KR102287236B1 - Anti-cancer adjuvant comprising catalpol derivative compound - Google Patents

Abstract

To an anticancer adjuvant containing a catalpol derivative compound, the compound according to an aspect exhibits an excellent endotrophin inhibitory effect, and thus resistance to platinum-based anticancer drugs without side effects in patients who have developed resistance to platinum-based anticancer drugs including cisplatin It can be applied to effectively treat cancers such as breast cancer and cervical cancer.

Description

Anti-cancer adjuvant comprising catalpol derivative compound

It relates to an anticancer adjuvant comprising a catalpol derivative compound.

Currently, surgery, radiation therapy, chemotherapy, and the like are used for the treatment of cancer. Chemotherapy is a method of treating cancer using anticancer drugs. Today, about 60 types of various anticancer drugs are being used. Cisplatin (cis-diamminedichloroplatinum; CDDP), known as the most effective cancer treatment, is a heavy metal compound containing platinum, with two chlorine atoms and two ammonia molecules centered on a platinum atom in a cis-form. It binds to two adjacent guanines on a DNA strand to form an interstrand crosslink, thereby inhibiting DNA synthesis. That is, it is known that it is attached to the DNA double helix structure present in the nucleus of cancer cells, inhibits DNA replication, suppresses cancer cell growth and proliferation, and exhibits anticancer effects by removing cancer cells. Cisplatin is a very effective anticancer drug against various types of cancer, such as breast cancer, cervical cancer, head and neck cancer, lung cancer, esophageal cancer, testicular cancer, ovarian cancer, bladder cancer, prostate cancer, and stomach cancer. is increasing

The mountain-tailed grass (Veronica rotunda var. subintegra) is a perennial herb belonging to the family Scrophulariaceae, and is distributed in Korea, Japan, Manchuria, Sakhalin Island, and the Ussuri River. Although it has been reported that lichen is effective in the treatment of allergies, inflammation, asthma, etc. (Korean Patent Application Laid-Open No. 10-2016-0148936), studies on its role as an anticancer adjuvant for suppressing resistance to anticancer drugs are insignificant.

One aspect is to provide a composition for adjuvant anticancer treatment comprising a compound represented by Formula 1, a solvate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

Another aspect is to provide a health functional food composition for adjuvant anticancer treatment comprising a compound represented by Formula 1, a solvate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

One aspect provides an acid kkoripul (Veronica rotunda var. Subintegra) chemotherapy secondary composition comprising an extract or a fraction as an active ingredient.

The wild horsetail ( Veronica rotunda var. subintegra ) extract may be an extract extracted with a solvent from a wild herb outcrop, a part thereof, or a material derived therefrom. The part may be a root, a stem, a leaf, a fruit, a flower, or a petal of a wild horsetail.

The botanical name is Veronica rotunda var. As a subintegra , it is a perennial herb belonging to the family Scrophulariaceae. The height of the wild-tailed grass is about 40-80 cm, and the stem is upright and may have curved hairs. The leaves of serrata are opposite and may be narrow ovate or long oval. . There may be some hairs on the veins on the underside of the leaves. The flowers of the hornwort may have bluish purple flowers at the tips of branches and stems in raceme, each with 4 sepals and petals, and may have sharp ends, may have 2 stamens, and the anthers may be dark purple. The fruit of the wild-tailed plant may be in the shape of a wide egg-turned capsule. Wildtail grass may be distributed in Korea, Japan, Manchuria, Sakhalin Island, and the Ussuri River.

The solvent may be water, an alcohol, for example a C1-C6 alcohol, for example a C1-C4 alcohol, or a mixture thereof. The C1-C6 alcohol may be methanol, ethanol, propanol, isopropanol, 1,3-propanediol, butanol, pentanol, nucleic acidol, and the like. The solvent may be, for example, a mixture of water and alcohol, that is, an aqueous alcohol solution. The alcohol concentration of the aqueous alcohol solution is 1 to 99.5 (v/v)%, for example, 10 to 99.5 (v/v)%, 1 to 90 (v/v)%, 5 to 80 (v/v)%, 10 to 70 (v/v)%, 15 to 60 (v/v)%, 20 to 55 (v/v)%, or 25 to 50 (v/v)%, more specifically 30 to 50 (v/v)%. The aqueous alcohol solution may be an aqueous ethanol solution.

The extraction is 3 to 20 (volume/weight) times, for example, 3 to 17 (volume/weight) times, 3 to 15 times the extraction solvent with respect to the L. (volume/weight) times, 5 to 15 (volume/weight) times, or 4 to 20 times may include adding. For example, it may include adding 3 to 20 L of the extraction solvent with respect to 1 kg of the wild hornwort outpost, a part thereof, or a material derived therefrom.

The extraction may be performed by hot water extraction, cold extraction, reflux extraction, reflux cooling extraction, ultrasonic extraction, or a combination thereof, and there is no limitation as long as the extraction method is obvious to those skilled in the art, and specifically, cold extraction or reflux extraction. For example, the process of performing reflux extraction after cold extraction is repeatedly extracted 1 to 5 times, and the filtered extract is concentrated under reduced pressure at 20 to 100° C., for example, room temperature with a reduced pressure concentrator with water, lower alcohol or these It is possible to obtain an extract of Pseudomonas oleracea soluble in a mixed solvent of The extract includes an extract, a diluted or concentrated solution of the extract, a dried product obtained by drying the extract, or a crude product or a purified product thereof.

The extraction is performed at 4°C to 100°C, for example, 4°C to 90°C, 4°C to 85°C, 4°C to 80°C, 10°C to 90°C, 10°C to 85°C, 10°C to 80°C, 15 °C to 90 °C, 15 °C to 85 °C, 15 °C to 80 °C, 20 °C to 90 °C, 20 °C to 85 °C, 20 °C to 80 °C, 10 °C to 40 °C, 10 °C to 35 °C, 10 °C to It may be carried out at 30 °C, 50 °C to 90 °C, 50 °C to 80 °C, 60 °C to 85 °C, for example, it may be at room temperature, and may be 65 °C to 85 °C. The extraction time may vary depending on conditions such as the extraction solvent or extraction temperature, for example, 1 hour to 10 days, for example, 1 hour to 10 days, 1 hour to 5 days, 1 hour to 3 days, 1 hour to 2 days. , 1 hour to 1 day, 1 hour to 12 hours, 5 hours to 10 days, 5 hours to 5 days, 5 hours to 3 days, 5 hours to 2 days, 5 hours to 1 day, 5 hours to 12 hours, 10 hours to 10 days, 10 hours to 5 days, 10 hours to 3 days, 10 hours to 2 days, 10 hours to 1 day, or 10 hours to 12 hours. The extraction may include mixing the wild liana outpost, a part thereof, or a material derived therefrom in the solvent and allowing it to stand for a certain period of time. The standing may include moderate agitation. The extraction may be performed one or more times in order to obtain a larger amount of the active ingredient, and specifically 1 to 5 times, more specifically, extracts combined by continuous extraction twice may be used.

