Composition comprising rivoceranib and cannabigerol and / or cannabidiol for treating cancer, and use thereof

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating cancer, the composition comprising cannabigerol and rivocernib as active ingredients, and a use thereof. The composition according to the present invention is based on the finding that remarkably excellent cancer inhibitory efficacy is exhibited when rivoceranib and cannabigerol and / or cannabidiol are used in combination, and thus a cancer treatment effect can be enhanced using the composition.

Description

Cancer treatment composition comprising cannabigerol and / or cannabidiol and rivoceranib and the use thereof

[0001] The present invention relates to a pharmaceutical composition for the prevention or treatment of cancer comprising cannabizerol and rivoceranib as active ingredients, and to the use thereof.

[0002] Cannabis sativa L. is an annual plant of the genus Cannabis of the family Cannabaceae that has been widely cultivated in tropical and temperate regions, centered in Central Asia, for 12,000 years. It includes wild hemp and refers collectively to Cannabis chemovars and their variants, including varieties var. indica and var. kafiristanica, as well as Cannabis sativa subspecies sativa, Cannabis sativa subspecies indica, Cannabis sativa subspecies ruderalis, and their genetically crossbred, self-crossbred, or hybrid plants containing various types of cannabinoid compounds known as medicinal and pharmaceutical components.

[0003] In traditional medical texts from China and Korea, hemp seeds with the hulls removed, known as *Majain* or *Hwamain*, have been used for constipation, diabetes, pain disorders, menstrual irregularities, skin diseases, and dysentery. Additionally, hemp leaves (*Macha*, *Mayeop*) have been used as an anthelmintic, hair protectant, for asthma, for pain relief, anesthesia, and as a diuretic. Furthermore, records indicate that hemp roots were used for treating difficult childbirth and resolving blood stasis, hemp bark for bruises and open wounds, hemp flowers for paralysis and itching, and hemp powder was used for difficult childbirth, constipation, gout, phlegm, and insomnia, with each part of the hemp plant being used according to the specific condition.

[0004] Meanwhile, according to an analysis by Statistics Korea, cancer is the leading cause of death in South Korea, accounting for 31.7% of deaths among men and 22.5% among women, with 31.7% of the total population dying from cancer. Treatment methods include surgery, radiation therapy, and chemotherapy; however, these methods are often accompanied by side effects or are applied restrictively depending on the stage of cancer progression. In particular, most anticancer drugs operate by halting the cell cycle of rapidly dividing cells and causing their death. Consequently, they attack normally dividing cells in addition to active ones, leading to side effects such as hair loss, loss of appetite, and weakened immunity due to a decrease in white blood cells. Therefore, there is a need for technology that can maximize therapeutic efficacy while using low concentrations of anticancer drugs.

[0005] Against this background, the present invention was completed by confirming significantly enhanced anticancer efficacy resulting from the combined treatment of cannabizerol and rivoceranib.

[0006] One aspect provides a pharmaceutical composition for the prevention or treatment of cancer comprising 1) cannabigerol (CBG), derivatives thereof, stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, or combinations thereof; and 2) rivoseranib as an active ingredient.

[0007] Another aspect provides a pharmaceutical composition for enhancing the anticancer effect of rivoceranib, comprising cannabigerol (CBG), derivatives thereof, stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, or combinations thereof as an active ingredient.

[0008] Another aspect provides a pharmaceutical composition for the prevention or treatment of cancer comprising 1) cannabidiol (CBD), derivatives thereof, stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, or combinations thereof; and 2) rivoseranib as an active ingredient.

[0009] Another aspect provides a pharmaceutical composition for enhancing the anticancer effect of rivoceranib, comprising as an active ingredient cannabidiol (CBD), derivatives thereof, stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, or combinations thereof.

[0010] One aspect provides a pharmaceutical composition for the prevention or treatment of cancer comprising 1) cannabigerol (CBG), derivatives thereof, stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, or combinations thereof; and 2) rivoseranib as an active ingredient.

[0011] The term "Cannabigerol (CBG) (Cas no. 25654-31-3)" in this specification refers to a type of non-psychoactive cannabinoid found in cannabis plants, known to have efficacy in lowering anxiety, depression, and intraocular pressure associated with glaucoma. Cannabigerol can be represented by the following chemical formula 1.

[0012] [Chemical Formula 1]

[0013]

[0014] The term "isomer" in this specification means a compound or a salt thereof that has the same chemical formula or molecular formula but is optically or stereochemically different. Specifically, the isomer may comprise one or more selected from the group consisting of enantiomers, stereoisomers, mixtures of enantiomers, diastereomers, mixtures of diastereomers, racemics, and pharmaceutically acceptable salts thereof.

[0015] The term "pharmaceuticalally acceptable salt" in this specification refers to a form of salt that is pharmaceutically usable, among substances in which a cation and an anion are bonded by electrostatic attraction. Typically, it may be a metal salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, etc. For example, metal salts may be alkali metal salts (sodium salt, potassium salt, etc.), alkaline earth metal salts (calcium salt, magnesium salt, barium salt, etc.), aluminum salt, etc.; salts with organic bases may be salts with triethylamine, pyridine, picoline, 2,6-rutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N-dibenzylethylenediamine, etc.; and salts with inorganic acids may be salts with hydrochloric acid, hydrobromide, nitric acid, sulfuric acid, phosphoric acid, etc. Salts with organic acids may include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.; salts with basic amino acids may include arginine, lysine, ornithine, etc.; and salts with acidic amino acids may include aspartic acid, glutamic acid, etc. Particularly desirable salts include inorganic salts such as alkali metal salts (e.g., sodium salts, potassium salts, etc.) and alkaline earth metal salts (e.g., calcium salts, magnesium salts, barium salts, etc.) and organic salts such as ammonium salts when the compound has acidic functional groups therein, and salts with inorganic acids such as hydrochloric acid, hydrobromide, nitric acid, sulfuric acid, phosphoric acid, etc. and salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, etc. when the compound has basic functional groups therein.

[0016] The term "solvate" in this specification refers to a compound solvated in an organic or inorganic solvent. The solvate may be, for example, a hydrate.

[0017] In the above composition, the cannabizerol, its derivatives, its stereoisomers, its pharmaceutically acceptable salts, its hydrates, its solvates, or combinations thereof may be administered in combination with rivoceranib; specifically, the cannabizerol, its derivatives, its stereoisomers, its pharmaceutically acceptable salts, its hydrates, its solvates, or combinations thereof may be administered simultaneously with rivoceranib as one formulation, or simultaneously or sequentially with rivoceranib as a separate formulation.

