the present invention provides an inositol derivative in which inositol is bonded to a sugar (monosaccharide or oligosaccharide) for inhibiting cancer cell proliferation. The cancer cell proliferation is preferably cancer cell proliferation promoted by an air pollutant.

In one embodiment, the present invention provides an inositol derivative in which inositol is bonded to a sugar (monosaccharide or oligosaccharide) for inhibiting cancer cell infiltration. The cancer cell infiltration is preferably cancer cell infiltration promoted by an air pollutant.

In one embodiment, the present invention provides an inositol derivative in which a sugar (monosaccharide or oligosaccharide) is bound to inositol for inhibiting the expression of at least one gene selected from the group consisting of the CYP1a1 gene, the CYP1B1 gene, and the ARNT gene. The gene expression is preferably a gene expression promoted by an air pollutant.

In one embodiment, the present invention provides an inositol derivative in which a sugar (monosaccharide or oligosaccharide) is bonded to inositol for inhibiting the generation of ROS. The above ROS production is preferably ROS production promoted by atmospheric pollutants.

In one embodiment, the present invention provides use of an inositol derivative in which a sugar (monosaccharide or oligosaccharide) is bonded to inositol for producing a cancer cell growth inhibitor. Preferably, the cancer cell growth inhibitor inhibits cancer cell growth promoted by an air pollutant.

In one embodiment, the present invention provides use of an inositol derivative in which a sugar (monosaccharide or oligosaccharide) is bonded to inositol for producing a cancer cell infiltration inhibitor. Preferably, the cancer cell infiltration inhibitor inhibits cancer cell infiltration promoted by an air pollutant.

In one embodiment, the present invention provides use of an inositol derivative in which a sugar (monosaccharide or oligosaccharide) is bound to inositol for producing an expression inhibitor of at least one gene selected from the group consisting of a CYP1a1 gene, a CYP1B1 gene, and an ARNT gene. Preferably, the gene expression inhibitor inhibits gene expression promoted by an air pollutant.

In one embodiment, the present invention provides use of an inositol derivative in which a sugar (monosaccharide or oligosaccharide) is bonded to inositol for producing an ROS production inhibitor. Preferably, the above ROS production inhibitor inhibits ROS production promoted by atmospheric pollutants.

In one embodiment, the present invention provides use of an inositol derivative in which a sugar (monosaccharide or oligosaccharide) is bonded to inositol for producing a composition for inhibiting cancer cell proliferation. Preferably, the cancer cell growth inhibitory composition inhibits the growth of cancer cells promoted by an air pollutant.

In one embodiment, the present invention provides use of an inositol derivative in which a sugar (monosaccharide or oligosaccharide) is bonded to inositol for producing a composition for inhibiting cancer cell infiltration. Preferably, the cancer cell infiltration-suppressing composition suppresses infiltration of cancer cells promoted by an air pollutant.

In one embodiment, the present invention provides use of an inositol derivative in which a sugar (monosaccharide or oligosaccharide) is bound to inositol for producing a composition for inhibiting expression of at least one gene selected from the group consisting of a CYP1a1 gene, a CYP1B1 gene, and an ARNT gene. Preferably, the composition for suppressing gene expression suppresses gene expression promoted by an air pollutant.

In one embodiment, the present invention provides use of an inositol derivative in which a sugar (monosaccharide or oligosaccharide) is bonded to inositol for producing a composition for inhibiting ROS production. The above-mentioned composition for inhibiting ROS production preferably inhibits ROS production promoted by atmospheric pollutants.

In one embodiment, the present invention provides a method for inhibiting cancer cell proliferation, which comprises administering an inositol derivative in which a sugar (monosaccharide or oligosaccharide) is bound to inositol and tocopherol phosphate or a salt thereof to a mammal. The cancer cell proliferation is preferably cancer cell proliferation promoted by an air pollutant.