The extraction may be performed by separating plant residues and extracts by known methods such as filtration. The extraction may also include removing the solvent from the obtained extract by a known method such as concentration under reduced pressure. The extraction may also include preparing a dry extract by drying the obtained extract, such as freeze-drying.

The extract is 0.001 wt% to 80 wt%, for example, 0.01 wt% to 60 wt%, 0.01 wt% to 40 wt%, 0.01 wt% to 30 wt%, 0.01 wt% to 20 wt% with respect to the total weight of the composition %, 0.01% to 10%, 0.01% to 5%, 0.05% to 60%, 0.05% to 40%, 0.05% to 30%, 0.05% to 20% by weight, 0.05% to 10% by weight, 0.05% to 5% by weight, 0.1% to 60% by weight, 0.1% to 40% by weight, 0.1% to 30% by weight, 0.1% to 20% by weight, 0.1% by weight % to 10% by weight, or 0.1% to 5% by weight.

In the above composition, the term "fraction" refers to a substance, that is, a fractionated substance, in which the extract is divided into a part thereof. After suspending the L. oleracea extract in water according to an aspect, by fractionation using a polar solvent such as water, methanol, ethanol, or a non-polar solvent such as nucleic acid or ethyl acetate, the polar solvent fraction and the non-polar solvent fraction are respectively separated can be obtained. Specifically, after suspending the L. oleracea extract in water, 1 to 100 times the volume of the suspension, for example, 1 to 5 times the volume of water, C1-C4 alcohol, chloroform, ethyl acetate, nucleic acid, butanol, or a mixed solvent thereof It can be obtained by extracting and separating the polar or non-polar solvent soluble layer over 1 to 10 times, for example, 2 to 5 times by adding a polar or non-polar solvent such as . In addition, a conventional fractionation process may be additionally performed (Harborne J.B. Phytochemical methods: A guide to modern techniques of plant analysis, 3rd Ed. p6-7, 1998). More specifically, after suspending the extract of P. oleracea in water, water, methanol, or a mixed solvent thereof [MeOH-H 2 O (73:27, 65:35, 0:100, 0:100, 73:27, 73: 27)] can be used as a solvent to obtain each solvent-soluble fraction of serrata after continuous extraction.

Separation of the fraction may be accomplished by a known method such as filtration. The fractionation may also include removing the solvent from the fraction obtained by a known method such as concentration under reduced pressure. The fractionation may also include concentrating and/or drying the fraction obtained. The concentration may be concentration under reduced pressure. The drying may include reduced pressure drying, boiling drying, spray drying, room temperature drying or freeze drying.

The extract or fraction according to an aspect may include the following Chemical Formulas 1 to 4.

The term "anticancer therapy adjuvant composition", "anti-cancer therapy adjuvant", or "anti-cancer adjuvant" refers to an adjuvant used to inhibit or improve anticancer drug resistance or side effects of anticancer drugs. can mean The term "suppression" may refer to any action that reduces the side effects or resistance of an anticancer agent by administration of an anticancer adjuvant, and the term, "improvement" refers to a decrease in anticancer drug side effects or resistance or anticancer drug side effects or resistance by administration of an anticancer adjuvant. It can mean any action in which symptoms caused by cancer are improved or changed to a beneficial effect due to a decrease in The term “treat” refers to an individual suffering from or at risk of developing a disease, to ameliorate the condition (eg, one or more symptoms) of the individual, delay the progression of the disease, delay the onset of symptoms, or means any form of treatment or prophylaxis that provides an effect, including slowing the progression of symptoms, and the like. Accordingly, the term “treatment” also includes prophylactic treatment of a subject that prevents the occurrence of symptoms. The terms “treatment” and “prevention” are not intended to mean cure or complete elimination of symptoms. They refer to any form of treatment that provides an effect to a patient suffering from a disease, including amelioration of the patient's condition (eg, one or more symptoms), delaying the progression of the disease, and the like.

In one embodiment, the composition may be administered in combination with the anticancer agent simultaneously, separately, or sequentially to enhance the anticancer effect of the anticancer agent, for example, the cancer cell growth inhibitory effect or the cancer metastasis inhibitory effect. The composition may mean that the effect generated when the composition is administered in combination with the anticancer agent is greater than the effect generated when the composition is administered alone. For example, the composition does not exhibit a significant anticancer effect when administered alone, but may enhance the anticancer effect of the anticancer agent when administered in combination with an anticancer agent. The term “enhancement of the anticancer effect of an anticancer agent” may refer to increasing the anticancer effect persistence during repeated administration of the anticancer agent by enhancing the anticancer agent sensitivity.

In one embodiment, the composition may be for enhancing the anti-cancer effect of an anti-cancer agent against anti-cancer drug-resistant cancer. The term "anticancer drug-resistant cancer" refers to a state in which the prevention, improvement or treatment of cancer is not effectively performed in anticancer treatment by administration of an anticancer agent. Specifically, the sensitivity of cancer cells to an anticancer agent is lowered, so that the cell induced by the anticancer agent In addition to all types of cancer for which apoptosis and cytotoxicity mechanisms are not effectively achieved, cancers that showed anticancer effects according to the administration of anticancer drugs in the early stage, but whose anticancer effects were gradually reduced or disappeared due to repeated administration of anticancer drugs It may be all inclusive.

In one embodiment, the composition may inhibit the endotrophin (ETP) activity involved in the EMT (Epithelial Mesenchymal Transition) pathway associated with cancer metastasis or anticancer drug resistance of cancer cells, specifically, metastasis of breast cancer. .

In one embodiment, the anticancer agent may be a platinum-based anticancer agent. The term "anticancer agent" refers to known agents used in conventional cancer treatment that act on various metabolic pathways of cancer cells and exhibit cytotoxicity or cytostatic effects on cancer cells. It may include all of metabolic antagonists, plant alkaloids, topoisomerase inhibitors, alkylating agents, anticancer antibiotics, hormones, and other drugs. In one embodiment, the platinum-based anticancer agent cisplatin (Cisplatin), carboplatin (carboplatin), nedaplatin (nedaplatin), oxaliplatin (oxaliplatin), ormaplatin, geniplatin, enroplatin, lovaplatin , may be at least one selected from the group consisting of spiroplatin, tetraplatin, ormiplatin and iproplatin.

In one embodiment, the anticancer agent is breast cancer, head or neck cancer, uterine cancer, cervical cancer, ovarian cancer, lung cancer, bladder cancer, esophageal cancer, mesothelioma, neuroblastoma, testicular cancer, leukemia, stomach cancer, liver cancer, colorectal cancer, skin cancer, brain cancer, It may be for any one cancer selected from the group consisting of laryngeal cancer, prostate cancer, thyroid cancer, kidney cancer, blood cancer, and rectal cancer.