[0018] The term "combined administration" in this specification may be achieved by administering individual components of a therapeutic regimen simultaneously, sequentially, or individually. It may be defined as obtaining a combined therapeutic effect by administering two or more drugs simultaneously or sequentially, or by administering them alternately at regular or indeterminate intervals, and although not limited thereto, the combined therapy may be defined as providing a synergistic effect in which the efficacy, measured, for example through the degree of response, response rate, time to disease progression, or survival period, is therapeutically superior to the efficacy that can be obtained by administering one or the rest of the components of the combined therapy at a normal dose.

[0019] The term "Rivoceranib (cas no. 811803-05-1)" in this specification is an oral targeted anticancer agent that selectively inhibits vascular endothelial growth factor receptor 2 (VEGFR-2), and is known to inhibit the formation of new blood vessels within tumors, thereby preventing cancer cells from receiving oxygen and nutrients and inhibiting tumor growth. The above-mentioned rivoceranib is also called apatinib and may be represented by the following chemical formula 2.

[0020] [Chemical Formula 2]

[0021]

[0022] In the present specification, the riboceranib may represent riboceranib selected from riboceranib, derivatives of riboceranib, stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and combinations thereof. Accordingly, the composition may comprise riboceranib, derivatives of riboceranib, stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and combinations thereof.

[0023] The above composition may comprise cannabigerol, its derivatives, its stereoisomers, its pharmaceutically acceptable salts, its hydrates, its solvates, or combinations thereof, and rivoceranib in a concentration ratio of 9:1 to 1:9. Specifically, the concentration ratio of cannabigerol and riboceranib (cannabigerol:rivoceranib) is 9:1 to 1:9, 9:1 to 1:7, 9:1 to 1:5, 9:1 to 1:4, 9:1 to 1:3, 9:1 to 1:2, 9:1 to 1:1, 7:1 to 1:9, 7:1 to 1:7, 7:1 to 1:5, 7:1 to 1:4, 7:1 to 1:3, 7:1 to 1:2, 7:1 to 1:1, 5:1 to 1:9, 5:1 to 1:7, 5:1 to 1:5, 5:1 to 1:4, 5:1 to 1:3, 5:1 to 1:2, 5:1 to 1:1, 4:1 to 1:9, 4:1 to 1:7, 4:1 to 1:5, 4:1 to 1:4, 4:1 to 1:3, 4:1 to 1:2, 4:1 to 1:1, 3:1 to 1:9, 3:1 to 1:7, 3:1 to 1:5, 3:1 to 1:4, 3:1 to 1:3, 3:1 to 1:2, 3:1 to 1:1, 2:1 to 1:9, 2:1 to 1:7, 2:1 to 1:5, 2:1 to 1:4, 2:1 to 1:3, 2:1 to 1:2, 2:1 to 1:1, 1:1 to 1:9, 1:1 to 1:7, 1:1 to 1:5, 1:1 to 1:4, It may be 1:1 to 1:3, or 1:1 to 1:2.

[0024] The above cannabizerol, its derivatives, its stereoisomers, its pharmaceutically acceptable salts, its hydrates, its solvates, or combinations thereof may be included in the composition at a concentration of 1 to 50 μM. Specifically, the cannabizerol, etc. comprises 1 to 50 μM, 1 to 45 μM, 1 to 40 μM, 1 to 35 μM, 1 to 30 μM, 1 to 25 μM, 1 to 20 μM, 1 to 15 μM, 5 to 50 μM, 5 to 45 μM, 5 to 40 μM, 5 to 35 μM, 5 to 30 μM, 5 to 25 μM, 5 to 20 μM, 5 to 15 μM, 10 to 50 μM, 10 to 45 μM, 10 to 40 μM, 10 to 35 μM, 10 to 30 μM, 10 to 25 μM, 10 to 20 μM, 10 to 15 μM, 15 to 50 μM, 15 It may be included at a concentration of 15 to 45 μM, 15 to 40 μM, 15 to 35 μM, 15 to 30 μM, 15 to 25 μM, 15 to 20 μM, 20 to 50 μM, 20 to 45 μM, 20 to 40 μM, 20 to 35 μM, 20 to 30 μM, or 20 to 25 μM.

[0025] In one embodiment, the cannabizerol, its derivatives, its stereoisomers, its pharmaceutically acceptable salts, its hydrates, its solvates, or combinations thereof may be included in the composition at a concentration that does not itself exhibit anticancer efficacy.

[0026] The above riboceranib may be included in the composition at a concentration of 1 to 150 μM. Specifically, the riboceranib is 1 to 150 μM, 1 to 130 μM, 1 to 100 μM, 1 to 80 μM, 1 to 60 μM, 1 to 50 μM, 1 to 45 μM, 1 to 40 μM, 1 to 35 μM, 1 to 30 μM, 1 to 25 μM, 1 to 20 μM, 1 to 15 μM, 5 to 150 μM, 5 to 130 μM, 5 to 100 μM, 5 to 80 μM, 5 to 60 μM, 5 to 50 μM, 5 to 45 μM, 5 to 40 μM, 5 to 35 μM, 5 to 30 μM, 5 to 25 μM, 5 to 20 μM, 5 to 15 μM, 10 to 150 μM, 10 to 130 μM, 10 to 100 μM, 10 to 80 μM, 10 to 60 μM, 10 to 50 μM, 10 to 45 μM, 10 to 40 μM, 10 to 35 μM, 10 to 30 μM, 10 to 25 μM, 10 to 20 μM, 10 to 15 μM, 15 to 150 μM, 15 to 130 μM, 15 to 100 μM, 15 to 80 μM, 15 to 60 μM, 15 to 50 μM, 15 to 45 μM, 15 to 40 μM, 15 to 35 μM, 15 to 30 μM, 15 to 25 It may be included at a concentration of μM, 15 to 20 μM, 20 to 150 μM, 20 to 130 μM, 20 to 100 μM, 20 to 80 μM, 20 to 60 μM, 20 to 50 μM, 20 to 45 μM, 20 to 40 μM, 20 to 35 μM, 20 to 30 μM, or 20 to 25 μM.

[0027] The above composition may further comprise cannabidiol (CBD), derivatives thereof, stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, or combinations thereof.

[0028] The term "Cannabidiol (CBD) (cas no. 13956-29-1)" in this specification refers to one of the main compounds constituting cannabis, a substance often compared to tetrahydrocannabinol (THC), which causes hallucinogenic symptoms. In Korea, it is designated as a narcotic and therefore not subject to extensive research; however, as it has virtually no psychotropic effects, it is used for medical purposes in other countries to alleviate symptoms such as pain, memory impairment, and anxiety. Additionally, it is known to suppress excessive sebum production, leading to active research regarding its use as an ingredient in cosmetics for acne-prone skin. The above-mentioned cannabidiol can be represented by the following chemical formula 3.

