Pharmaceutical composition for enhancing anticancer effect of anticancer agent comprising actin polymerization agent as active ingredient

Abstract

The present invention relates to a pharmaceutical composition for enhancing the anticancer effect of an anticancer agent, the pharmaceutical composition comprising an actin polymerization agent as an active ingredient. The pharmaceutical composition induces differentiation of AT2 cells, which are main cells of a lung cancer cell population, into AT1 cells to reduce the number of lung cancer cells and cell activity, thereby exhibiting an anticancer effect. It was also confirmed that treatment with an anticancer agent, after pretreatment with an actin polymerization agent followed by inducing differentiation into AT1 cells, significantly increases sensitivity to the anticancer agent. Therefore, the present invention can be effectively used as an excellent therapeutic agent for lung cancer or a composition for enhancing the anticancer activity of an anticancer agent for lung cancer.

Description

Pharmaceutical composition for enhancing the anticancer effect of an anticancer agent containing an actin polymerization agent as an active ingredient

[0001] The present invention relates to a pharmaceutical composition for enhancing the anticancer effect of an anticancer agent comprising an actin polymerization agent as an active ingredient.

[0002] This application claims priority to Korean Patent Application No. 10-2024-0026735, filed February 23, 2024, the entire disclosure of which is incorporated herein by reference.

[0003] Cancer is one of the leading causes of death in modern society. It is a disease caused by genetic mutations that cause changes in normal cells. It refers to malignant tumors that do not follow normal cell differentiation, proliferation, and growth patterns. Among these, lung cancer is the leading cause of cancer-related deaths.

[0004] Most anticancer drugs currently in use are chemotherapy-based, and their pharmacological effects vary depending on the type of cancer, and they exhibit diverse side effects due to toxicity. This has been pointed out as a problem in cancer treatment, and there is also the problem of drug resistance developing, which reduces sensitivity. Specifically, existing anticancer drugs penetrate not only cancer cells but also normal cells, damaging their function and activity. This causes side effects such as bone marrow dysfunction, gastrointestinal disorders, and alopecia. In addition, long-term chemotherapy leads to drug resistance, presenting a major problem in cancer treatment. Therefore, to solve these serious problems of existing anticancer drugs, there is a growing need to develop substances that can enhance the anticancer effects of anticancer drugs or substances for combination administration.

[0005] Among these, lung cancer is divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), with NSCLC accounting for more than 80% of all lung cancers. NSCLC is further subdivided into lung adenocarcinoma (LUAD), squamous cell carcinoma, and large cell carcinoma, of which lung adenocarcinoma is known to be the most common type.

[0006] Meanwhile, among the various cells that make up the lungs, the cells that perform major functions include adult AT1 (alveolar type 1) cells and stem cells AT2 (alveolar type 2) cells. AT1 cells are cells that make up the alveoli and perform the main function of mediating gas exchange, while AT2 cells secrete surfactant to protect and maintain the alveoli. As precursor cells, they repair damaged epithelial cells by producing AT1 cells.

[0007] Against this technical backdrop, despite the fact that lung cancer is a disease with a high recurrence rate due to frequent metastasis compared to other cancer types, there have been few reports on substances that enhance the sensitivity of anticancer drugs.

[0008] The purpose of the present invention is to provide a pharmaceutical composition for enhancing the anticancer effect of an anticancer agent, which comprises an actin polymerization agent as an active ingredient.

[0009] Another object of the present invention is to provide a pharmaceutical composition for combined administration with an anticancer agent, comprising an actin polymerization agent as an active ingredient.

[0010] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer, comprising an actin polymerization agent as an active ingredient.

[0011] Another object of the present invention is to provide a kit for enhancing the anticancer effect of an anticancer agent, including an actin polymerization agent and an instruction manual; for administering the same in combination with an anticancer agent; or for preventing or treating cancer.

[0012]

[0013] However, the technical problems to be solved by the present invention are not limited to the problems mentioned above, and other problems not mentioned can be clearly understood by a person having ordinary skill in the technical field to which the present invention belongs from the description below.

