Composition for enhancing anti-cancer effect of RAF inhibitor containing aripiprazole as active ingredient
By combining aripiprazole in the treatment of RAF inhibitors, inducing NOXA and PUMA protein expression or PARP cleavage, the problem of insufficient efficacy of RAF inhibitor resistance and BH3 analogue alone was solved, and the apoptosis of cancer cells was significantly enhanced. Improve the treatment efficiency of various cancers.
Patent Information
- Application Number
- CN202380039696.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Priority Date
- 2023-05-03
- Filing Date
- 2023-05-10
- Publication Date
- 2024-12-20
AI Technical Summary
RAF inhibitors are prone to drug resistance when treating cancers such as melanoma. BH3 analogues or BH3-only protein-induced drugs used alone are not enough to cause a large amount of apoptosis and cannot effectively enhance the anti-cancer effect.
Combined with aripiprazole and RAF inhibitors, the apoptotic effect of cancer cells is enhanced by inducing NOXA and PUMA protein expression or PARP cleavage.
It significantly enhances the anti-cancer effect of RAF inhibitors, induces apoptosis of cancer cells, and improves the treatment efficiency of a variety of cancers, especially in cases with strong drug resistance such as melanoma.
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Abstract
Description
Technical Field
[0001] The present disclosure relates to a composition for enhancing the anticancer effect of a RAF inhibitor, the composition comprising aripiprazole as an active ingredient, and more particularly, to a composition for enhancing the anticancer effect of a RAF inhibitor, the composition being capable of treating cancer by acting as an anticancer effect enhancer of the RAF inhibitor in a combined therapy with aripiprazole. Background Art
[0002] Brain metastasis of melanoma is the third most common after lung cancer and breast cancer, and occurs in 40%-50% of stage IV melanoma patients. Due to the low survival rate, patients with melanoma brain metastasis are rarely eligible for clinical trials. RAF inhibitors selectively inhibit RAF proteins and show significant anticancer efficacy against a variety of cancers including melanoma at the early chemotherapy stage, but resistance develops in almost all cancers. A representative strategy to overcome the problem of resistance to targeted anticancer drugs caused by intratumor heterogeneity is the combination therapy strategy, which aims to reduce the incidence of resistant cell populations by prescribing two or more different drugs together.
[0003] BH3-only proteins can promote or induce apoptosis by inhibiting apoptosis regulatory functions. Loss of ERK1 / 2 activity inhibits phosphorylation of BIM, one of the BH3-only proteins, and loss of ERK-mediated phosphorylation leads to BIM stabilization and increased BIM expression. However, BIM induction alone is not sufficient to cause extensive apoptosis because BIM is bound and inhibited by anti-apoptotic proteins, such as those in the BCL2 family. Therefore, BH3 analogs or BH3-only protein-inducing drugs that inhibit the function of anti-apoptotic proteins can cause strong apoptosis when used simultaneously with drugs that induce loss of ERK1 / 2 activity, and BIM induction caused by inhibition of ERK signaling is responsible for the increased apoptosis.
[0004] Using the same principle, BH3 analogs and BH3-only protein-inducing drugs are being studied to enhance the potent anticancer effects associated with apoptosis when used concomitantly with RAF inhibitors. Summary of the invention
[0005] Technical Purpose
[0006] An object of the present disclosure is to provide a pharmaceutical composition for enhancing the anti-cancer effect of a RAF inhibitor, the pharmaceutical composition comprising aripiprazole as an active ingredient.
[0007] Another object of the present disclosure is to provide a health functional food composition for enhancing the anti-cancer effect of a RAF inhibitor, the health functional food composition comprising aripiprazole as an active ingredient.
[0008] Another object of the present disclosure is to provide a pharmaceutical composition for preventing or treating cancer, the pharmaceutical composition comprising a RAF inhibitor or a pharmaceutically acceptable salt thereof; and aripiprazole or a pharmaceutically acceptable salt thereof as active ingredients.
[0009] Another object of the present disclosure is to provide a health functional food composition for preventing or improving cancer, the health functional food composition comprising a RAF inhibitor or a pharmaceutically acceptable salt thereof; and aripiprazole or a pharmaceutically acceptable salt thereof as active ingredients.
[0010] Technical Solution
[0011] To achieve the above objectives, the present disclosure provides a pharmaceutical composition for enhancing the anti-cancer effect of a RAF inhibitor, wherein the pharmaceutical composition comprises aripiprazole as an active ingredient.