In one embodiment, the present invention provides a method for inhibiting cancer cell infiltration, which comprises administering an inositol derivative in which a sugar (monosaccharide or oligosaccharide) is bound to inositol and tocopherol phosphate or a salt thereof to a mammal. The cancer cell infiltration is preferably cancer cell infiltration promoted by an air pollutant.

In one embodiment, the present invention provides a method for inhibiting the expression of at least one gene selected from the group consisting of a CYP1a1 gene, a CYP1B1 gene, and an ARNT gene, comprising the step of administering an inositol derivative in which a sugar (monosaccharide or oligosaccharide) is bound to inositol and tocopherol phosphate or a salt thereof to a mammal. The gene expression is preferably a gene expression promoted by an air pollutant.

In one embodiment, the present invention provides a method for inhibiting ROS production, which comprises administering an inositol derivative in which a sugar (monosaccharide or oligosaccharide) is bonded to inositol, and tocopherol phosphate or a salt thereof to a mammal. The above ROS production is preferably ROS production promoted by atmospheric pollutants.

In one embodiment, the present invention provides a combination of an inositol derivative in which a sugar (monosaccharide or oligosaccharide) is bonded to inositol and tocopherol phosphate or a salt thereof for inhibiting cancer cell proliferation. The cancer cell proliferation is preferably cancer cell proliferation promoted by an air pollutant.

In one embodiment, the present invention provides a combination of an inositol derivative in which a sugar (monosaccharide or oligosaccharide) is bonded to inositol and tocopherol phosphate or a salt thereof for inhibiting cancer cell infiltration. The cancer cell infiltration is preferably cancer cell infiltration promoted by an air pollutant.

In one embodiment, the present invention provides a combination of an inositol derivative in which a sugar (monosaccharide or oligosaccharide) is bound to inositol and tocopherol phosphate or a salt thereof, for inhibiting the expression of at least one gene selected from the group consisting of a CYP1a1 gene, a CYP1B1 gene, and an ARNT gene. The gene expression is preferably a gene expression promoted by an air pollutant.

In one embodiment, the present invention provides a combination of an inositol derivative in which a sugar (monosaccharide or oligosaccharide) is bonded to inositol and tocopherol phosphate or a salt thereof for inhibiting the generation of ROS. The above ROS production is preferably ROS production promoted by atmospheric pollutants.

In one embodiment, the present invention provides a combination of an inositol derivative in which a sugar (monosaccharide or oligosaccharide) is bonded to inositol and tocopherol phosphate or a salt thereof, for use in the production of a cancer cell growth inhibitor. Preferably, the cancer cell growth inhibitor inhibits cancer cell growth promoted by an air pollutant.

In one embodiment, the present invention provides a combination of an inositol derivative in which a sugar (monosaccharide or oligosaccharide) is bonded to inositol and tocopherol phosphate or a salt thereof, for use in the production of a cancer cell infiltration inhibitor. Preferably, the cancer cell infiltration inhibitor inhibits cancer cell infiltration promoted by an air pollutant.

In one embodiment, the present invention provides use of a combination of an inositol derivative having a sugar (monosaccharide or oligosaccharide) bound to inositol and tocopherol phosphate or a salt thereof for producing an expression inhibitor for at least one gene selected from the group consisting of a CYP1a1 gene, a CYP1B1 gene, and an ARNT gene. Preferably, the gene expression inhibitor inhibits gene expression promoted by an air pollutant.

In one embodiment, the present invention provides use of a combination of an inositol derivative in which a sugar (monosaccharide or oligosaccharide) is bonded to inositol and tocopherol phosphate or a salt thereof for producing an ROS production inhibitor. Preferably, the above ROS production inhibitor inhibits ROS production promoted by atmospheric pollutants.

In one embodiment, the present invention provides use of a combination of an inositol derivative in which a sugar (monosaccharide or oligosaccharide) is bonded to inositol and tocopherol phosphate or a salt thereof for producing a composition for inhibiting cancer cell proliferation. Preferably, the cancer cell growth inhibitory composition inhibits the growth of cancer cells promoted by an air pollutant.