[0029] [Chemical Formula 3]

[0030]

[0031] The above cannabidiol, its derivatives, its stereoisomers, its pharmaceutically acceptable salts, its hydrates, its solvates, or combinations thereof may be included in the composition at a concentration of 1 to 50 μM. Specifically, the cannabidiol, etc. is 1 to 50 μM, 1 to 45 μM, 1 to 40 μM, 1 to 35 μM, 1 to 30 μM, 1 to 25 μM, 1 to 20 μM, 1 to 15 μM, 5 to 50 μM, 5 to 45 μM, 5 to 40 μM, 5 to 35 μM, 5 to 30 μM, 5 to 25 μM, 5 to 20 μM, 5 to 15 μM, 10 to 50 μM, 10 to 45 μM, 10 to 40 μM, 10 to 35 μM, 10 to 30 μM, 10 to 25 μM, 10 to 20 μM, 10 to 15 μM, 15 to 50 μM, 15 It may be included at a concentration of 15 to 45 μM, 15 to 40 μM, 15 to 35 μM, 15 to 30 μM, 15 to 25 μM, 15 to 20 μM, 20 to 50 μM, 20 to 45 μM, 20 to 40 μM, 20 to 35 μM, 20 to 30 μM, or 20 to 25 μM.

[0032] In one embodiment, the cannabidiol, its derivatives, its stereoisomers, its pharmaceutically acceptable salts, its hydrates, its solvates, or combinations thereof may be included in the composition at a concentration that does not itself exhibit anticancer efficacy.

[0033] The term "treatment" in this specification refers to any act of improving or beneficially altering the symptoms of cancer by administering the composition of the present invention.

[0034] The term "prevention" in this specification refers to any act in which the possibility of cancer or disease onset is suppressed or delayed by the administration of the composition of the present invention.

[0035] The term "cancer" in this specification refers to a tumor that has grown abnormally due to the autonomous overgrowth of body tissue, or a disease that forms a tumor.

[0036] In one embodiment, the cancer comprises one or more selected from the group consisting of gastric cancer, liver cancer, cholangiocarcinoma, lung cancer, pancreatic cancer, non-small cell lung cancer, colon cancer, bone cancer, skin cancer, head or neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, colorectal cancer, prostatic cancer, colon cancer, breast cancer, cervical cancer, fallopian tube carcinoma, endometrial carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine gland cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal cell carcinoma, renopelvic carcinoma, central nervous system (CNS) tumor, primary CNS lymphoma, spinal cord tumor, brainstem glioma, and pituitary adenoma. It may be. Specifically, the above cancer may include one or more selected from the group consisting of liver cancer, colorectal cancer, colon cancer, rectal cancer, lung cancer, prostate cancer, stomach cancer, breast cancer, and bile duct cancer.

[0037] The above composition may more effectively induce inhibition of cancer cell proliferation, apoptosis, and / or immune checkpoint inhibition by co-administering cannabigerol and / or cannabidiol with rivoceranib. Specifically, the above composition may induce or enhance inhibition of cancer cell proliferation, apoptosis, and / or immune checkpoint inhibition.

[0038] In one embodiment, the composition may increase the expression / activity level of an apoptosis-related factor, and specifically, the apoptosis-related factor may include one or more selected from the group consisting of CHOP (C / EBP-homologous protein), Cleaved PARP (Poly (ADP-ribose) polymerase), Cleaved caspase 9, Cleaved caspase 8, and Cleaved caspase 3.

[0039] In one embodiment, the composition may reduce the expression / activity level of a factor related to cell cycle regulation and cell proliferation promotion, and specifically, the factor related to cell cycle regulation and cell proliferation promotion may include FOXM1 (Forkhead box protein M1).

[0040] In one embodiment, the composition may reduce the expression / activity level of an immune checkpoint-related factor, and specifically, the immune-related factor may include PD-L1 (Programmed death-ligand 1).

[0041] The above pharmaceutical composition may include a pharmaceutically acceptable carrier. The term "pharmaceuticalally acceptable carrier" may refer to a carrier or diluent that does not irritate living organisms and does not impair the biological activity and properties of the injected compound. Here, "pharmaceuticalally acceptable" means that the target of application (prescription) does not possess toxicity beyond an acceptable level without inhibiting the activity of the active ingredient. Any type of carrier that is commonly used in the relevant technical field and is pharmaceutically acceptable may be used in the above pharmaceutical composition. Non-limiting examples of the above carriers include lactose, dextrose, maltodextrin, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, glycerol, ethanol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, saline solution, sterile water, Ringer's solution, buffered saline solution, albumin injection solution, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil. These may be used alone or in a mixture of two or more. The above pharmaceutical composition may be prepared into an oral or parenteral formulation according to the route of administration by conventional methods known in the art, including a pharmaceutically acceptable carrier in addition to the active ingredient. The above pharmaceutical compositions may each be formulated and used in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, external preparations, suppositories, or sterile injectable solutions according to conventional methods.

[0042] The above pharmaceutical composition may be formulated and used in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, external preparations, suppositories, or sterile injectable solutions, each according to conventional methods. When formulating the above pharmaceutical composition, it may be prepared by adding diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, or surfactants.

[0043] When the above pharmaceutical composition is prepared as an oral formulation, it may be prepared in the form of powder, granules, tablets, pills, coated tablets, capsules, liquids, gels, syrups, suspensions, wafers, etc., in accordance with methods known in the art together with a suitable carrier. Examples of pharmaceutically acceptable suitable carriers include sugars such as lactose, glucose, sucrose, dextrose, sorbitol, mannitol, and xylitol; starches such as corn starch, potato starch, and wheat starch; celluloses such as cellulose, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, and hydroxypropylmethylcellulose; polyvinylpyrrolidone; water; methylhydroxybenzoate; propylhydroxybenzoate; magnesium stearate; mineral oil; malt; gelatin; talc; polyols; vegetable oils, etc. In the case of formulation, the formulation may include diluents and / or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants as needed.

[0044] When the above pharmaceutical composition is prepared as a parenteral formulation, it may be formulated in the form of an injectable, transdermal, nasal inhalant, and suppository according to methods known in the art with a suitable carrier. When formulated as an injectable, suitable carriers may include sterile water, ethanol, polyols such as glycerol or propylene glycol, or mixtures thereof; preferably, Ringer's solution, PBS (phosphate buffered saline) containing triethanolamine, sterile water for injection, isotonic solutions such as 5% dextrose, etc. When formulated as a transdermal formulation, it may be formulated in the form of an ointment, cream, lotion, gel, topical solution, paste, liniment, aerosol, etc. In the case of nasal inhalers, they can be formulated in the form of an aerosol spray using suitable propellants such as dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, and carbon dioxide, and when formulated as suppositories, the base may be Witepsol, Tween 61, polyethylene glycols, cocoa starch, laurin starch, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearate, and sorbitan fatty acid esters.