[0012] In addition, the present disclosure provides a health functional food composition for enhancing the anti-cancer effect of a RAF inhibitor, the health functional food composition comprising aripiprazole as an active ingredient.
[0013] In addition, the present disclosure provides a pharmaceutical composition for preventing or treating cancer, the pharmaceutical composition comprising a RAF inhibitor or a pharmaceutically acceptable salt thereof; and aripiprazole or a pharmaceutically acceptable salt thereof as active ingredients.
[0014] In addition, the present disclosure provides a health functional food composition for preventing or improving cancer, the health functional food composition comprising a RAF inhibitor or a pharmaceutically acceptable salt thereof; and aripiprazole or a pharmaceutically acceptable salt thereof as active ingredients.
[0015] Beneficial Effects
[0016] The present disclosure relates to a composition for enhancing the anticancer effect of a RAF inhibitor, the composition comprising aripiprazole as an active ingredient, and more specifically, to a composition for enhancing the anticancer effect of a RAF inhibitor, the composition being capable of treating cancer by acting as an anticancer effect enhancer of a RAF inhibitor in a combined therapy with aripiprazole. By co-administering an effective amount of aripiprazole according to the present disclosure with a RAF inhibitor, the composition can be used as an anticancer effect enhancer of a RAF inhibitor due to its excellent effect in enhancing the anticancer effect of the RAF inhibitor (e.g., inducing apoptosis of cancer cells). BRIEF DESCRIPTION OF THE DRAWINGS
[0017] Figure 1 Results show the effect of aripiprazole treatment on NOXA and PUMA protein expression in COLO 205 cells.
[0018] Figure 2 Schematic diagram illustrating the effect of expression of NOXA and PUMA protein (one of the BH3-only proteins) on the anti-cancer efficacy of RAF inhibitors.
[0019] Figure 3 Results are shown showing the effect of aripiprazole alone or in combination with aripiprazole and a RAF inhibitor on PARP cleavage in A375 cells.
[0020] Figure 4 Shown are the effects of aripiprazole treatment alone or in combination with a RAF inhibitor on PARP cleavage in COLO 205 cells. DETAILED DESCRIPTION
[0021] Hereinafter, the present disclosure will be described in more detail.
[0023] The present disclosure provides a pharmaceutical composition for enhancing the anti-cancer effect of a RAF inhibitor, the pharmaceutical composition comprising aripiprazole as an active ingredient.
[0024] The RAF inhibitor may be any one selected from the group consisting of belvarafenib, vemurafenib, lifirafenib, dabrafenib, naporafenib and tovorafenib, but is not limited thereto.
[0025] The cancer may be melanoma, breast cancer, lymphoma, brain tumor, brain cancer, colorectal cancer, prostate cancer, lung cancer, osteosarcoma, bone cancer, pancreatic cancer, skin cancer, oral cancer, oropharyngeal cancer, uterine cancer, ovarian cancer, rectal cancer, gastric cancer, endometrial cancer, cervical cancer, vaginal cancer, small intestine cancer, thyroid cancer, parathyroid cancer, chronic leukemia or acute leukemia, bladder cancer, kidney cancer or liver cancer, but is not limited thereto.
[0026] The pharmaceutical composition can induce PARP cleavage of cancer cells, or increase the expression of NOXA or PUMA.
[0027] In another embodiment of the present disclosure, the pharmaceutical composition may further comprise one or more additives selected from the group consisting of: suitable carriers, excipients, disintegrants, sweeteners, coating agents, bulking agents, lubricants, glydents, flavoring agents, antioxidants, buffers, antibacterial agents, diluents, dispersants, surfactants, binders and lubricants, which are conventionally used in the manufacture of pharmaceutical compositions. Specifically, for carrier, excipient and diluent, lactose, glucose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talcum, magnesium stearate and mineral oil can be used, the solid preparation for oral administration can include tablet, pill, acid agent, granule and capsule, these solid preparations can be prepared by mixing at least one excipient (for example starch, calcium carbonate, sucrose or lactose and gelatin) in the composition. Except simple excipient, lubricant, for example magnesium stearate and talcum can also be used. Oral liquid preparation can be suspensoid, liquid, emulsion and syrup, and except commonly used simple diluent (for example water and liquid paraffin), also contain various excipients, for example humectant, sweetener, spices and preservative. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized agents and suppositories. For non-aqueous solvents and suspensions, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, esters for injection such as ethyl oleate can be used. As the base material of suppositories, Witepsol, macrogol, Tween 61, cocoa butter, laurin fat and glycerin gelatin can be used. According to an embodiment of the present disclosure, the pharmaceutical composition can be given to the subject in a conventional manner by intravenous, intraarterial, intraperitoneal, intramuscular, intraarterial, intraperitoneal, intrasternal, transdermal, nasal, inhaled, local, rectal, oral, intraocular or intradermal routes. The dosage of the active ingredient according to the present disclosure may vary according to the condition and weight of the subject, the type and severity of the disease, the drug form, and the route and duration of administration, and is appropriately selected by those skilled in the art, and the daily dosage may be 0.01 mg / kg to 200 mg / kg, preferably 0.1 mg / kg to 200 mg / kg, and more preferably 0.1 mg / kg to 100 mg / kg. It may be administered once a day or divided into multiple doses, but the scope of the present disclosure is not limited thereto.