In one embodiment, the present invention provides a combination of an inositol derivative in which a sugar (monosaccharide or oligosaccharide) is bonded to inositol and tocopherol phosphate or a salt thereof, for use in the production of a composition for inhibiting cancer cell infiltration. Preferably, the cancer cell infiltration-suppressing composition suppresses infiltration of cancer cells promoted by an air pollutant.

In one embodiment, the present invention provides use of a combination of an inositol derivative having an inositol bonded to a sugar (monosaccharide or oligosaccharide) and tocopherol phosphate or a salt thereof for producing a composition for inhibiting expression of at least one gene selected from the group consisting of a CYP1a1 gene, a CYP1B1 gene, and an ARNT gene. Preferably, the composition for suppressing gene expression suppresses gene expression promoted by an air pollutant.

In one embodiment, the present invention provides use of a combination of an inositol derivative in which a sugar (monosaccharide or oligosaccharide) is bonded to inositol and tocopherol phosphate or a salt thereof for producing a composition for inhibiting ROS production. The above-mentioned composition for inhibiting ROS production preferably inhibits ROS production promoted by atmospheric pollutants.

Examples

The present invention will be described below with reference to examples, but the present invention is not limited to the following examples.

[ production examples of inositol derivatives ]

Myoinositol is reacted with β -cyclodextrin in the presence of cyclodextrin glycosyltransferase to produce an inositol derivative in which myoinositol is bound to glucose or an oligosaccharide having glucose as a monosaccharide unit. As a result of analyzing the produced inositol derivative by liquid chromatography mass spectrometry (LC-MS), the ratio of 1 molecule of the number of glucose bound to myoinositol was 12 mass%, the ratio of 2 molecules of the number of glucose bound to myoinositol was 30 mass%, the ratio of 3 molecules of the number of glucose bound to myoinositol was 9 mass%, the ratio of 4 molecules of the number of glucose bound to myoinositol was 12 mass%, and the ratio of 5 molecules of the number of glucose bound to myoinositol was 2 mass%.

In the following experimental examples, the inositol derivative obtained in the present production example was used.

[ Experimental example 1]

(effects of inhibiting the expression of CYP1A1 Gene and CYP1B1 Gene)

The effects of inhibiting the expression of CYP1A1 gene and CYP1B1 gene in human normal epidermal cells (NHEK, manufactured by NHEK クラボウ Co., Ltd.) derived from an inositol derivative were measured under the following conditions.

NHEK cells were cultured at 10000/cm²The inoculation density of (2) was inoculated into HuMedia KG2 medium manufactured by クラボウ Co., Ltd at 37 ℃ with 5% CO₂Was cultured under the conditions of (1) for 24 hours. Subsequently, an aqueous solution of an inositol derivative or an aqueous solution of myoinositol was added to the culture medium so that the final concentration of the inositol derivative or myoinositol became 0.001 mass%, or water (pure water) was added to the culture medium, and further culture was carried out for 24 hours. Thereafter, atmospheric dust (NIST1648a) in DMSO was added in an amount of 0.1mL per 100mL of the medium so that the final concentration of atmospheric dust in the medium became 500. mu.g/mL, and further incubation was performed for 48 hours. Thereafter, the NHEK cells were recovered and Nucleospin was used^TMRX (タカラバイオ Co.) to extract total RNA. cDNA was synthesized from the obtained RNA using PrimeScript (registered trademark) RT Master Mix (タカラバイオ Co.). The expression levels of the CYP1A1 gene and CYP1B1 gene were quantified by quantitative real-time PCR using the cDNA as a template and primers specific to the CYP1A1 gene and CYP1B1 gene (QuantiTect Primer Assays, キアゲン, Inc.). As an internal standard gene, the expression level of GAPDH gene (used Primer: Perfect Real Time Primer, manufactured by タカラ) as a housekeeping gene in which no expression fluctuation due to atmospheric dust was observed was quantified, and the expression levels of CYP1A1 gene and CYP1B1 gene were normalized with respect to the expression level of GAPDH. The case where no atmospheric dust was added was taken as a control.