[0045] The above pharmaceutical composition may be administered in a pharmaceutically effective amount, wherein the term "pharmaceutically effective amount" means an amount sufficient to treat or prevent a disease with a reasonable benefit / risk ratio applicable to medical treatment or prevention, and the effective dose level may be determined based on factors including the severity of the disease, drug activity, patient's age, weight, health, gender, patient's sensitivity to the drug, the time of administration of the composition of the present invention used, the route of administration and elimination rate, the duration of treatment, drugs combined or used concurrently with the composition of the present invention used, and other factors well known in the medical field. The above pharmaceutical composition may be administered alone or in combination with a component known to exhibit therapeutic effects for known diseases. It is important to administer an amount that obtains maximum effect with a minimum amount without side effects, taking all of the above factors into consideration.

[0046] The dosage of the above pharmaceutical composition may be determined by a person skilled in the art by taking into consideration the purpose of use, the degree of toxicity of the disease, the patient's age, weight, gender, medical history, or the type of substance used as an active ingredient. For example, the pharmaceutical composition of the present invention may be administered to an adult at a dose of about 0.1 ng to about 1,000 mg / kg, preferably 1 ng to about 100 mg / kg. The frequency of administration of the composition of the present invention is not particularly limited thereto, but may be administered once a day or divided into several doses. The above dosage or frequency of administration does not limit the scope of the present invention in any way.

[0047]

[0048] Another aspect provides a method for treating or preventing cancer comprising the step of administering to an individual a pharmaceutical composition for the prevention or treatment of cancer, comprising 1) cannabigerol, derivatives thereof, stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, or combinations thereof; and 2) rivoceranib as an active ingredient. The same parts as described above apply equally to the method.

[0049] As used in this specification, the term "individual" may include, without limitation, mammals including rats, livestock, and humans, birds, reptiles, farmed fish, etc., that have developed or are at risk of developing cancer.

[0050] The above pharmaceutical composition may be administered as a single or multiple doses in pharmaceutically effective amounts. In this case, the composition may be administered in the form of a liquid, powder, aerosol, injection, intravenous fluid (Ringer), capsule, pill, tablet, suppository, or patch. The route of administration of the above pharmaceutical composition for the prevention or treatment of lung cancer may be any general route as long as it can reach the target tissue.

[0051] The above pharmaceutical composition is not particularly limited thereto, but may be administered via routes such as intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, transdermal patch administration, oral administration, nasal administration, pulmonary administration, or rectal administration, depending on the purpose. However, when administered orally, it may be administered in an unformulated form, and since the active ingredient of the above pharmaceutical composition may be denatured or degraded by gastric acid, the oral composition may be administered into the mouth in a form coated with the active agent or formulated to protect it from degradation in the stomach, or in the form of an oral patch. Additionally, the above composition may be administered by any device capable of transporting the active substance to target cells.

[0052]

[0053] Another aspect provides for the use of a composition comprising 1) cannabigerol, derivatives thereof, stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, or combinations thereof; and 2) riboceranib as an active ingredient for the prevention or treatment of cancer. The same parts as described above apply equally to the said use.

[0054] The above composition may further comprise cannabidiol, derivatives thereof, stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, or combinations thereof.

[0055]

[0056] Another aspect provides a pharmaceutical composition for enhancing the anticancer effect of rivoceranib, comprising cannabigerol, derivatives thereof, stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, or combinations thereof as an active ingredient. The same parts described above apply equally to the said composition.

[0057] The terms “enhancement of anticancer effect” or “enhancement of cancer treatment effect” in this specification may mean improving and / or enhancing the cancer treatment effect of an anticancer drug by inducing or enhancing the activity of an anticancer drug such as riboceranib, reducing the resistance of cancer cells to the anticancer drug, suppressing or enhancing immune checkpoints of cancer cells, or increasing sensitivity to the anticancer drug.

[0058] The above composition may further comprise cannabidiol, derivatives thereof, stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, or combinations thereof.

[0059] The above composition may be a composition for co-administration with rivoceranib, and specifically, the above composition may be administered in combination with rivoceranib.

[0060]

[0061] Another aspect provides a method for enhancing the anticancer effect of rivoceranib, comprising the step of administering to an individual a pharmaceutical composition for enhancing the anticancer effect of rivoceranib, comprising as an active ingredient cannabigerol, a derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, or a combination thereof. The same parts as described above apply equally to the method.

[0062] The above composition may further comprise cannabidiol, derivatives thereof, stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, or combinations thereof.

[0063] The above method may further include a step of administering riboceranib to an individual, and specifically, the step of administering riboceranib may include being performed before, after, and / or simultaneously with the step of administering the pharmaceutical composition for enhancing anticancer effect.

[0064]

[0065] Another aspect provides a use for enhancing the anticancer effect of riboceranib with a composition comprising cannabigerol, its derivatives, its stereoisomers, its pharmaceutically acceptable salts, its hydrates, its solvates, or combinations thereof as an active ingredient. The same parts described above apply equally to the said use.

[0066] The above composition may further comprise cannabidiol, derivatives thereof, stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, or combinations thereof.

[0067]

[0068] Another aspect provides a pharmaceutical composition for the prevention or treatment of cancer, comprising 1) cannabidiol, derivatives thereof, stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, or combinations thereof; and 2) rivoceranib as an active ingredient. The same parts described above apply equally to the composition.

[0069] The above composition may comprise the cannabidiol, its derivatives, its stereoisomers, its pharmaceutically acceptable salts, its hydrates, its solvates, or combinations thereof, and rivoceranib in a concentration ratio of 9:1 to 1:9. Specifically, the concentration ratio of cannabidiol and riboceranib (cannabidiol:rivoceranib) is 9:1 to 1:9, 9:1 to 1:7, 9:1 to 1:5, 9:1 to 1:4, 9:1 to 1:3, 9:1 to 1:2, 9:1 to 1:1, 7:1 to 1:9, 7:1 to 1:7, 7:1 to 1:5, 7:1 to 1:4, 7:1 to 1:3, 7:1 to 1:2, 7:1 to 1:1, 5:1 to 1:9, 5:1 to 1:7, 5:1 to 1:5, 5:1 to 1:4, 5:1 to 1:3, 5:1 to 1:2, 5:1 to 1:1, 4:1 to 1:9, 4:1 to 1:7, 4:1 to 1:5, 4:1 to 1:4, 4:1 to 1:3, 4:1 to 1:2, 4:1 to 1:1, 3:1 to 1:9, 3:1 to 1:7, 3:1 to 1:5, 3:1 to 1:4, 3:1 to 1:3, 3:1 to 1:2, 3:1 to 1:1, 2:1 to 1:9, 2:1 to 1:7, 2:1 to 1:5, 2:1 to 1:4, 2:1 to 1:3, 2:1 to 1:2, 2:1 to 1:1, 1:1 to 1:9, 1:1 to 1:7, 1:1 to 1:5, 1:1 to 1:4, It may be 1:1 to 1:3, or 1:1 to 1:2.