[0014] The present invention provides a pharmaceutical composition for enhancing the anticancer effect of an anticancer agent, comprising an actin polymerization agent as an active ingredient.

[0015] In one embodiment of the present invention, the actin polymerization agent may be any one selected from the group consisting of jasplakinolide, phalloidin, cytochalasin, and Arp2 / 3 complex activators, but is not limited thereto.

[0016] In one embodiment of the present invention, the composition can induce differentiation from AT2 cells (alveolar type 2 cells) into AT1 cells (alveolar type 1 cells), but is not limited thereto.

[0017] In one embodiment of the present invention, the composition may increase the sensitivity of an anticancer agent, but is not limited thereto.

[0018] In one embodiment of the present invention, the anticancer agent may be, but is not limited to, a mitotic inhibitor or an EGFR inhibitor.

[0019] In one embodiment of the present invention, the mitotic inhibitor may be any one selected from the group consisting of cisplatin, doxorubicib, 5-FU (5-flurouracil), dactinomycin, and docetaxel, but is not limited thereto.

[0020] In one embodiment of the present invention, the EGFR inhibitor may be any one selected from the group consisting of erlotinib, gefitinib, lapatinib, vadetanib, neratinib, osimertinib, cetuximab, pantimumab, and necitumumab, but is not limited thereto.

[0021] In one embodiment of the present invention, the cancer may be any one selected from the group consisting of adenocarcinoma, squamous cell lung cancer, large cell lung cancer, and small cell lung cancer, but is not limited thereto.

[0022] In one embodiment of the present invention, the composition can reduce at least one of the number of cancer cells or the activity of cancer cells, but is not limited thereto.

[0023] In one embodiment of the present invention, the composition can reduce the expression of one or more markers selected from the group consisting of, but not limited to, the following in a lung cancer cell population:

[0024] a) AT1 transition-related marker TP53; and

[0025] b) Cancer cell marker NKX2-1.

[0026] In one embodiment of the present invention, the composition may be formulated separately with the anticancer agent and administered sequentially, but is not limited thereto.

[0027] In one embodiment of the present invention, the composition may be administered before the anticancer agent, but is not limited thereto.

[0028] The present invention provides a pharmaceutical composition for combined administration with an anticancer agent, comprising an actin polymerization agent as an active ingredient.

[0029] In one embodiment of the present invention, the composition may be formulated separately with the anticancer agent and administered sequentially, but is not limited thereto.

[0030] In one embodiment of the present invention, the composition may be administered before the anticancer agent, but is not limited thereto.

[0031] The present invention provides a pharmaceutical composition for preventing or treating cancer, comprising an actin polymerization agent as an active ingredient.

[0032] In one embodiment of the present invention, the composition may be characterized by at least one selected from the group consisting of, but not limited to:

[0033] a) Change the morphology of cancer cell clusters into the form of wide and flat AT1 cells, induce actin arrangement, and increase cell size;

[0034] b) induce and increase the expression of podoplanin (PDPN), an AT1 cell-specific marker, in cancer cell populations; and

[0035] c) Reduces the cell proliferation rate of cancer cell populations.

[0036] In one embodiment of the present invention, the composition may additionally include an anticancer agent, but is not limited thereto.

[0037] The present invention provides a kit for enhancing the anticancer effect of an anticancer agent, including an actin polymerization agent and an instruction manual.

[0038] The present invention provides a kit for combination administration of an anticancer agent or a kit for preventing or treating cancer, comprising an actin polymerization agent and an instruction manual.

[0039]

[0040] In addition, the present invention provides a method for enhancing an anticancer effect, a method for administering an anticancer agent in combination, or a method for preventing or treating cancer, comprising a step of administering a composition containing an actin polymerization agent as an active ingredient to a subject in need thereof.

[0041] In addition, the present invention provides a use for enhancing the anticancer effect of a composition containing an actin polymerization agent as an active ingredient, a use for co-administration with an anticancer agent, or a use for preventing or treating cancer.