The composition for adjuvant anticancer treatment according to an aspect may be a pharmaceutical composition. In this case, the pharmaceutical composition may further include a pharmaceutically acceptable carrier. The type of the carrier is not particularly limited, and any carrier commonly used in the art may be used. Non-limiting examples of the carrier include saline, sterile water, Ringer's solution, buffered saline, albumin injection solution, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, maltodextrin, glycerol, ethanol, and the like. can These may be used alone or in mixture of two or more. In addition, the pharmaceutical composition may be used by adding other pharmaceutically acceptable additives such as excipients, diluents, antioxidants, buffers or bacteriostatic agents, if necessary, and fillers, extenders, wetting agents, disintegrants, dispersants, surfactants, binders Alternatively, it may be used by additionally adding a lubricant or the like.

The pharmaceutical composition may be formulated and used in various formulations suitable for oral or parenteral administration.

Non-limiting examples of the formulation for oral administration include troches, lozenges, tablets, aqueous suspensions, oily suspensions, prepared powders, granules, pills, powders, emulsions, hard capsules, soft capsules , syrup or elixirs. In order to formulate the composition for oral administration, a binder such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose or gelatin; excipients such as dicalcium phosphate; disintegrating agents such as corn starch or sweet potato starch; Lubricating oils such as magnesium stearate, calcium stearate, sodium stearyl fumarate or polyethylene glycol wax can be used, and sweeteners, fragrances, syrups, etc. can also be used. can Furthermore, in the case of capsules, in addition to the above-mentioned substances, a liquid carrier such as fatty oil may be additionally used.

Non-limiting examples of the parenteral formulation include intravenous injection, intramuscular injection, intraperitoneal injection, subcutaneous injection, etc., suppository, respiratory inhalation powder, spray aerosol, ointment, powder for application, oil, cream and the like. In order to formulate the composition for parenteral administration, sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, external preparations, etc. may be used, and the non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, olive oil. Vegetable oils such as ethyl oleate, injectable esters such as ethyl oleate, and the like can be used. Specifically, when the composition is formulated as an injection solution, the composition is mixed in water with a stabilizer or buffer to prepare a solution or suspension, and it may be formulated for unit administration in an ampoule or vial. In addition, when the composition is formulated as an aerosol, a propellant or the like may be blended with an additive so that the water-dispersed concentrate or wet powder is dispersed. In addition, when formulating the composition into an ointment or cream, animal oil, vegetable oil, wax, paraffin, starch, tracanth, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc, zinc oxide, etc. as a carrier It can be formulated using

The therapeutically effective amount and effective dosage of the pharmaceutical composition may vary depending on the formulation method, administration method, administration time and/or administration route of the pharmaceutical composition, and the type of response to be achieved by administration of the composition and Several factors, including the degree, type of subject to be administered, age, weight, general health status, symptoms or severity of disease, sex, diet, excretion, and components of drugs or other compositions used simultaneously or at the same time in the subject and similar factors well known in the pharmaceutical field, and those of ordinary skill in the art can easily determine and prescribe an effective dosage for the desired treatment. The term "therapeutically effective amount" refers to, in a patient with cancer, side effects or anticancer drug resistance, improvement of a condition (eg, one or more symptoms), delay of disease progression, etc. means an amount sufficient to produce the desired effect, including

Another aspect provides a health functional food composition for adjuvant anticancer treatment comprising an extract or a fraction thereof (Veronica rotunda var. subintegra) as an active ingredient.

In the health functional food composition, licoriceae extract, extract, fraction, and composition for adjuvant anticancer treatment are the same as those described above.

The anticancer adjuvant according to one aspect may be added to the health functional food composition for the purpose of suppressing or improving side effects due to the administration of anticancer drugs or for the purpose of suppressing or alleviating anticancer drug resistance.

The health functional food composition corresponds to all forms of health functional food, nutritional supplements, nutritional supplements, pharmaceutical food, health food, nutraceutical, designer food, food additives, and the like.

When the anticancer adjuvant according to one aspect is used as a food additive, the health food composition may be added as it is or used with other foods or food ingredients, and may be appropriately used according to a conventional method. The mixing amount of the active ingredient may be suitably determined according to the stage of cancer progression, the type of cancer, and the type of anticancer agent administered in combination.

There is no particular limitation on the type of the food. Examples of foods to which the above substances can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, various soups, beverages, tea, drinks, There are alcoholic beverages, vitamin complexes, and the like, and may include all health foods in a conventional sense.

In addition to the above, the food composition of the present invention includes various nutrients, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols , a carbonation agent used in carbonated beverages, and the like. In addition, the food composition of the present invention may contain the flesh for the production of natural fruit juice, fruit juice beverage, and vegetable beverage.

Another aspect provides a composition for adjuvant anticancer treatment comprising a compound represented by the following Chemical Formula 1, a solvate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 1]

wherein R1 and R2 are each independently a hydroxyl group, a thiol group, or a C1-C6 alkoxy group; and A is CH2 or HC=CH, wherein n is an integer of 0 or 1.

In the composition for adjuvant anticancer treatment, the composition for adjuvant anticancer treatment is as described above.

In one embodiment, R1 and R2 may be each independently a hydroxy group or a methoxy group. Specifically, the compound represented by Formula 1 may be any one selected from the group consisting of Formulas 2 to 5 below.

[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

Verminoside (compound 1) represented by Formula 2 is a compound having a molecular formula of C24H28O13 and a molecular weight of 524.5 g/mol, a catalpol derivative, and a natural isolated from Veronica rotunda var. subintegra. It may be a compound, but is not limited thereto, and may be isolated from plants of the genus C. serrata or other genus.

Picroside II (compound 2) represented by Formula 3 is a compound having a molecular formula of C23H28O13 and a molecular weight of 512.5 g/mol, a catalpol derivative, and isolated from Veronica rotunda var. subintegra. It may be a natural compound that has been used, but is not limited thereto, and may be isolated from a related species of the genus Caulia or other genus plants.

Isovanillyl catalpol (compound 3) represented by Formula 4 is a compound having a molecular formula = C23H28O13 and a molecular weight of 512.5 g/mol, and is a catalpol derivative, from Veronica rotunda var. subintegra. It may be an isolated natural compound, but is not limited thereto, and it may be isolated from a plant of the genus Caulia or other genus plants.

6-O-veratroyl catalpol (6-O-veratroyl catalpol, compound 4) represented by Formula 5 is a compound having a molecular formula of C24H30O13 and a molecular weight of 526.5 g/mol, and is a catalpol derivative, and It may be a natural compound isolated from (Veronica rotunda var. subintegra), but is not limited thereto, and may be isolated from a plant of the genus or a related species of the genus Cactus.

The "solvate" may refer to a compound of the present invention or a salt thereof that contains a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents therefor may be solvents that are volatile, non-toxic, and/or suitable for administration to humans.

The "stereoisomer" refers to a molecular formula and a method for linking members, but a different spatial arrangement between atoms. The stereoisomer may be an enantiomer, or a diastereomer, of the compound.