[0070] The above cannabidiol, its derivatives, its stereoisomers, its pharmaceutically acceptable salts, its hydrates, its solvates, or combinations thereof may be included in the composition at a concentration of 1 to 50 μM. Specifically, the cannabidiol, etc. is 1 to 50 μM, 1 to 45 μM, 1 to 40 μM, 1 to 35 μM, 1 to 30 μM, 1 to 25 μM, 1 to 20 μM, 1 to 15 μM, 5 to 50 μM, 5 to 45 μM, 5 to 40 μM, 5 to 35 μM, 5 to 30 μM, 5 to 25 μM, 5 to 20 μM, 5 to 15 μM, 10 to 50 μM, 10 to 45 μM, 10 to 40 μM, 10 to 35 μM, 10 to 30 μM, 10 to 25 μM, 10 to 20 μM, 10 to 15 μM, 15 to 50 μM, 15 It may be included at a concentration of 15 to 45 μM, 15 to 40 μM, 15 to 35 μM, 15 to 30 μM, 15 to 25 μM, 15 to 20 μM, 20 to 50 μM, 20 to 45 μM, 20 to 40 μM, 20 to 35 μM, 20 to 30 μM, or 20 to 25 μM.

[0071] In one embodiment, the cannabidiol, its derivatives, its stereoisomers, its pharmaceutically acceptable salts, its hydrates, its solvates, or combinations thereof may be included in the composition at a concentration that does not itself exhibit anticancer efficacy.

[0072] The above riboceranib may be included in the composition at a concentration of 1 to 150 μM. Specifically, the riboceranib is 1 to 150 μM, 1 to 130 μM, 1 to 100 μM, 1 to 80 μM, 1 to 60 μM, 1 to 50 μM, 1 to 45 μM, 1 to 40 μM, 1 to 35 μM, 1 to 30 μM, 1 to 25 μM, 1 to 20 μM, 1 to 15 μM, 5 to 150 μM, 5 to 130 μM, 5 to 100 μM, 5 to 80 μM, 5 to 60 μM, 5 to 50 μM, 5 to 45 μM, 5 to 40 μM, 5 to 35 μM, 5 to 30 μM, 5 to 25 μM, 5 to 20 μM, 5 to 15 μM, 10 to 150 μM, 10 to 130 μM, 10 to 100 μM, 10 to 80 μM, 10 to 60 μM, 10 to 50 μM, 10 to 45 μM, 10 to 40 μM, 10 to 35 μM, 10 to 30 μM, 10 to 25 μM, 10 to 20 μM, 10 to 15 μM, 15 to 150 μM, 15 to 130 μM, 15 to 100 μM, 15 to 80 μM, 15 to 60 μM, 15 to 50 μM, 15 to 45 μM, 15 to 40 μM, 15 to 35 μM, 15 to 30 μM, 15 to 25 It may be included at a concentration of μM, 15 to 20 μM, 20 to 150 μM, 20 to 130 μM, 20 to 100 μM, 20 to 80 μM, 20 to 60 μM, 20 to 50 μM, 20 to 45 μM, 20 to 40 μM, 20 to 35 μM, 20 to 30 μM, or 20 to 25 μM.

[0073]

[0074] Another aspect provides a method for treating or preventing cancer comprising the step of administering to an individual a pharmaceutical composition for the prevention or treatment of cancer, comprising 1) cannabidiol, derivatives thereof, stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, or combinations thereof; and 2) rivoceranib as an active ingredient. The same parts as described above apply equally to the method.

[0075]

[0076] Another aspect is to provide a cancer prevention or treatment use of a composition comprising 1) cannabidiol, its derivatives, its stereoisomers, its pharmaceutically acceptable salts, its hydrates, its solvates, or combinations thereof; and 2) rivoceranib as an active ingredient. The same parts described above apply equally to the said use.

[0077]

[0078] Another aspect provides a pharmaceutical composition for enhancing the anticancer effect of rivoceranib, comprising as an active ingredient cannabidiol, a derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, or a combination thereof. The same as described above applies equally to the said composition.

[0079] The above composition may be a composition for co-administration with rivoceranib, and specifically, the above composition may be administered in combination with rivoceranib.

[0080]

[0081] Another aspect provides a method for enhancing the anticancer effect of rivoceranib, comprising the step of administering to an individual a pharmaceutical composition for enhancing the anticancer effect of rivoceranib, comprising as an active ingredient the cannabidiol, its derivatives, its stereoisomers, its pharmaceutically acceptable salts, its hydrates, its solvates, or combinations thereof. The same parts as described above apply equally to the method.

[0082] The above method may further include a step of administering riboceranib to an individual, and specifically, the step of administering riboceranib may include being performed before, after, and / or simultaneously with the step of administering the pharmaceutical composition for enhancing anticancer effect.

[0083]

[0084] Another aspect provides a use for enhancing the anticancer effect of rivoceranib with a composition comprising cannabidiol, its derivatives, its stereoisomers, its pharmaceutically acceptable salts, its hydrates, its solvates, or combinations thereof as an active ingredient. The same parts described above apply equally to the said use.

[0085] It has been confirmed that the composition of the present invention exhibits significantly superior cancer-inhibiting efficacy when combined with cannabigenol and / or cannabidiol and riboceranib, and thus the cancer treatment effect can be enhanced by using the said composition.

[0086] Figure 1 is a diagram confirming the cytotoxicity of liver cancer cell lines according to treatment with different concentrations of riboceranib.

[0087] Figure 2 is a diagram showing the results of screening cannabis-derived compounds that have excellent synergistic effects with riboceranib.

[0088] Figure 3 is a diagram showing the results of confirming the anticancer activity of cannabigerol and rivoceranib in combination treatment in various liver cancer cell lines.

[0089] Figure 4 is a diagram showing the results of evaluating the synergistic effect of the combined treatment of cannabizerol and riboceranib.

[0090] Figure 5 is a diagram showing the results of confirming the tumor growth inhibitory effect of combination treatment with cannabigerol and rivoceranib in an animal model of liver cancer.