[0030] In addition, the present disclosure provides a health functional food composition for enhancing the anti-cancer effect of a RAF inhibitor, the health functional food composition comprising aripiprazole as an active ingredient.
[0031] Health functional food can contain various nutritional supplements, vitamins, minerals (electrolytes), flavoring agents (such as synthetic flavoring agents and natural flavoring agents), coloring agents and thickeners (cheese and chocolate), pectin acid and its salt, alginate and its salt, organic acid, protective colloid thickener, pH regulator, stabilizer, preservative, glycerine, alcohol and the carbonating agent used in carbonated beverage. In addition, it can also contain the pulp used to make natural fruit juice, synthetic fruit juice and vegetable beverage. These ingredients can be used alone or in combination. In addition, health functional food composition can be in any form in meat, sausage, bread, chocolate, candy, snacks, sweets, pizza, instant noodles, chewing gum, ice cream, soup, beverage, tea, functional water, drinks, alcohol and vitamin complex. In addition, health functional food can further include food additives, unless otherwise specified, by according to the general rules of the Korean Food Additives Codex approved by the Ministry of Food and Drug Safety (Ministry of Food and Drug Safety) and the standards and criteria related to the corresponding items of the general test method, determine the applicability as "food additives". The items listed in the "Korean Food Additive Code" may include, for example, chemically synthesized compounds such as ketones, glycine, potassium citrate, nicotinic acid and cinnamic acid; natural additives such as persimmon pigment, licorice extract, crystalline cellulose, sorghum pigment and guar gum; and mixed preparations such as sodium L-glutamate preparations, noodle alkali agents, preservatives and tar colorants. Here, in the process of manufacturing health functional foods, the content of the active ingredient added to the food may be appropriately adjusted if necessary, and preferably, the active ingredient may be added so as to be contained in an amount of 1 to 90 parts by weight based on 100 parts by weight of the food.
[0033] In addition, the present disclosure provides a pharmaceutical composition for preventing or treating cancer, the pharmaceutical composition comprising a RAF inhibitor or a pharmaceutically acceptable salt thereof; and aripiprazole or a pharmaceutically acceptable salt thereof as active ingredients.
[0034] The RAF inhibitor may be any one selected from the group consisting of bevafenib, vemurafenib, rifirafenib, dabrafenib, naborafenib, and tovorafenib, but is not limited thereto.
[0035] The cancer may be melanoma, breast cancer, lymphoma, brain tumor, brain cancer, colorectal cancer, prostate cancer, lung cancer, osteosarcoma, bone cancer, pancreatic cancer, skin cancer, oral cancer, oropharyngeal cancer, uterine cancer, ovarian cancer, rectal cancer, gastric cancer, endometrial cancer, cervical cancer, vaginal cancer, small intestine cancer, thyroid cancer, parathyroid cancer, chronic leukemia or acute leukemia, bladder cancer, kidney cancer or liver cancer, but is not limited thereto.
[0037] In addition, the present disclosure provides a health functional food composition for preventing or improving cancer, the health functional food composition comprising a RAF inhibitor or a pharmaceutically acceptable salt thereof; and aripiprazole or a pharmaceutically acceptable salt thereof as active ingredients.
[0039] Hereinafter, the present disclosure will be described in more detail by examples to help understand the present disclosure. However, the following examples are only intended to illustrate the content of the present disclosure, but the scope of the present disclosure is not limited to the following examples. The embodiments of the present disclosure are provided to more fully describe the present disclosure to those of ordinary skill in the art.
[0040] Example
[0041] <Example 1> Identification of the effect of aripiprazole on NOXA and PUMA protein expression
[0042] To identify the effect of aripiprazole on NOXA and PUMA protein expression in cancer cells, COLO205 cells were treated with aripiprazole. After 8 h, proteins were extracted from the cells after washing with PBS, and the expression levels of NOXA and PUMA were examined by Western blotting.