The "enantiomers" are compounds that have the same molecular formula as a specific compound, have the same bonding order of atoms, but have different three-dimensional steric arrangement of atoms in the space, in a relationship that does not overlap a specific compound and its mirror image. It may mean a compound with

The composition may be a racemic mixture in which the two enantiomers are mixed in 1:1, i.e. equal ratio.

The "diastereomers" may refer to all stereoisomers that are not enantiomers. When a cyclic compound or alkene having a cis or trans configuration without a stereocenter is in a relationship of diastereomers and when there are two or more stereocenters, it refers to a relationship between a compound having a partially opposite configuration. can

The above "pharmaceutically acceptable" means that the benefit/risk ratio is reasonable without undue toxicity, irritation, allergic reaction, or other problems or complications, so that it is suitable for use in contact with a subject, e.g., human tissue, and within the scope of sound medical judgment. It may mean a phosphorus compound or composition.

The “salt” may be an acid addition salt formed with a pharmaceutically acceptable free acid. The free acid may be an inorganic acid or an organic acid, the inorganic acid may be hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, perchloric acid, phosphoric acid, etc., and the organic acid is citric acid, acetic acid, lactic acid, maleic acid, fumaric acid, gluconic acid, methanesulfonate phonic acid, glycolic acid, succinic acid, tartaric acid, galacturonic acid, embonic acid, glutamic acid, aspartic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, 4-toluenesulfonic acid, salicylic acid, citric acid, benzoic acid, or malonic acid. In addition, the salt may include alkali metal salts (sodium salt, potassium salt, etc.) and alkaline earth metal salt (calcium salt, magnesium salt, etc.). For example, the acid addition salt is acetate, aspartate, benzate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, Gluceptate, gluconate, glucuronate, hexafluorophosphate, hebenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, malate ate, malonate, mesylate, methylsulfate, naphthylate, 2-naphsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate Late, stearate, succinate, tartrate, tosylate, trifluoroacetate, aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, zinc salts, and the like.

In one embodiment, the composition may be administered in combination with the anticancer agent simultaneously, separately, or sequentially to enhance the anticancer effect of the anticancer agent, for example, the cancer cell growth inhibitory effect or the cancer metastasis inhibitory effect. The composition may mean that the effect generated when administered in combination with an anticancer agent is greater than the effect generated when the composition is administered alone. For example, when administered alone, the composition does not exhibit a significant anticancer effect, but when administered in combination with an anticancer agent, it may enhance the anticancer effect of the anticancer agent. The term "enhancement of the anticancer effect of an anticancer agent" is the same as described above.

In one embodiment, the composition may be for enhancing the anti-cancer effect of an anti-cancer agent against anti-cancer drug-resistant cancer. The term “anticancer drug-resistant cancer” is the same as described above.

In one embodiment, the composition may inhibit the endotrophin (ETP) activity involved in the EMT (Epithelial Mesenchymal Transition) pathway associated with cancer metastasis or anticancer drug resistance of cancer cells, specifically, metastasis of breast cancer. .

In one embodiment, the anticancer agent may be a platinum-based anticancer agent. The term "anticancer agent" is as described above. In one embodiment, the platinum-based anticancer agent is cisplatin (Cisplatin), carboplatin (carboplatin), nedaplatin (nedaplatin), oxaliplatin (oxaliplatin), ormaplatin, geniplatin, enroplatin, lovaplatin , may be at least one selected from the group consisting of spiroplatin, tetraplatin, ormiplatin and iproplatin.

In one embodiment, the anticancer agent is breast cancer, head or neck cancer, uterine cancer, cervical cancer, ovarian cancer, lung cancer, bladder cancer, esophageal cancer, mesothelioma, neuroblastoma, testicular cancer, leukemia, stomach cancer, liver cancer, colorectal cancer, skin cancer, brain cancer, It may be for any one cancer selected from the group consisting of laryngeal cancer, prostate cancer, thyroid cancer, kidney cancer, blood cancer, and rectal cancer.

Another aspect provides a health functional food composition for adjuvant anticancer treatment comprising a compound represented by the following Chemical Formula 1, a solvate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 1]

wherein, R ₁ and R ₂ are each independently a hydroxyl group, a thiol group, or a C ₁ -C ₆ alkoxy group; and A is CH ₂ or HC=CH, wherein n is an integer of 0 or 1.

In the health functional food composition, solvates, stereoisomers, pharmaceutically acceptable salts, and compositions for adjuvant anticancer treatment are as described above.

The anticancer adjuvant according to one aspect may be added to the health functional food composition for the purpose of suppressing or improving side effects due to the administration of anticancer drugs or for the purpose of suppressing or alleviating anticancer drug resistance.

The health functional food composition corresponds to all forms of health functional food, nutritional supplements, nutritional supplements, pharmaceutical food, health food, nutraceutical, designer food, food additives, and the like.

When the anticancer adjuvant according to one aspect is used as a food additive, the health food composition may be added as it is or used with other foods or food ingredients, and may be appropriately used according to a conventional method. The mixing amount of the active ingredient may be suitably determined according to the stage of cancer progression, the type of cancer, and the type of anticancer agent administered in combination.

There is no particular limitation on the type of the food. Examples of foods to which the above substances can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, various soups, beverages, tea, drinks, There are alcoholic beverages, vitamin complexes, and the like, and may include all health foods in a conventional sense.

In addition to the above, the food composition of the present invention includes various nutrients, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols , a carbonation agent used in carbonated beverages, and the like. In addition, the food composition of the present invention may contain the flesh for the production of natural fruit juice, fruit juice beverage, and vegetable beverage.

Another aspect provides a method of treating cancer comprising administering to a subject a therapeutically effective amount of the composition. The term "subject" refers to a mammal that is the subject of treatment, observation or experiment, and may specifically be a human. The "therapeutically effective amount" is as described above. The dosage of the composition may vary depending on various factors, and the route of administration also depends on various factors such as the patient's age, administration period, weight, disease severity, patient's consciousness, type of anticancer agent, type of concomitant drug, etc. Various routes of administration, oral or parenteral, can be used. In addition, each may be administered separately simultaneously or sequentially, or separately over time.

Since the compound according to one aspect exhibits an excellent endotropin inhibitory effect, in patients who have developed resistance to platinum-based anticancer drugs, including cisplatin, resistance to platinum-based anticancer drugs can be overcome without side effects, and cancers such as breast cancer and cervical cancer It can be used for effective treatment.