The results are shown in Table 1. In table 1, the expression levels of the respective genes in the atmospheric dust-added group are shown as relative expression levels when the expression levels of the respective genes in a control to which no atmospheric dust was added are set to 1. In the inositol derivative-added group, the expression level of any of the CYP1a1 gene and CYP1B1 gene was suppressed compared to the water-added group and the myoinositol-added group. From these results, it was confirmed that the inositol derivative has a high inhibitory effect on the expression of the CYP1a1 gene and the CYP1B1 gene induced by atmospheric dust.

[ Table 1]

[ Experimental example 2]

(inhibitory Effect of ARNT Gene expression)

The effect of inhibiting the expression of the ARNT gene in human normal epidermal cells (NHEK, manufactured by クラボウ) derived from an inositol derivative was measured under the following conditions.

NHEK cells were cultured at 10000/cm²The inoculation density of (2) was inoculated into HuMedia KG2 medium manufactured by クラボウ Co., Ltd at 37 ℃ with 5% CO₂Was cultured under the conditions of (1) for 24 hours. Subsequently, an aqueous solution of an inositol derivative or an aqueous solution of myoinositol was added to the culture medium so that the final concentration of the inositol derivative or myoinositol became 0.001 mass%, or water (pure water) was added to the culture medium, and further culture was carried out for 24 hours. Thereafter, atmospheric dust (NIST1648a) in DMSO was added in an amount of 0.1mL per 100mL of the medium so that the final concentration of atmospheric dust in the medium became 500. mu.g/mL, and further incubation was performed for 48 hours. Thereafter, the NHEK cells were recovered and Nucleospin was used^TMRX (タカラバイオ Co.) to extract total RNA. cDNA was synthesized from the obtained RNA using PrimeScript (registered trademark) RT Master Mix (タカラバイオ Co.). Using this cDNA as a template, the expression level of the ARNT gene was quantified by quantitative Real-Time PCR using a Primer specific to the ARNT gene (Perfect Real Time Primer, manufactured by タカラ). As an internal standard gene, the expression level of GAPDH (used Primer: Perfect Real Time Primer, manufactured by タカラ) was quantified, and the expression level of ARNT gene was normalized with respect to the expression level of GAPDH. The case where no atmospheric dust was added was taken as a control.

The results are shown in Table 2. In table 2, the expression level of the ARNT gene in the atmospheric dust-added group is shown as the relative expression level when the expression level of the ARNT gene in the control to which no atmospheric dust was added is 1. In the inositol derivative-added group, the expression level of the ARNT gene was suppressed as compared with the water-added group and the myoinositol-added group. From these results, it was confirmed that the inositol derivative has a high inhibitory effect on the expression of ARNT gene induced by atmospheric dust.

[ Table 2]

[ Experimental example 3]

(inhibitory Effect (1) on ROS production)

The ROS production inhibitory effect on human normal epidermal cells (NHEK, manufactured by NHEK クラボウ) produced by inositol derivatives was measured under the following conditions.

NHEK cells were cultured at 10000/cm²The inoculation density of (2) was inoculated into HuMedia KG2 medium manufactured by クラボウ Co., Ltd at 37 ℃ with 5% CO₂Was cultured under the conditions of (1) for 24 hours. Subsequently, an aqueous solution of an inositol derivative or an aqueous solution of myoinositol was added to the culture medium so that the final concentration of the inositol derivative or myoinositol became 0.001 mass%, or water (pure water) was added to the culture medium, and further culture was carried out for 24 hours. Thereafter, 0.1mL of atmospheric dust (NIST1648a) in DMSO was added per 100mL of the medium so that the final concentration of atmospheric dust in the medium became 500. mu.g/mL, and the medium was further incubated for 48 hours under the same conditions as described above. Thereafter, the amount of ROS produced was measured using a ROS assay kit (OZ BIOSCIENCES Co., Ltd.). After the cells obtained by removing the medium were washed with phosphate buffer solution (PBS, manufactured by wako pure chemical industries), 100 μ L of dichlorofluorescein diacetate (dichlorofluorescein diacetate) attached to the ROS analysis kit was added to each group of cells, and the cells were left to stand at 37 ℃ for 30 minutes in the absence of light. The cells were washed again with PBS, 100. mu.L of PBS was added, and the excitation wavelength was measured at 485nm by a microplate reader i-Control (manufactured by テカン)Fluorescence intensity at the absorption wavelength of 535 nm. The case where no atmospheric dust was added was taken as a control.