[0042] In addition, the present invention provides a use for manufacturing a composition comprising an actin polymerization agent as an active ingredient for manufacturing a preparation for enhancing anticancer effect, a preparation for combined administration of anticancer agents, or a preparation for preventing or treating cancer.

[0043] According to a pharmaceutical composition for enhancing the anticancer effect of an anticancer agent containing an actin polymerization agent as an active ingredient, the composition exhibits an anticancer effect by inducing differentiation of AT2 cells, which are the main cells of a lung cancer cell population, into AT1 cells, thereby reducing the number and cell activity of lung cancer cells. In addition, it was confirmed that when pretreatment with an actin polymerization agent was performed for a period of time to induce differentiation into AT1 cells and then treatment with an anticancer agent, the sensitivity of the anticancer agent significantly increased. Therefore, the present invention can be usefully utilized as an excellent lung cancer treatment agent or a composition for enhancing the anticancer activity of an anticancer agent for lung cancer.

[0044] Figure 1a is a schematic diagram showing the overall relationship between alveolar cells, AT1 cells, and AT2 cells.

[0045] Figure 1b is a diagram showing the changing ratio of AT1 cells and AT2 cells under the situation where the original lung adenocarcinoma tissue differentiates into tissue composed of adult cells.

[0046] Figures 2a and 2b show the results of observing the concentration-dependent cell death effect when cisplatin and erlotinib were treated on lung cancer cell lines, respectively.

[0047] Figures 2c and 2d show the cell death effect confirmed by analyzing the activity of surviving cells when cisplatin and erlotinib were treated on lung cancer cell lines, respectively.

[0048] Figure 2e shows the results of confirming the low concentration condition in which jasplakinolide itself does not cause toxicity by observing a concentration-dependent cell death effect when jasplakinolide was treated on a lung cancer cell line.

[0049] Figure 3a shows the results confirming that when jasplakinolide at a concentration that does not show cytotoxicity was treated to lung cancer cell lines, morphological changes occurred into cells with larger and flatter shapes.

[0050] Figure 3b shows the results that when jasplakinolide was treated to lung cancer cell lines, in addition to SFTPC, a marker of AT2 lung cancer cells that is basically expressed, Podoplanin, a marker of AT1 cells but not lung cancer cells, began to be observed.

[0051] Figure 3c shows a decrease in the cell growth rate of lung cancer cell populations when jasplakinolide was treated to lung cancer cell lines.

[0052] Figure 4 is a protocol for an experiment performed to confirm the anticancer effect enhancement activity of an anticancer agent when differentiation of AT1 cells was induced for 3 days through jasplakinolide.

[0053] Figures 5a and 5b show the results of an experiment on the anticancer activity enhancement effect of an anticancer agent when an anticancer agent was treated on a lung cancer cell line in which AT1 cell differentiation was induced by treatment with jasplakinolide for 3 days, showing that the effect of reducing lung cancer cell lines and the effect of reducing cell activity were amplified, respectively.

[0054] Figure 6a is a protocol of an experiment performed to confirm the anticancer effect enhancement activity of an anticancer agent when differentiation of AT1 cells was induced for 7 days through jasplakinolide.

[0055] Figures 6b and 6c show the results of an experiment on the anticancer activity enhancement effect of an anticancer agent when an anticancer agent was treated on a lung cancer cell line in which AT1 cell differentiation was induced by treatment with jasplakinolide for 7 days, showing that the effect of reducing lung cancer cell lines and the effect of reducing cell activity were amplified, respectively. In addition, Figure 6d shows the decrease in the expression levels of TP53, an AT1 cell transformation-related marker, and NKX2-1, a cancer cell marker, in a lung cancer cell line under the same circumstances.

[0056] The present invention provides a pharmaceutical composition for enhancing the anticancer effect of an anticancer agent, comprising an actin polymerization agent as an active ingredient.