1 is a result of UPLC-QTof-MS analysis of an extract of P. oleracea.
Figure 2 is a graph measuring the endotrophin activity inhibitory effect of the santail grass fraction and compounds 1 to 4;
3 is a graph measuring the tumor growth inhibitory effect according to the combined administration of cisplatin with a fraction or compounds 1 to 4 in breast cancer cell lines.
Figure 4 is a graph measuring the inhibitory effect of the anticancer drug resistance mechanism of the sancorystinum fraction in breast cancer cell lines.
5 is a photograph and graph measuring the effect of inhibiting tumor growth and metastasis to lung cancer according to the co-administration of cisplatin and a lichen fraction in an MMTV-PyMT breast cancer animal model.
Figure 6 is a photograph and graph measuring the tumor growth inhibitory effect and the metastasis inhibitory effect to lung cancer according to the combined administration of cisplatin with a fraction or compounds 1 to 4 in the MMTV-PyMT breast cancer animal model.
Figure 7 is a photograph and graph measuring the tumor growth inhibitory effect and the metastasis inhibitory effect to lung cancer according to the combined administration of cisplatin fraction and cisplatin in a 4T1 breast cancer metastasis animal model.
8 is a photograph and graph measuring the effect of inhibiting tumor growth and metastasis to lung cancer according to the combined administration of Compounds 1 to 4 and cisplatin in a 4T1 breast cancer metastasis animal model.
Figure 9 is a graph measuring the anticancer drug resistance mechanism inhibitory effect of the hornwort fraction, Compound 1, and Compound 4 in the 4T1 breast cancer metastasis animal model.

Hereinafter, the present invention will be described in more detail through examples. However, these examples are for illustrative purposes of the present invention, and the scope of the present invention is not limited to these examples.

Example 1. Preparation of extract and fraction

(1.1) Manufacture of wild hornwort extract and identification of indicator components

After drying and cutting 1.0 kg of Pseudolysimachion rotundum var. subintegrum = Veronica rotunda var. subintegra (GAP cultivation, 244 Bisan-ri, Somyun, Eumseong-gun, Chungcheongbuk-do), 10 L of 40% ethanol was added to the Pseudolysimachion rotundum var. Cold extraction for hours. Thereafter, reflux extraction was performed while stirring at 78° C. for 12 hours, followed by vacuum filtration to recover the supernatant. The above process was repeated twice to recover the supernatant, and the extract was concentrated under reduced pressure with a reduced pressure concentrator (EYELA, N-2100, JAPAN) to obtain 202 g of a 40% ethanol extract of oleracea.

High performance liquid chromatography (UPLC, Waters Corporation, Milford, Ma. 1 is a result of UPLC-QTof-MS analysis of an extract of P. oleracea.

As a result, as shown in Figure 1, verproside at 3.78 min, longifolioside A at 4.90 min, catalpolside at 5.44 min, verminoside at 5.93 min, picroside II at 6.05 min, picroside C at 6.17 min, isovanillylcatalpol at 6.47 min, 7.83 min. It was confirmed that specioside, minecoside at 8.85 minutes, and 6-O-veratroyl catalpol at 9.23 minutes were separated, and the components corresponding to the peaks confirmed by chromatography are shown in [Table 2] below.

Name UV (nm) Detected ion
( m/z ) [M-H] ^- Molecular
formula Purity Verproside 263, 296 497.1302 C ₂₂ H ₂₆ O ₁₃ > 98.0% Longifolioside A 263, 296 533.1075 C ₂₂ H ₂₇ ClO ₁₃ > 98.0% Catalpolside 258 481.1327 C ₂₂ H ₂₆ O ₁₂ >95.0% Verminoside 328 523.1436 C ₂₄ H ₂₈ O ₁₃ > 85.0% Picroside II 263, 294 511.1436 C ₂₃ H ₂₈ O ₁₃ > 97.0% Picroside C 263, 296 533.1055 C ₂₂ H ₂₇ ClO ₁₃ ~ 90% Isovanillylcatalpol 263, 296 511.1440 C ₂₃ H ₂₈ O ₁₃ > 97.0% Specioside 331 507.1504 C ₂₄ H ₂₈ O ₁₂ > 98.0% Minecoside 326 537.1620 C ₂₅ H ₃₀ O ₁₃ > 98.0% 6- O -Veratroyl catalpol 263 525.1636 C ₂₄ H ₃₀ O ₁₃ > 95% 3-Methoxy-catalposide 260 513.1608 C ₂₃ H ₃₀ O ₁₃ > 91.0%

(1.2) Preparation of hornwort fraction and isolation of compounds 1 to 4

33.8 g of the 40% ethanol extract of P. oleracea prepared by the method (1.1) was suspended in 2 L in distilled water, and the same amount of butanol was added to the suspension and mixed, followed by fractionation of a butanol-soluble fraction and a water-soluble fraction. The above-described butanol fraction was filtered and concentrated under reduced pressure to remove the solvent to obtain 13.2 g of a purified butanol fraction. Column fractions 1-6 (fractions 1 to 6) were prepared in order to confirm the indicator components contained in the purified butanol fraction and purified product, and column chromatography was performed to separate the single components.

The specific experimental process is as follows. Preparative HPLC (K-Prep LAB-300G, YMC, Kyoto, Japan) was equipped with a reversed-phase column (YMC-ODS-AQ-HG, 10 um, 520 g), and 4 g of the extract obtained in (1.1) was Fractions 1-6 were obtained by eluting with reverse phase column chromatography [MeOH-H ₂ O (73:27, 65:35, 0:100, 0:100, 73:27, 73: 27)]. Specifically, as shown in Table 3 below, 27% methanol was used as a solvent for isocratic elution, and column fractions 1-6 (fraction 1) detected at a wavelength of UV 254 nm at an elution rate of 150 mL/min. to 6) were repeatedly performed.

Fraction 1 is 29.8 g, Fraction 2 is 3.5 g, Fraction 3 is 6.7 g, Fraction 4 is 6.0 g, Fraction 5 is 4.6 g, Fraction 6 is 20.4 g. Of these, fractions 4+5 (10.6 g) were subjected to repeated column chromatography under preparative HPLC (SynergyPolar-RP4 μm, 21.2 Х 2 50 mm, Phenomenex, Torrance, CA, USA, 22% ACN in H2O) conditions to compound the compound. 1 (2.0 g), compound 2 (4.5 g), and compound 3 (5.0 g) were obtained. Fraction 6 (20.4 g) was subjected to preparative HPLC [40% MeOH (0-60 min); column, Merck (5 Х 30 cm); resin: Zeoprep C18 (75 μm, 250 g); flow rate 30 mL/min] to obtain compound 4 (670.0 mg) by repeated column chromatography. Among them, the purified butanol fraction (13.2 g) was named as the "Factus A. oleracea fraction (#13)" and was used in the following experimental examples.

(1.3) NMR analysis of compounds 1 to 4

Compounds 1 to 4 were subjected to NMR to analyze their structures. 1D and 2D NMR spectra were obtained from JEOL ECZ500R (1H NMR at 500 MHz, 13C NMR at 125 MHz, Tokyo, JP), Varian UNITY 400 NMR (1H NMR at 400 MHz, 13C NMR at 100) using DMSO-d _{6 as a solvent.} MHz, PaloAlto, USA), Bruker AVANCE III HD 700 (1H NMR at 700 MHz, 13C NMR at 175 MHz) spectrometer.