The results are shown in Table 3. Table 3 shows the amount of ROS produced in the atmospheric dust-added group as a relative amount when the fluorescence intensity of the control to which no atmospheric dust was added was set to 1. In the inositol derivative-added group, the amount of ROS production was suppressed compared to the water-added group and the myoinositol-added group. From the results, it was confirmed that the inositol derivative has a high inhibitory effect on the generation of ROS induced by atmospheric dust. On the other hand, in the myoinositol-added group, no inhibitory effect on the generation of ROS was observed compared to the water-added group.

[ Table 3]

[ Experimental example 4]

(inhibitory Effect on cancer cell growth (1))

The cell growth inhibitory effect of a Lewis lung cancer-derived cell line (LLC, JCRB cell bank) derived from an inositol derivative was measured under the following conditions.

LLC cells are treated at 50000 cells/cm²Was inoculated into a mixture of HamF10 medium and L15 medium (both Sigma-Aldrich) at a ratio of 3: 7 (volume ratio) in a medium at 37 ℃ with 5% CO₂Was cultured under the conditions of (1) for 24 hours. Subsequently, an aqueous solution of an inositol derivative or an aqueous solution of myoinositol was added to the culture medium so that the final concentration of the inositol derivative or myoinositol became 0.001 mass%, or water (pure water) was added to the culture medium, and further culture was carried out for 24 hours. Thereafter, 0.1mL of atmospheric dust (NIST1648a) in DMSO was added per 100mL of the medium so that the final concentration of atmospheric dust in the medium became 500. mu.g/mL, and the culture was further carried out for 48 hours under the same conditions as described above. Thereafter, the medium was replaced with a medium containing 10% (V/V) WST-8 manufactured by ナカライ, and after further culturing for 3 hours, the medium was measured by a microplate reader i-Control (manufactured by テカン) at a wavelength of 450nmAbsorbance. The case where no atmospheric dust was added was taken as a control.

The results are shown in Table 4. Table 4 shows the cell growth amounts in the atmospheric dust-added group as relative amounts when the absorbance of a control to which no atmospheric dust was added was set to 1. In the inositol derivative-added group, the amount of cell growth of cancer cells was suppressed as compared with the water-added group and myoinositol-added group. From these results, it was confirmed that the inositol derivative has a high inhibitory effect on the cell proliferation of cancer cells accelerated by atmospheric dust.

[ Table 4]

[ Experimental example 5]

(cancer cell infiltration-suppressing effect)

The cell infiltration inhibitory effect of a Lewis lung cancer-derived cell line (LLC, JCRB cell bank) derived from an inositol derivative was measured under the following conditions. The test was carried out using a Cytoselect infiltration assay kit manufactured by CELLBIOLABS, INC.

A mixture of HamF10 medium and L15 medium (both Sigma-Aldrich) was used in a ratio of 3: 7 (volume ratio), LLC cells were plated on a chamber plate (chamber plate) for infiltration assay attached to the infiltration assay kit so as to be 100000 cells/mL, and 5% CO was added at 37 ℃ to₂Was cultured under the conditions of (1) for 24 hours. Subsequently, an aqueous solution of an inositol derivative or an aqueous solution of myoinositol was added to the culture medium so that the final concentration of the inositol derivative or myoinositol became 0.001 mass%, or water (pure water) was added to the culture medium, and further culture was carried out for 24 hours. Thereafter, atmospheric dust (NIST1648a) in DMSO was added in an amount of 0.1mL per 100mL of the medium so that the final concentration of atmospheric dust in the medium became 500. mu.g/mL, and further incubation was performed for 6 hours. Next, the medium containing atmospheric dust was removed, replaced with new medium, and 0.1mL of atmospheric dust (NIST1648a) in DMSO solution was added per 100mL of medium to make the atmosphereThe final concentration of the dust in the medium was 500. mu.g/mL, and the culture was further continued for 18 hours. Thereafter, the cells were stained with the above-mentioned infiltration analysis kit, and the fluorescence intensity at the excitation wavelength of 480 nm/the absorption wavelength of 570nm was measured with a microplate reader i-Control (manufactured by テカン). The case where no atmospheric dust was added was taken as a control.