[0057] To induce AT2 cell differentiation into AT1 cells by promoting actin production, the present inventors treated A549 cells, which are used as a model for lung adenocarcinoma and AT2 cells, with jasplakinolide, an actin polymerization agent. Treatment with jasplakinolide resulted in the formation of new, broad, flat cells, characteristic of AT1 cells, within A549 cell colonies, unlike the small, cuboid AT2 cells. Furthermore, the overall proliferation rate of the cell colonies was significantly reduced. Since it was confirmed that increased intracellular actin transformed AT2 cells into AT1 cells and slowed overall cell proliferation, cisplatin and erlotinib were administered to determine whether these changes influenced the anticancer drug's inhibitory effect on cancer cells. Cisplatin and erlotinib, widely used clinically representative anticancer drugs, were administered to AT1-derived lung cancer cell colonies, and it was confirmed that the apoptotic effect was significantly increased.

[0058] This technology, which induces the amplification of the anticancer effect on cancer cells through simple treatment, is not limited to practical applications in lung cancer treatment, and is expected to be widely utilized in basic research on the mechanisms that induce lung cancer proliferation.

[0059] In the present invention, "actin" is one of two fundamental proteins, along with myosin, that make up muscle proteins. It is a double-stranded linear protein that forms thin filaments. It has a fibrous structure and is known to be widely distributed in cells other than muscle.

[0060] In the present invention, the term "actin polymerization agent" may have a broad meaning including any substance for forming actin or maintaining actin that has already been formed. Accordingly, it may include a substance that produces actin through a polymerization reaction, produces or forms actin through other reactions, or induces actin formation. Therefore, it is a concept that includes an "actin forming agent" or an "actin inducing agent" and may be used interchangeably therewith, but is not limited thereto. In addition, a substance that prevents dissociation of already formed actin or inhibits actin reduction through stabilization may also be included in the actin polymerization agent of the present invention. Accordingly, it may be used interchangeably with "actin dissociation inhibitors," "actin reduction inhibitors," and "actin stabilizers," but is not limited thereto.

[0061] In one embodiment of the present invention, the actin polymerization agent may be any one selected from the group consisting of jasplakinolide, phalloidin, cytochalasin, and Arp2 / 3 complex activators, but is not limited thereto.

[0062] In the present invention, "jasplakinolide" is a cyclic peptide naturally occurring in the marine sponge Jaspis johnstoni, possessing both bactericidal and antiproliferative activities. Jasplakinolide potently mediates actin polymerization and may be a substance that stabilizes existing actin filaments.

[0063] Phalloidin is a peptide toxin isolated from the mushroom Amanita phalloides, and is known to selectively bind to F-actin and stabilize actin polymers by inhibiting the dissociation of actin monomers from filament ends. In one embodiment of the present invention, the anticancer effect enhancing activity of jasplakinolide, the effect of combined administration of anticancer drugs, the effect of anticancer treatment, and in particular, the effect on lung cancer (more preferably lung adenocarcinoma) are disclosed as an example of an actin polymerization agent. In particular, it may be self-evident that any one actin polymerization agent selected from the group consisting of Phalloidin, Cytochalasin, and Arp2 / 3 Complex Activators exhibits the same effect as jasplakinolide, which is a substance that polymerizes actin through the same mechanism as jasplakinolide. However, such substances are not limited to the substances described above, and it may be self-evident that the actin polymerization agent of the present invention, as described above, exhibits an effect equal to or greater than the effect of jasplakinolide disclosed in one embodiment of the present invention.

[0064] In the present invention, jasplakinolide may be greater than 0 and 100 nM, 5 nM and 100 nM, 10 nM and 100 nM, 15 nM and 100 nM, 20 nM and 100 nM, 25 nM and 100 nM, 30 nM and 100 nM, 35 nM and 100 nM, 40 nM and 100 nM, 45 nM and 100 nM, preferably 50 to 100 nM, but is not limited thereto.

[0065] In one embodiment of the present invention, the composition can induce differentiation from AT2 cells (alveolar type 2 cells) into AT1 cells (alveolar type 1 cells), but is not limited thereto.

[0066] In the present invention, it was confirmed that jasplakinolide induces differentiation of AT2 cells into AT1 cells by promoting actin production, and therefore, in the lung cancer cell line treated with jasplakinolide of the present invention, AT2 cells may be decreased and AT1 cells may be increased compared to the lung cancer cell line not treated with jasplakinolide, but is not limited thereto.