Compound 1: verminoside (6-O- (3,4-dihydroxycinnamoyl) catalpol)

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 5.08 (d, J = 9.2 Hz, H-1), 6.42 (d, J = 6.0 Hz, H-3), 4.93 (d, J = 5.2) , 8.8 Hz, H-4), 2.47 (br s, H-5), 4.99 (d, J = 6.8 Hz, H-6), 3.64 (br s, H-7), 2.43 (br d, J = 7.6 Hz, H-9), 3.71 (br d, J = 12.8 Hz, H-10), 3.91 (br d, J = 13.2 Hz, H-10), 7.09 (d, J = 2.0 Hz, H-2) '), 6.78 (d, J = 8.4 Hz, H-5'), 7.04 (dd, J = 2.4, 8.4 Hz, H-6'), 7.54 (d, J = 15.6 Hz, H-7'), 6.34 (d, J = 15.6 Hz, H-8'), 4.61 (d, J = 7.6 Hz, H-Glc-1''), 3.04 (m, H-Glc-2''), 3.19 (m, H-Glc-3''), 3.04 (m, H-Glc-4''), 3.15 (m, H-Glc-5''), 3.42 (dd, J = 7.6, 12.0 Hz, H-Glc- 6'') 3.71 (br d, J = 12.8 Hz. H-Glc-6'').

¹³ C-NMR (100 MHz, DMSO-d ₆ ) δ: 92.9 (C-1), 141.1 (C-3), 101.7 (C-4), 35.0 (C-5), 79.1 (C-6), 58.1 (C-7), 65.7 (C-8), 41.7 (C-9), 58.4 (C-10), 125.3 (C-1'), 115.7 (C-2'), 146.0 (C-3') ), 148.6 (C-4'), 113.2 (C-5'), 121.5 (C-6'), 145.5 (C-7'), 115.0 (C-8'), 166.5 (C-9'), 97.8 (C-Glc-1''), 73.4 (C-Glc-2''), 76.4 (C-Glc-3''), 70.2 (C-Glc-4''), 77.4 (C-Glc- 5''), 61.3 (C-Glc-6'').

Compound 2: Picroside II (Picroside II; 6-O-(4-hydroxy-3-methoxybenzoyl)catalpol)

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 5.11 (d, J = 9.3 Hz, H-1), 6.42 (d, J = 5.8 Hz, H-3), 4.97 (dd, J = 5.8) , 4.4 Hz, H-4), 2.58 (dd, J = 9.3, 7.6 Hz, H-5), 5.06 (d, J = 7.6 Hz, H-6), 3.67 (br s, H-7), 2.47 (d, J = 9.3 Hz, H-9), 3.72 (m, H-10), 3.93 (d, J = 13.2 Hz, H-10), 7.46 (s, H-2'), 6.85 (d, J = 7.6 Hz, H-5'), 7.52 (d, J = 7.6 Hz, H-6'), 4.63 (d, J = 7.6 Hz, H-Glc-1''), 3.07 (dd, J = 8.0, 7.6 Hz, H-Glc-2''), 3.18 (m, H-Glc-3''), 3.03 (m, H-Glc-4''), 3.14 (m, H-Glc-5') '), 3.44 (dd, J = 13.2, 6.4 Hz, H-Glc-6''), 3.72 (d, J = 13.2 Hz, H-Glc-6''), 3.82 (s, 3-OCH ₃ ) .

¹³ C-NMR (100 MHz, DMSO-d ₆ ) δ: 93.0 (C-1), 141.1 (C-3), 101.9 (C-4), 35.2 (C-5), 79.4 (C-6), 58.2 (C-7), 65.9 (C-8), 41.8 (C-9), 58.5 (C-10), 119.9 (C-1'), 112.7 (C-2'), 147.5 (C-3') ), 152.1 (C-4'), 115.3 (C-5'), 123.9 (C-6'), 165.6 (C-7'), 97.9 (C-Glc-1''), 73.5 (C-Glc -2''), 76.5 (C-Glc-3''), 70.3 (C-Glc-4''), 77.5 (C-Glc-5''), 61.4 (C-Glc-6''), 55.7 (3-OCH ₃ )

Compound 3: isovanillyl catalpol (6-O- (3-hydroxy-4-methoxybenzoyl) catalpol)

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 5.10 (d, J = 9.2 Hz, H-1), 6.42 (dd, J = 6.0 Hz, 1.6, H-3), 4.95 (dd, J) = 6.0, 4.0 Hz, H-4), 2.50 (m, H-5), 5.05 (dd, J = 8.4, 1.2 Hz, H-6), 3.72 (d, J = 8.4 Hz, H-7), 2.47 (d, J = 9.2 Hz, H-9), 3.72 (d, J = 13.2 Hz, H-10), 3.92 (d, J = 13.2 Hz, H-10), 7.41 (d, J = 2.0 Hz) , H-2'), 7.04 (d, J = 8.4 Hz, H-5'), 7.48 (dd, J = 8.4 Hz, 2.0, H-6'), 4.63 (d, J = 7.6 Hz, H- Glc-1''), 3.05 (d, J = 7.6 Hz, H-Glc-2''), 3.17 (m, H-Glc-3''), 3.02 (d, J = 8.0 Hz, H-Glc -4''), 3.14 (m, H-Glc-5''), 3.43 (dd, J = 13.2 Hz, 6.8, H-Glc-6''), 3.72 (dd, J = 13.2 Hz, 6.0, H-Glc-6''), 3.84 (s, 4-OCH ₃ ).

¹³ C-NMR (100 MHz, DMSO-d ₆ ) δ: 92.9 (C-1), 141.1 (C-3), 101.7 (C-4), 35.2 (C-5), 79.7 (C-6), 58.2 (C-7), 65.8 (C-8), 41.8 (C-9), 58.4 (C-10), 121.4 (C-1'), 115.8 (C-2'), 146.3 (C-3') ), 152.2 (C-4'), 111.5 (C-5'), 121.9 (C-6'), 165.5 (C-7'), 97.8 (C-Glc-1''), 73.4 (C-Glc -2''), 76.4 (C-Glc-3''), 70.3 (C-Glc-4''), 77.4 (C-Glc-5''), 61.4 (C-Glc-6''), 55.7 (4-OCH ₃ ).

Compound 4: 6-O-veratroyl catalpol (6-O-veratroyl catalpol; 6-O- (3,4-dimethoxybenzoyl) catalpol)

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 5.11 (d, J = 9.02 Hz, H-1), 6.43 (dd, J = 2.0, 6.0 Hz, H-3), 4.97 (d, H -4), 2.59 (m, H-5), 5.09 (d, J = 8.8 Hz, H-6) 3.71 (br s, H-7), 2.47 (m, H-9), 3.71 (d, H -10), 3.92 (d, J = 13.2 Hz, H-10) 7.47 (d, J = 2.4 Hz, H-2') 7.10 (d, J = 8.8 Hz, H-5'), 7.45 (dd, J = 2.0, 8.4 Hz, H-6'), 4.62 (d, J = 7.6 Hz, H-Glc-1''), 3.06 (d, J = 8.0, 7.6 Hz, H-Glc-2'') , 3.17 (m, H-Glc-3''), 3.02 (m, H-Glc-4''), 3.14 (m, H-Glc-5''), 3.43 (dd, J = 13.2, 6.4 Hz) , H-Glc-6''), 3.72 (d, J = 13.2 Hz, H-Glc-6'').