The results are shown in Table 5. In table 5, cell infiltration in the atmospheric dust-added group is shown as a relative amount when the fluorescence intensity of the control to which no atmospheric dust was added is set to 1. In the inositol derivative-added group, the cell infiltration of cancer cells was suppressed as compared with the water-added group and the myoinositol-added group. From these results, it was confirmed that the inositol derivative inhibited cell infiltration of cancer cells accelerated by atmospheric dust.

[ Table 5]

[ Experimental example 6]

(inhibitory Effect (2) on ROS production)

The ROS production inhibitory effect on human normal epidermal cells (NHEK, manufactured by クラボウ Co., Ltd.) due to an inositol derivative and tocopherol phosphate Na was measured under the following conditions. TPNa (registered trademark) was used as sodium dl- α -tocopherol phosphate (manufactured by Showa Denko K.K.) as tocopherol phosphate Na described below.

NHEK cells were cultured at 10000/cm²The inoculation density of (2) was inoculated into HuMedia KG2 medium manufactured by クラボウ Co., Ltd at 37 ℃ with 5% CO₂Was cultured under the conditions of (1) for 24 hours. Subsequently, tocopherol phosphate Na alone (final concentration in the medium is 10 μ M), inositol derivative alone (final concentration in the medium is 0.001 mass%), or a combination of tocopherol phosphate Na (final concentration in the medium is 10 μ M) and inositol derivative (final concentration in the medium is 0.001 mass%) was added to the medium. Tocopherol phosphate Na and inositol derivative were added to the medium so as to be dissolved in 0.05% (V/V) aqueous ethanol solution to the above-mentioned final concentration. In addition, 0.05% of the total weight of the powder is prepared(V/V) ethanol aqueous solution to the culture medium. Thereafter, 5% CO at 37 ℃₂Was cultured under the conditions of (1) for 24 hours. Thereafter, atmospheric dust (NIST1648a) in DMSO was added in an amount of 0.1mL per 100mL of the medium so that the final concentration of atmospheric dust in the medium became 500. mu.g/mL, and further incubation was performed for 48 hours. Thereafter, the amount of ROS produced was measured using a ROS assay kit (OZ BIOSCIENCES Co., Ltd.). After the cells obtained by removing the medium were washed with phosphate buffer solution (PBS, manufactured by Wako pure chemical industries, Ltd.), 100. mu.L of dichlorofluorescein diacetate attached to the ROS assay kit was added to each group of cells, and the cells were left to stand at 37 ℃ under light shielding for 30 minutes. After the cells were washed again with PBS, 100. mu.L of PBS was added, and the fluorescence intensity at 485nm of excitation wavelength and 535nm of absorption wavelength was measured with a microplate reader i-Control (manufactured by テカン). The case where no atmospheric dust was added was taken as a control.

The results are shown in Table 6. Table 6 shows the amount of ROS produced in the atmospheric dust-added group as a relative amount when the fluorescence intensity of the control to which no atmospheric dust was added was set to 1. In any of the inositol derivative-alone-added group, the tocopherol phosphate Na-alone-added group, and the inositol derivative + tocopherol phosphate Na-added group, the amount of ROS production was suppressed as compared with the 0.05% ethanol-added group. In the inositol derivative + tocopherol phosphate Na-added group, the generation of ROS was further suppressed compared to the inositol derivative-added group alone and the tocopherol phosphate Na-added group alone. From these results, it was confirmed that the inositol derivative exhibits a synergistic inhibitory effect on the generation of ROS induced by atmospheric dust when used together with tocopherol phosphate Na.