[0067] Alveoli are generally composed of two types of cells that perform primary functions: AT1 cells, which are adult cells that mediate gas exchange, and AT2 cells, which secrete surfactant to protect the alveoli and are progenitor cells with stem cell potential that repair damaged epithelial cells. Therefore, of these two types of cells, AT1 cells are adult cells, while AT2 cells are a state of stem cells. The process of AT2 cells differentiating into AT1 cells is a mechanism that generally occurs naturally within lung tissue.

[0068] When lung tissue is damaged by chemicals, external harmful particles, viruses, etc., AT2 cells differentiate into AT1 cells to replace and supplement the cells that make up the damaged area. AT2 cells have stem cell potential and self-renew to perform their function as suppliers to AT1 cells, whereas AT1 cells lose stem cell potential and self-renewable potential as they differentiate to perform their function as components of tissue. When tissue damage occurs and AT1 cells are needed, p53 induces AT2 cells to differentiate into AT1 cells, thereby maintaining overall tissue homeostasis.

[0069] Meanwhile, AT2 cells, a component of lung cancer, rapidly proliferate and enter an intermediate differentiation stage before differentiating into AT1 cells. This metastatic state ultimately generates AT1 cells due to p53. Because AT2 cells and cells in this intermediate differentiation stage proliferate, ultimately leading to cancer tissue proliferation and recurrence, the proliferative capacity of cancer cells is a key variable affecting the effectiveness of anticancer drugs.

[0070] AT1 and AT2 cells differ in their internal structure, a representative example being F-actin. In AT1 cells, actin forms a structure extending from the inside of the cytoplasm to the outside of the nucleus, but in AT2 cells, actin is not observed in the cytoplasm and does not contact the outside of the nucleus. In addition, with regard to contact with actin, the nucleus of AT1 cells, where actin contacts the outside of the nucleus, has an oval shape, whereas the nucleus of AT2 cells, where actin does not contact the outside of the nucleus, has a relatively close to circular shape.

[0071] In the present invention, it was confirmed that jasplakinolide promotes actin production, thereby inducing differentiation of AT2 cells, the primary cancer cell type in lung cancer cell populations, into AT1 cells, thereby reducing the number or activity of cancer cells. Accordingly, in one embodiment of the present invention, the composition may increase sensitivity to anticancer agents, but is not limited thereto.

[0072] The composition according to the present invention (or its active ingredients) can increase sensitivity to anticancer drugs by enhancing their anticancer effects and reducing their side effects. This is because increasing sensitivity to anticancer drugs through appropriate combination therapy can minimize the dosage of anticancer drugs with side effects.

[0073] Here, “enhancing anticancer effects” refers to all effects that can ultimately strengthen the function of anticancer drugs, including not only enhancing the anticancer effects of anticancer drugs such as suppressing tumor growth, suppressing tumor metastasis, and suppressing tumor recurrence, but also inhibiting the formation of resistance or tolerance in cancer cells to anticancer drugs, thereby ultimately enhancing the anticancer effect. Furthermore, it can be the broadest concept to include increasing the sensitivity of anticancer drugs, thereby manifesting or strengthening the function of the aforementioned anticancer drugs by pretreatment with a small dose of the anticancer drug or the same anticancer drug to an individual who has already developed resistance.

[0074] Meanwhile, chemotherapy is the most common treatment for malignant tumors, primarily utilizing anticancer drugs. These drugs act directly on cancer cell DNA, blocking replication, transcription, and translation processes, or inhibiting cell division, thereby inhibiting proliferation. Currently, anticancer drugs used in cancer treatment are broadly categorized into alkylating agents, antimetabolites, antibiotics, mitotic inhibitors, hormones, and other agents. Currently, approximately 60 different anticancer drugs are in use.

[0075] In one embodiment of the present invention, the anticancer agent may be, but is not limited to, a mitotic inhibitor or an EGFR inhibitor.

[0076] In one embodiment of the present invention, the mitotic inhibitor may be any one selected from the group consisting of cisplatin, doxorubicib, 5-FU (5-flurouracil), dactinomycin, and docetaxel, but is not limited thereto.