[0091] Figure 6 is a diagram showing the results of confirming the expression levels of cell death-related factors following the combined treatment of cannabigerol and riboceranib in liver cancer cell lines.

[0092] Figure 7 is a diagram showing the results of confirming the expression level of FOXM1 following the combined treatment of cannabigerol and riboceranib in liver cancer cell lines.

[0093] Figure 8 is a diagram showing the results of confirming changes in body weight following the combined treatment of cannabizerol and riboceranib in a colorectal cancer animal model.

[0094] Figure 9 is a diagram showing the results of confirming the tumor growth inhibitory effect of combination treatment with cannabigerol and riboceranib in a colorectal cancer animal model.

[0095] Figure 10 is a diagram showing the results of confirming the expression levels of cell death-related factors following the combined treatment of cannabigerol and riboceranib in colorectal cancer cell lines.

[0096] Figure 11 is a diagram showing the results of confirming the anticancer efficacy of cannabigerol and rivoceranib combination treatment in various cancer cells.

[0097] Figure 12 is a diagram showing the results of confirming the anticancer efficacy of combination treatment of cannabigerol and / or cannabidiol and rivoceranib in liver cancer cell lines.

[0098] Figure 13 is a diagram showing the results of confirming the anticancer efficacy of combination treatment with cannabigerol and / or cannabidiol and rivoceranib in colorectal cancer cell lines.

[0099] Figure 14 is a diagram showing the results of confirming the anticancer efficacy of combination treatment of cannabigerol and / or cannabidiol and rivoceranib in pancreatic cancer cell lines.

[0100] Figures 15 and 16 show the results of confirming the anticancer efficacy of combination treatment with cannabigerol and / or cannabidiol and rivoceranib in colorectal cancer cell lines.

[0101] Figure 17 is a diagram showing the results of confirming the expression levels of cell death-related factors following the combined treatment of cannabigerol and cannabidiol and riboceranib in colorectal cancer cell lines.

[0102] Figure 18 is a diagram showing the results of confirming the tumor growth inhibitory effect of cannabigerol and the combination treatment of cannabidiol and riboceranib in colorectal cancer cell lines.

[0103] Figure 19 is a diagram showing the results of confirming the immune checkpoint inhibitory effect of cannabigerol and cannabidiol combined with riboceranib in various cancer cells.

[0104] The following examples will be explained in more detail. However, these examples are for illustrative purposes only and the scope of the present invention is not limited to these examples.

[0105]

[0106] Example 1: Evaluation of anticancer efficacy under in vitro conditions following combination treatment of cannabigerol (CBG) and rivoceranib

[0107] To evaluate the anticancer activity of combination therapy with cannabigerol (CBG) and rivoceranib, the following experiment was performed.

[0108] First, as an example of cancer cells, HepG2 cells, a liver cancer cell line, were placed in a 96-well plate at a ratio of 1 x 10 4Cells were inoculated at a cells / well concentration and cultured for 24 hours in a 37°C, 10% CO2 incubator. Subsequently, riboceranib was added at various concentrations and cultured for an additional 48 hours under the same conditions. After the culture was completed, WST-8 solution (Quanti-Max™, BIOMAX, Korea) was added to the medium at a 1 / 10 volume ratio and incubated at 37°C for 1 hour. Cell viability was calculated by measuring absorbance at 450 nm. Cell viability was expressed as a ratio relative to the untreated control group, and this experiment was performed independently in triplicate. As a result of the above experiment, the IC50 for riboceranib in HepG2 cells 50 The value was confirmed to be 28.1 μM (Fig. 1), and it can be seen that at concentrations below this level, it does not exhibit significant cytotoxicity to HepG2 cells.

[0109] Next, to screen for compounds among various cannabis-derived compounds that exhibit excellent synergistic effects with riboceranib, the treatment concentration of riboceranib was set to 20 μM, a concentration that does not exhibit cytotoxicity to cancer cells on its own, and anticancer activity against HepG2 cells, a liver cancer cell line, was confirmed by co-treatment with various cannabis-derived compounds. As a result of the above experiment, it was confirmed that among the cannabis-derived compounds, cannabigerol (CBG) significantly increased cytotoxicity to HepG2 cells in the co-treatment group compared to the riboceranib monotherapy group compared to other cannabis-derived compounds (Fig. 2).

[0110] Next, as a result of confirming the anticancer activity following combination treatment with cannabigerol and riboceranib in various liver cancer cell lines, the IC50 of riboceranib upon combination treatment with cannabigerol in various liver cancer cell lines 50 As it was confirmed that the value decreased by more than 50% (Fig. 3), it can be seen that the anticancer activity of riboceranib was significantly increased by cannabigerol.

[0111] In addition, to evaluate the synergistic effect of the combination treatment of cannabigerol and riboceranib, the ZIP Synergy score was calculated, and a high value of 11.48 was confirmed (Fig. 4).

[0112]

[0113] Example 2: Evaluation of anti-inflammatory efficacy under in vivo conditions following combination treatment of cannabigerol (CBG) and rivoceranib

[0114] To evaluate the in vivo anticancer activity of cannabigerol (CBG) and rivoceranib combination therapy, the following experiment was performed.

[0115] Specifically, as an example of cancer cells, to construct a xenograft mouse model using the HepG2 cell line, HepG2 cells were suspended in RPMI in BALB / c nude mice (male, 4 weeks old) at a rate of 1 x 10 7 Tumors were induced by subcutaneous injection at a concentration of cells / mouse. From the time the tumor size reached approximately 50 to 100 mm³, mice were randomly divided into groups of 5: (1) control group, (2) sorafenib monotherapy group (50 mg / kg), (3) rivoceranib monotherapy group (50 mg / kg), (4) cannabizerol monotherapy group (50 mg / kg), and (5) cannabizerol (100 mg / kg) and high-concentration rivoceranib combination therapy group (50 mg / kg). Each drug was administered orally at a scheduled dose and frequency, and the antitumor effect was evaluated by periodically measuring changes in tumor size and body weight over a certain period.

[0116] As a result of the above experiment, it was confirmed that the tumor growth inhibitory effect was significantly improved in the group treated with cannabigerol (CBG) and riboceranib in combination compared to the group treated with riboceranib alone (Fig. 5).

[0117] Based on the above results, it can be seen that the combined treatment of CBG and Rivoceranib exhibits a significantly superior synergistic effect of enhanced anticancer activity against cancer.

[0118]

[0119] Example 3: Analysis of the anticancer mechanism of action of combination therapy with cannabigerol (CBG) and rivoceranib

[0120] To analyze the mechanism of action of anticancer activity following the combination treatment of cannabigerol (CBG) and rivoceranib, the following experiments were performed.