[ Table 6]

[ Experimental example 7]

(inhibitory Effect on cancer cell growth (2))

The cell growth inhibitory effect of a cell line derived from Lewis lung carcinoma (LLC, JCRB cell bank) produced from an inositol derivative and tocopherol phosphate Na was measured under the following conditions. TPNa (registered trademark) was used as sodium dl- α -tocopherol phosphate (manufactured by Showa Denko K.K.) as tocopherol phosphate Na described below.

LLC cells are treated at 50000 cells/cm²Was inoculated into a mixture of HamF10 medium and L15 medium (both Sigma-Aldrich) at a ratio of 3: 7 (volume ratio) in a medium at 37 ℃ with 5% CO₂Was cultured under the conditions of (1) for 24 hours. Subsequently, tocopherol phosphate Na alone (final concentration in the medium is 10 μ M), inositol derivative alone (final concentration in the medium is 0.001 mass%), or a combination of tocopherol phosphate Na (final concentration in the medium is 10 μ M) and inositol derivative (final concentration in the medium is 0.001 mass%) was added to the medium. Tocopherol phosphate Na and inositol derivative were added to the medium so as to be dissolved in 0.05% (V/V) aqueous ethanol solution to the above-mentioned final concentration. In addition, a product obtained by adding 0.05% (V/V) ethanol aqueous solution to the medium was also prepared. Thereafter, 5% CO at 37 ℃₂Was cultured under the conditions of (1) for 24 hours. Thereafter, atmospheric dust (NIST1648a) in DMSO was added in an amount of 0.1mL per 100mL of the medium so that the final concentration of atmospheric dust in the medium became 500. mu.g/mL, and further incubation was performed for 48 hours. Thereafter, the medium was replaced with a medium containing 10% (V/V) of WST-8 manufactured by ナカライ, and after further culturing for 3 hours, the absorbance at a wavelength of 450nm was measured by a microplate reader i-Control (manufactured by テカン). The case where no atmospheric dust was added was taken as a control.

The results are shown in Table 7. Table 7 shows the cell growth amounts in the atmospheric dust-added group as relative amounts when the absorbance of a control to which no atmospheric dust was added was set to 1. In any of the inositol derivative-only-added group, the tocopherol phosphate Na-only-added group, and the inositol derivative + tocopherol phosphate Na-added group, the cell growth amount was suppressed as compared with the 0.05% ethanol-added group. In the inositol derivative + tocopherol phosphate Na-added group, the cell growth amount was further suppressed as compared with the inositol derivative-added group and the tocopherol phosphate Na-added group. From these results, it was confirmed that the inositol derivative synergistically inhibits the cell proliferation of cancer cells accelerated by atmospheric dust by being used together with tocopherol phosphate Na.

[ Table 7]

[ prescription example ]

The following shows a formulation example of a composition for inhibiting cancer cell growth. Examples of the inositol derivative in the following formulation examples include the inositol derivative produced in [ production example of inositol derivative ]. Further, as the tocopherol phosphate Na, TPNa (registered trademark) which is sodium dl- α -tocopherol phosphate (manufactured by Showa Denko K.K.) can be exemplified.

(prescription example 1)

The formulation of the spray (spray) is shown in table 8.

[ Table 8]

(prescription example 2)

Table 9 shows an example of the formulation of the dispersion (aerosol).

[ Table 9]

(prescription example 3)

Table 10 shows formulation examples of the spreading agent (skin spray).

[ Table 10]

(prescription example 4)

The prescription of nasal drops is shown in table 11.

[ Table 11]

Industrial applicability

The present invention provides a cancer cell growth inhibitor capable of inhibiting the growth of cancer cells that are accelerated by atmospheric pollutants, and a cancer cell growth inhibitor composition containing the cancer cell growth inhibitor.