₁₃ C-NMR (100 MHz, DMSO-d ₆ ) δ: 92.9 (C-1), 141.0 (C-3), 101.7 (C-4), 35.1 (C-5), 79.8 (C-6), 58.1 (C-7), 65.8 (C-8), 41.7 (C-9), 58.3 (C-10), 121.3 (C-1'), 111.7 (C-2'), 148.0 (C-3') ), 153.2 (C-4'), 111.1 (C-5'), 123.5 (C-6'), 165.4 (C-7'), 55.7 (C-8'), 55.5 (C-9'), 97.8 (C-Glc-1''), 73.4 (C-Glc-2''), 76.4 (C-Glc-3''), 70.2 (C-Glc-4''), 77.4 (C-Glc- 5''), 61.3 (C-Glc-6'').

Example 2. Endotrophin (ETP) inhibitory effect natural compound candidate screening

In order to find a new compound capable of inhibiting the anticancer drug resistance mechanism of cancer cells, candidate substances that can act as endotropin inhibitors were screened from a library of natural compounds related to anti-inflammatory.

Specifically, the following experiment was performed to confirm the antagonism effect with endotrophin of the A. serrata fraction (#13) and compounds 1 to 4 (#104 to #107). Since compounds that inhibit HRE transcriptional activity mediated by endotropin induced in hypoxic conditions can inhibit anticancer drug resistance, inhibition of endotrophin activity through HRE transcriptional activity inhibition was confirmed. In order to measure the HRE transcriptional activity inhibition level of the HRE fraction and compounds 1 to 4, the HRE (Hypoxia) present in the human VEGFA gene in a pGL3-basic vector (Promega) using luciferase as a reporter. Responsive Element, 5'-ACGTG-3') was cloned to a multi-cloning site so that it was repeated six times, and a pGL3-HRE-luciferase vector was prepared and used.

HeLA cells, a human cervical cancer cell line, were seeded in a 48-well cell culture vessel, and one day later, 100 ng of pGL3-HRE-luciferase vector and 10 ng A Renilla control vector was co-transfected. After culturing for 24 hours, the medium was changed, further cultured for 4 hours, and then treated with the hornwort fraction or compounds 1 to 4, and cultured for 24 hours under hypoxic conditions (oxygen 1%, nitrogen 94%, carbon dioxide 5%). did. Obtain a lysate using NETN buffer and measure the activity of luciferase induced under hypoxic conditions using a dual-luciferase assay system (Promega) By doing so, the endotrophin inhibitory activity of the lichen fraction or compounds 1 to 4 was measured, and the results are shown in FIG. 2 .

As a result, as shown in FIG. 2 , it was confirmed that the HRE transcriptional activation inhibitory effect mediated by endotropin induced under hypoxic conditions was excellent in the fractions and compounds 1 to 4 of the serrata. This means that the wild hornwort fraction and compounds 1 to 4 are excellent in the effect of inhibiting endotropin related to anticancer drug resistance, and thus can be usefully used as a pharmaceutical composition for inhibiting endotropin activity or inhibiting anticancer drug resistance.

Experimental Example 1. Confirmation of in vitro anticancer effect according to the co-administration of Coleoptera fraction or Compounds 1 to 4 and cisplatin

In order to confirm the tumor growth inhibitory effect following the co-administration of the lichen fraction (#13) or compounds 1 to 4 (#104 to #107) and cisplatin, MTT analysis was performed.

Specifically, MDA-MB-231, which is a breast cancer cell line, was treated with the lichen fraction (#13) or compounds 1 to 4 (#104 to #107) and cisplatin (cisplatin, 0.5 mM). A group treated with cisplatin alone, a group treated with ciplatin and a positive control, rosiglitazone (10 microgram/ml), cisplatin and a serrata fraction (#13, 10 microgram/ml) or compounds 1 to 4 (# 104 to #107, 10 microgram/ml) corresponds to the group treated with the group, the lichen fraction (#13), or the group treated only with compounds 1 to 4 (#104 to #107). 3 is a graph measuring the tumor growth inhibitory effect according to the combined administration of cisplatin with a fraction or compounds 1 to 4 in breast cancer cell lines.

As a result, as shown in FIG. 3 , compared with the single treatment of the anticancer agent cisplatin, the anticancer effect was 70% in the case of combined treatment with the lichen fraction (#13) or compounds 1 to 4 (#104 to #107) and cisplatin. It was confirmed that the improvement was abnormal. In addition, it was confirmed that the anticancer effect did not appear when the hornwort fraction (#13) or compounds 1 to 4 (#104 to #107) were treated alone. This means that the lichen fraction (#13) or compounds 1 to 4 (#104 to #107) can be administered in combination with cisplatin and used as an anticancer adjuvant to enhance the anticancer effect.

Experimental Example 2. Confirmation of the inhibitory effect on the anticancer drug resistance mechanism in vitro

In order to confirm the inhibitory effect on the anticancer drug resistance mechanism of the wild hornwort fraction (#13), the relative expression level of the EMT marker protein was measured by performing western blot.

Specifically, MDA-MB-231, a breast cancer cell line, was pretreated with 0.5 μM of cisplatin, and then treated with 10 μM of a positive control, rosiglitazone, or the hornwort fraction (#13), followed by incubation for 24 hours, followed by western incubation. A blot was performed to measure the relative protein amount of the EMT (Epithelial Mesenchymal Transition) marker protein. Figure 4 is a graph measuring the inhibitory effect of the anticancer drug resistance mechanism of the sancolifolia fraction in breast cancer cell lines.

As a result, as shown in FIG. 4 , it was confirmed that the expression level of the EMT marker protein was remarkably reduced when cisplatin was administered in combination with the lichenoid fraction compared to when cisplatin was administered alone. This means that the lichen fraction can be used as an anticancer adjuvant to enhance the anticancer effect of anticancer drugs by inhibiting the EMT pathway related to anticancer drug resistance or cancer metastasis, specifically, metastasis of breast cancer.

Experimental Example 3. Confirmation of the anticancer effect in vivo according to the co-administration of Coleoptera fraction or Compounds 1 to 4 and cisplatin

In order to determine whether the lichen fraction or Compounds 1 to 4 enhances anticancer drug sensitivity, MMTV-PyMT breast cancer mouse model and 4T1 breast cancer metastasis model experiments were performed to inhibit tumor growth and metastasis to lung cancer according to co-administration with cisplatin The inhibitory effect was measured.