[0121] Specifically, as an example of cancer cells, HepG2 liver cancer cell lines were placed in a 6-well plate at a rate of 3×10 5 After inoculating at a cell / well concentration and culturing for 48 hours in a 37°C, 10% CO2 incubator, the cells were treated with (1) a control group, (2) a group treated with riboceranib alone (10 μM), (3) a group treated with cannabigerol alone (20 μM), and (4) a group treated with cannabigerol (20 μM) and riboceranib in combination (10 μM), and then further cultured for 48 hours under the same conditions.

[0122] Next, to confirm the expression levels of apoptosis and cell cycle-related factors in the cultured cells, Western blotting was performed to determine the expression levels of CHOP (C / EBP-homologous protein), Cleaved PARP (Poly (ADP-ribose) polymerase), Cleaved caspase9, Cleaved caspase8, Cleaved caspase3, and FOXM1 (Forkhead box protein M1) proteins.

[0123] As a result of the above experiment, it was confirmed that in the group treated with the combination of cannabigerol and riboceranib, the levels of cell death-related factors Cleaved PARP, Cleaved caspase9, Cleaved caspase8, Cleaved caspase3, and CHOP proteins increased (Fig. 6), and the expression level of FOXM1, a cell cycle and cell proliferation-related factor, decreased (Fig. 7).

[0124] Based on the above results, it can be seen that the combination treatment of cannabigerol and rivoceranib can exhibit an anticancer effect by promoting apoptosis in cancer cells through the induction or inhibition of the expression of apoptosis and cell cycle-related factors.

[0125]

[0126] Example 4: Evaluation of anticancer efficacy against various cancer types following combination treatment of cannabigerol (CBG) and rivoceranib

[0127] To evaluate the anticancer activity of cannabigerol (CBG) and rivoceranib combination therapy in various cancer types, the following experiments were performed.

[0128]

[0129] 4.1: Evaluation of Anticancer Activity Against Colorectal Cancer

[0130] To evaluate anticancer activity against colorectal cancer, a xenograft mouse model using the colorectal cancer cell line RKO was constructed and evaluated.

[0131] Specifically, RKO cells were suspended in RPMI in BALB / c nude mice (male, 4 weeks old) at a rate of 1 x 10 7Tumors were induced by subcutaneous injection at a concentration of cells / mouse. When the tumor size reached approximately 50 to 100 mm³, mice were randomly divided into groups of 5: (1) control group, (2) 5-Fluorouracil monotherapy group (40 mg / kg), (3) cannabigerol monotherapy group (100 mg / kg), (4) riboceranib monotherapy group (100 mg / kg), and (5) cannabigerol (100 mg / kg) and riboceranib combination therapy group (100 mg / kg). 5-Fluorouracil was administered intraperitoneally (once a week), and the remaining drugs were administered orally daily. Subsequently, changes in tumor size and body weight were periodically measured over a certain period to evaluate the antitumor effect.

[0132] As a result of the above experiment, there was no difference in body weight among the experimental groups (Fig. 8), and it was confirmed that the tumor growth inhibitory effect was significantly improved in the combination treatment group compared to the rivoceranib monotherapy group (Fig. 9).

[0133] Next, analysis of the protein expression levels of apoptosis-related factors revealed that in the group treated with cannabigerol and riboceranib, the levels of Cleaved PARP, Cleaved caspase9, Cleaved caspase8, and Cleaved caspase3 proteins increased, while the expression of Bcl-2, an apoptosis inhibitor, decreased (Fig. 10).

[0134] Based on the above results, it can be seen that the combined treatment of cannabigerol and rivoceranib demonstrates a significantly superior synergistic effect of anticancer activity against colorectal cancer.

[0135]

[0136] 4.2: Evaluation of anticancer activity against additional cancer types

[0137] To evaluate the anticancer activity of combination therapy with cannabigerol (CBG) and rivoceranib against lung cancer, gastric cancer, prostate cancer, breast cancer, and biliary tract cancer, the following experiments were performed.

[0138] Specifically, 1 x 10 cancer cells per 96-well plate 4 Cells were inoculated at a cell / well concentration and cultured for 24 hours in a 37°C, 10% CO2 incubator. Subsequently, the cells were treated with riboceranib at various concentrations, or treated with cannabigerol at non-cytotoxic concentrations (10 μM and 5 μM) or left untreated, and cultured for an additional 48 hours under the same conditions. After the culture was completed, WST-8 solution was added to the medium at a 1 / 10 volume ratio and incubated at 37°C for 1 hour; cell viability was calculated by measuring absorbance at 450 nm. Cell viability was expressed as a ratio relative to the untreated control group, and this experiment was performed independently in triplicate.

[0139] As a result of the above experiment, it was confirmed that the survival rate of cancer cells in lung cancer, gastric cancer, prostate cancer, breast cancer, and bile duct cancer cell lines was significantly reduced in the group treated with the combination of cannabigerol and riboceranib compared to the group treated with riboceranib alone (Fig. 11).

[0140] Based on the above results, it can be seen that the combination treatment of cannabigerol and rivoceranib exhibits significantly superior anticancer activity compared to monotherapy in various cancer types, including lung cancer, gastric cancer, prostate cancer, breast cancer, and biliary tract cancer.

[0141]

[0142] Example 5: Evaluation of anticancer efficacy against various cancer types following triple combination treatment of cannabigerol (CBG), cannabidiol (CBD), and rivoceranib

[0143] The anticancer activity of triple combination therapy with cannabizerol (CBG), cannabidiol (CBD), and rivoceranib was evaluated as follows.

[0144] Specifically, as an example of various cancer types, liver cancer, colorectal cancer, and pancreatic cancer cells were placed in a 96-well plate at a ratio of 1 x 10 4 Cells were inoculated at a cell / well concentration and cultured for 24 hours in a 37°C, 10% CO2 incubator. Subsequently, riboceranib was treated at various concentrations, and additionally cultured for 24 hours under the same conditions with cannabigerol and / or cannabidiol at non-cytotoxic concentrations (20 μM) or without treatment. After the culture was completed, WST-8 solution was added to the medium at a 1 / 10 volume ratio and incubated at 37°C for 1 hour; cell viability was calculated by measuring absorbance at 450 nm. Cell viability was expressed as a ratio relative to the untreated control group, and this experiment was performed independently three times.

[0145] As a result of the above experiment, it was confirmed that the toxicity to liver, colorectal, and pancreatic cancer cells was significantly increased when cannabigenol, cannabidiol, and riboceranib were triple-combined compared to treatment with riboceranib alone or treatment with riboceranib and cannabigenol (Figs. 12 to 14).

[0146] Based on the above results, it can be seen that the triple combination treatment of cannabigerol, cannabidiol, and riboceranib exhibits significantly superior cancer cell toxicity compared to the combination treatment of cannabigerol and riboceranib.