[0043] As a result, according to Figure 1 , the expression of NOXA and PUMA proteins in COLO 205 cells was increased by aripiprazole treatment, indicating that aripiprazole exhibited the effect of inducing the expression of NOXA and PUMA proteins.
[0045] <Example 2> Identification of the effect of aripiprazole on apoptosis induced by RAF inhibitors
[0046] (1) A375 cells
[0047] To identify the effect of aripiprazole on RAF inhibitor-induced apoptosis in cancer cells, A375 cells were treated with aripiprazole alone or in combination with a RAF inhibitor. After 24 hours, proteins were extracted from the cells after washing with PBS, and the extent of PARP cleavage was examined by Western blotting.
[0048] As a result, according to Figure 3 , found that the combined treatment of aripiprazole and RAF inhibitor showed a superior effect of inducing PARP cleavage than that observed with aripiprazole or RAF inhibitor treatment alone.
[0050] (2) COLO 205 cells
[0051] To identify the effect of aripiprazole on RAF inhibitor-induced apoptosis in cancer cells, COLO 205 cells were treated with aripiprazole alone or in combination with a RAF inhibitor. After 24 hours, proteins were extracted from the cells after washing with PBS, and the extent of PARP cleavage was examined by Western blotting.
[0052] As a result, according to Figure 4 , found that the combined treatment of aripiprazole and RAF inhibitor showed a superior effect of inducing PARP cleavage than that observed with aripiprazole or RAF inhibitor treatment alone.
[0054] The above description of the present disclosure is for illustrative purposes only, and those skilled in the art will understand that the present disclosure can be easily converted into other specific forms without changing the technical ideas or basic features of the present disclosure. Therefore, it should be understood that the above embodiments are illustrative in all aspects and not restrictive.
[0055] The scope of the present disclosure is expressed by the following claims, and the meaning and scope of the claims and any changes or modifications derived from equivalent concepts should be understood to be included in the scope of the present disclosure.
Claims
1. A pharmaceutical composition for enhancing the anticancer effect of a RAF inhibitor, the pharmaceutical composition comprising aripiprazole as an active ingredient.
2. The pharmaceutical composition according to claim 1, wherein The RAF inhibitor is any one selected from the group consisting of bevafenib, vemurafenib, rifampinib, dabrafenib, naborafenib and tovorafenib.
3. The pharmaceutical composition according to claim 1, wherein The cancer is melanoma, breast cancer, lymphoma, brain tumor, brain cancer, colorectal cancer, prostate cancer, lung cancer, osteosarcoma, bone cancer, pancreatic cancer, skin cancer, oral cancer, oropharyngeal cancer, uterine cancer, ovarian cancer, rectal cancer, stomach cancer, endometrial cancer, cervical cancer, vaginal cancer, small intestine cancer, thyroid cancer, parathyroid cancer, chronic leukemia or acute leukemia, bladder cancer, kidney cancer or liver cancer.
4. The pharmaceutical composition according to claim 1, wherein The pharmaceutical composition induces PARP cleavage of cancer cells, or increases the expression of NOXA or PUMA.
5. A health functional food composition for enhancing the anti-cancer effect of a RAF inhibitor, the health functional food composition comprising aripiprazole as an active ingredient.
6. A pharmaceutical composition for preventing or treating cancer, comprising: a RAF inhibitor or a pharmaceutically acceptable salt thereof; and aripiprazole or a pharmaceutically acceptable salt thereof as active ingredients.
7. The pharmaceutical composition according to claim 6, wherein The RAF inhibitor is any one selected from the group consisting of bevafenib, vemurafenib, rifampinib, dabrafenib, naborafenib and tovorafenib.
8. The pharmaceutical composition according to claim 6, wherein The cancer is melanoma, breast cancer, lymphoma, brain tumor, brain cancer, colorectal cancer, prostate cancer, lung cancer, osteosarcoma, bone cancer, pancreatic cancer, skin cancer, oral cancer, oropharyngeal cancer, uterine cancer, ovarian cancer, rectal cancer, stomach cancer, endometrial cancer, cervical cancer, vaginal cancer, small intestine cancer, thyroid cancer, parathyroid cancer, chronic leukemia or acute leukemia, bladder cancer, kidney cancer or liver cancer.
9. A health functional food composition for preventing or improving cancer, comprising: a RAF inhibitor or a pharmaceutically acceptable salt thereof; and aripiprazole or a pharmaceutically acceptable salt thereof as active ingredients.