Specifically, in the MMTV-PyMT model, which is a mouse model of breast cancer, each of cisplatin was administered alone, the lichen fraction was administered alone, cisplatin and the hornwort fraction were administered in combination, or cisplatin and compounds 1 to 4 were administered in combination to promote tumor growth and lung growth and lung cancer. Metastasis was monitored by fluorescence imaging (in vivo Xtreme, Bruker) equipment. As the breast cancer mouse model, MMTV-PYMT X MMTV-FP635 double transgenic mice were used for accurate quantification. 5 is a photograph and graph measuring the effect of inhibiting tumor growth and metastasis to lung cancer according to the co-administration of cisplatin and a lichen fraction in an MMTV-PyMT breast cancer animal model. Figure 6 is a photograph and graph measuring the tumor growth inhibitory effect and the metastasis inhibitory effect to lung cancer according to the combined administration of cisplatin with a fraction or compounds 1 to 4 in the MMTV-PyMT breast cancer animal model.

As a result, as shown in FIG. 5 , the tumor growth inhibitory effect and the metastasis inhibitory effect to lung cancer did not appear when the lichen fraction was administered alone. It was confirmed that the tumor growth inhibitory effect and the metastasis inhibitory effect to lung cancer were significantly increased as compared to . In addition, in the case of repeated administration of cisplatin alone, there was reactivity to the anticancer agent up to the 12th week, but from the 13th week, resistance to the anticancer agent developed and the reactivity to the anticancer agent decreased. On the other hand, it was confirmed that the anticancer effect was continuously maintained even after 13 weeks when cisplatin was administered in combination with the lichen fraction.

In addition, as shown in FIG. 6 , when cisplatin and the lichen fraction (#13), compound 1 (#104), compound 2 (#105), or compound 4 (#107) were co-administered, cisplatin was administered alone It was confirmed that tumor growth and lung metastasis were reduced compared to the first case, and it was confirmed that compound 1 (#104) had a remarkably excellent anticancer effect, in particular, metastasis inhibitory effect.

^{In addition, 4T1 (5x10 4} cells/100ul PBS), a mouse-derived breast cancer cell line, was intravenously injected into the tail of Balb/c mice to produce a breast cancer metastasis model, and cisplatin was administered to each of the models alone, and the lichen fraction was administered alone, cisplatin and the lichen fraction were administered in combination, or cisplatin and compounds 1 to 4 were administered in combination to monitor tumor growth and lung metastasis using a fluorescence imaging (in vivo Xtreme, Bruker) device. Cisplatin (1.5 mg/kg) was administered intraperitoneally (IP), and the lichen fraction and compounds 1 to 4 (20 mg/kg) were mixed with the powdered diet and ingested. Figure 7 is a photograph and graph measuring the tumor growth inhibitory effect and the metastasis inhibitory effect to lung cancer according to the combined administration of cisplatin fraction and cisplatin in a 4T1 breast cancer metastasis animal model. 8 is a photograph and graph measuring the effect of inhibiting tumor growth and metastasis to lung cancer according to the combined administration of Compounds 1 to 4 and cisplatin in a 4T1 breast cancer metastasis animal model.

As a result, as shown in FIG. 7 , the tumor growth inhibitory effect was not observed when the lichen fraction was administered alone. It was confirmed that there was a significant increase. In addition, it was confirmed that when cisplatin was co-administered with the lichenaceae fraction, the metastasis to lung cancer was reduced by more than 2 times compared to when cisplatin was administered alone, and the effect of inhibiting breast cancer metastasis was remarkably excellent.

In addition, as shown in FIG. 8 , when cisplatin and Compound 1, 2, or 4 were administered in combination, it was confirmed that the tumor growth inhibitory effect and the metastasis inhibitory effect to lung cancer were excellent compared to the case where cisplatin was administered alone. , It was confirmed that compound 1 (#104) and compound 4 (#107) improved the metastasis inhibitory effect of breast cancer more than 3 times. However, in the case of Compound 3, it was confirmed that the tumor growth inhibitory effect and the metastasis inhibitory effect to lung cancer did not appear according to the combined administration.

It can be used as an anti-cancer adjuvant for enhancing the anti-cancer effect of an anti-cancer agent when the hornwort fraction, compound 1, compound 2, or compound 4 is administered in combination with an anti-cancer agent, and can be used as an anti-cancer adjuvant for inhibiting anti-cancer drug resistance and inhibiting metastasis of breast cancer means there is

Experimental Example 4. Confirmation of the inhibitory effect on the anticancer drug resistance mechanism in vivo (in vivo) of the hornwort fraction, compound 1, compound 4

In order to confirm the inhibitory effect on the anticancer drug resistance mechanism of the hornwort fraction (#13), compound 1 (#104), and compound 4 (#107), quantitative-real time PCR and western blot were performed to determine the relative levels of EMT marker genes and proteins. The expression level was measured.

Specifically, the expression level of each gene was measured by separating breast cancer tissue from the breast cancer metastasis model mouse, extracting RNA, synthesizing cDNA and performing quantitative-real time PCR, and Western blotting was performed to determine the expression level of each protein. was measured. Figure 9 is a graph measuring the anticancer drug resistance mechanism inhibitory effect of the hornwort fraction, Compound 1, and Compound 4 in the 4T1 breast cancer metastasis animal model.

As a result, as shown in FIG. 9 , the expression of genes (Chd2, Snail, Vim), etc. known to cause EMT was reduced by the hornwort fraction, compound 1, and compound 4, and Chd1, the expression of which is decreased by EMT It was confirmed that the expression of was increased. In addition, it was confirmed through western blot that the same appears at the protein level.

This means that the lichen fraction, compound 1, and compound 4 can be used as anticancer adjuvants to enhance the anticancer effect of anticancer drugs by inhibiting the EMT pathway associated with anticancer drug resistance.

Claims (13)

As a composition for enhancing sensitivity to anticancer drugs administered in combination with anticancer drugs,
A compound represented by any one selected from the group consisting of the following formulas 2 to 5, a solvate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient,
The anticancer agent is cisplatin, and the composition is to enhance the anticancer agent sensitivity in any one cancer selected from the group consisting of breast cancer, cervical cancer, and lung cancer, anticancer agent sensitivity enhancement composition:
[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

. delete delete The composition of claim 1, wherein the composition is administered in combination with an anticancer agent simultaneously, separately, or sequentially. The composition of claim 1, wherein the composition inhibits anticancer drug resistance. The composition of claim 1, wherein the composition enhances the cancer cell growth inhibitory effect or the cancer metastasis inhibitory effect of the anticancer agent. The composition of claim 1, wherein the composition is for enhancing the anticancer effect of an anticancer agent against anticancer drug-resistant cancer or metastatic cancer. The method according to claim 1, wherein the composition is epithelial-mesenchymal transition (epithelial-mesenchymal transition) composition that inhibits the pathway. delete delete delete The composition of claim 1, wherein the composition is a pharmaceutical composition. The composition of claim 1, wherein the composition is a health functional food composition.

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