[0147]

[0148] Example 6: Further analysis of anticancer efficacy following triple combination treatment of cannabigerol (CBG), cannabidiol (CBD), and rivoceranib

[0149] To further analyze the anticancer activity resulting from triple combination therapy with cannabigenol (CBG), cannabidiol (CBD), and rivoceranib, the following experiment was performed.

[0150] Specifically, as an example of a carcinoma, the colorectal cancer cell line CT-26 is placed in a 96-well plate at a ratio of 1 x 10 4Cells were inoculated at a cell / well concentration and cultured for 24 hours in a 37°C, 10% CO2 incubator. Subsequently, riboceranib was treated at various concentrations, and additionally cultured for 48 hours under the same conditions with cannabigerol and cannabidiol at non-cytotoxic concentrations (10 μM) or without treatment. After the culture was completed, WST-8 solution was added to the medium at a 1 / 10 volume ratio and reacted at 37°C for 1 hour; cell viability was calculated by measuring absorbance at 450 nm. Cell viability was expressed as a ratio relative to the untreated control group, and this experiment was performed independently in triplicate.

[0151] As a result of the above experiment, it was confirmed that the toxicity to mouse colon cancer cells was significantly increased when cannabigenol, cannabidiol, and riboceranib were triple-combined compared to treatment with riboceranib alone or treatment with riboceranib and cannabigenol (Figs. 15 and 16).

[0152] Next, analysis of the protein expression levels of apoptosis-related factors revealed that the expression levels of Cleaved PARP and Cleaved caspase8 proteins increased in the triple combination treatment group of cannabigerol, cannabidiol, and rivoceranib (Fig. 17).

[0153] Next, to construct an allograft mouse model using the CT-26 cell line, CT-26 cells were suspended in RPMI and 1 x 10⁻¹⁰ cells were fed to BALB / c mice (male, 4 weeks old). 7Tumors were induced by subcutaneous injection at a concentration of cells / mouse. When the tumor size reached approximately 50 to 100 mm³, mice were randomly divided into groups of three: (1) a control group, and (2) a triple combination treatment group consisting of cannabizerol (50 mg / kg), cannabidiol (50 mg / kg), and rivoceranib (50 mg / kg). Each drug was administered orally at a scheduled dose and frequency. Subsequently, changes in tumor size and body weight were periodically measured over a certain period to evaluate the anti-tumor effect, and it was confirmed that the tumor growth inhibition effect was significantly enhanced in the triple combination treatment group compared to the control group (Fig. 18).

[0154]

[0155] Example 9: Evaluation of Immune Checkpoint Inhibitory Effects of Triple Combination Treatment with Cannabigerol (CBG), Cannabidiol (CBD), and Rivoceranib

[0156] To confirm the immune checkpoint inhibitory effect of triple combination therapy with cannabigerol (CBG), cannabidiol (CBD), and rivoceranib, the following experiment was performed.

[0157] Specifically, as an example of a carcinoma, the colorectal cancer cell line RKO or the liver cancer cell line HepG2 is placed in a 6-well plate at a ratio of 3 x 10 5 Cells were inoculated at a concentration of cells / well and cultured for 24 hours in an incubator at 37°C under 10% CO2 conditions. Subsequently, riboceranib (5 μM) and cannabigerol and cannabidiol (at non-cytotoxic concentrations of 20 μM) were treated individually or in combination and cultured under the same conditions for 24 hours. After the completion of culture, total RNA was extracted from each cell and cDNA was synthesized via reverse transcription. The expression level of the PD-L1 (CD247) gene was analyzed using quantitative real-time qRT-PCR. Relative expression levels were calculated using GAPDH as an endogenous control.

[0158] As a result of the above experiment, it was confirmed that in the colorectal cancer cell line RKO and liver cancer cell line HepG2, the expression of the PD-L1 gene was significantly reduced in the triple combination treatment group of cannabigerol, cannabidiol, and riboceranib compared to other experimental groups (Fig. 19).

[0159] Based on the above results, it can be seen that the combined treatment of cannabigerol and cannabidiol can inhibit the expression of PD-L1, an immune checkpoint factor in cancer cells, and that triple combination treatment with the addition of rivoceranib further inhibits PD-L1 expression, suggesting the possibility of involvement in the regulation of anticancer responses mediated by immunological mechanisms.

[0160]

[0161] The foregoing description of the present invention is for illustrative purposes only, and those skilled in the art will understand that other specific forms can be easily modified without altering the technical spirit or essential features of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive.

Claims

1) Cannabigerol (CBG), derivatives thereof, stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, or combinations thereof; and 2) Rivoceranib A pharmaceutical composition for the prevention or treatment of cancer, comprising as an active ingredient. A pharmaceutical composition according to claim 1, wherein the cannabizerol, its derivative, its stereoisomer, its pharmaceutically acceptable salt, its hydrate, its solvate, or a combination thereof is administered in combination with riboceranib. A pharmaceutical composition according to claim 1, wherein the cannabigerol, its derivative, its stereoisomer, its pharmaceutically acceptable salt, its hydrate, its solvate, or a combination thereof is administered simultaneously with rivoceranib in one formulation, or simultaneously or sequentially with rivoceranib in a separate formulation. A pharmaceutical composition according to claim 1, wherein the cannabizerol and rivoceranib are included in a concentration ratio of 9:1 to 1:

9. A pharmaceutical composition according to claim 1, wherein the composition further comprises cannabidiol (CBD), derivatives thereof, stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, or combinations thereof. In claim 1, the cancer comprises one or more selected from the group consisting of gastric cancer, liver cancer, cholangiocarcinoma, lung cancer, pancreatic cancer, non-small cell lung cancer, colon cancer, bone cancer, skin cancer, head or neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, colorectal cancer, pro-anal cancer, colon cancer, breast cancer, cervical cancer, fallopian tube carcinoma, endometrial carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine gland cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal cell carcinoma, renopelvic carcinoma, central nervous system (CNS) tumor, primary CNS lymphoma, spinal cord tumor, brainstem glioma, and pituitary adenoma. A composition that is. A composition according to claim 1, wherein the composition has anticancer activity through immune checkpoint inhibition. A pharmaceutical composition for enhancing the anticancer effect of rivoceranib, comprising cannabigerol (CBG), derivatives thereof, stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, or combinations thereof as an active ingredient. The composition of claim 8, wherein the composition is administered in combination with riboceranib. 1) Cannabidiol (CBD), derivatives thereof, stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, or combinations thereof; and 2) Rivoceranib A pharmaceutical composition for the prevention or treatment of cancer, comprising as an active ingredient.

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