[0077] In one embodiment of the present invention, the EGFR inhibitor may be any one selected from the group consisting of erlotinib, gefitinib, lapatinib, vadetanib, neratinib, osimertinib, cetuximab, pantimumab, and necitumumab, but is not limited thereto.

[0078] In one embodiment of the present invention, the cancer may be any one selected from the group consisting of adenocarcinoma, squamous cell lung cancer, large cell lung cancer, and small cell lung cancer, and preferably adenocarcinoma, but is not limited thereto.

[0079] In one embodiment of the present invention, the composition can reduce at least one of the number of cancer cells or the activity of cancer cells, but is not limited thereto.

[0080] In one embodiment of the present invention, the composition can reduce the expression of one or more markers selected from the group consisting of, but not limited to, the following in a lung cancer cell population:

[0081] a) AT1 cell transformation-related marker TP53; and

[0082] b) Cancer cell marker NKX2-1.

[0083] In the present invention, the "TP53" gene encodes the tumor protein p53 (or p53). p53 not only regulates cell division by preventing cells from growing and dividing (proliferating) too quickly or in an uncontrolled manner, but is also known as a marker essential for the final differentiation stage into AT1 cells.

[0084] In the present invention, the “NKX2-1” gene translates the homeobox protein Nkx-2.1, a member of the homeobox protein family. Homeobox proteins function as transcription factors, which can bind to DNA and control the activity (expression) of other genes. The homeobox protein Nkx-2.1 is involved in the development and function of the brain, lungs, and thyroid gland, and in particular, it is known to regulate the expression of surfactant genes, which regulate the development of lung structures in the lungs and provide instructions for the production of surfactant proteins, as well as to form surfactant, which, together with certain fats, envelops lung tissue and facilitates breathing.

[0085] In one embodiment of the present invention, the composition may be formulated separately with the anticancer agent and administered sequentially, but is not limited thereto.

[0086] In the present invention, a composition containing an actin polymerization agent as an active ingredient is characterized in that it is administered before an anticancer agent, i.e., before administration of an anticancer agent, to induce differentiation of AT2 cells into AT1 cells, thereby increasing the sensitivity of the anticancer agent and enhancing the anticancer effect of the anticancer agent. In one embodiment of the present invention, the composition may be administered before the anticancer agent, but is not limited thereto.

[0087]

[0088] The present invention provides a pharmaceutical composition for combined administration with an anticancer agent, comprising an actin polymerization agent as an active ingredient.

[0089] In the present invention, "combination administration" can be achieved by sequentially and individually administering the individual components of the treatment regimen. It is a method of obtaining a combined therapeutic effect by sequentially administering two or more drugs, or alternately administering them at regular or indefinite intervals, and combination therapy is not limited thereto, but can be defined as a combination therapy that provides a synergistic effect while being therapeutically superior to the efficacy obtained by administering one or the remaining components of the combination therapy at a regular dose, as measured by, for example, the degree of response, the rate of response, the period until disease progression, or the duration of survival.

[0090] When the composition of the present invention is administered first, and after a period of differentiation of AT2 cells, the main cell population of lung cancer cell populations, into AT1 cells, an anticancer agent is administered, the sensitivity of the anticancer agent can be significantly increased. Since the anticancer effect can be maximized when administered in combination with an anticancer agent through this mechanism, in one embodiment of the present invention, the composition may be formulated separately with the anticancer agent and administered sequentially, but is not limited thereto.

[0091] In one embodiment of the present invention, the composition may be administered before the anticancer agent, but is not limited thereto.

[0092] The composition of the present invention may be preferably administered prior to the anticancer agent, so that AT2 cells are sufficiently differentiated into AT1 cells, and then the anticancer agent is administered. In the present invention, it was confirmed that when pretreatment with jasplakinolide was performed for 1 to 7 days to induce differentiation into AT1 cells, and then the anticancer agent was administered, the anticancer activity enhancement effect of the anticancer agent was excellent. Preferably, the composition of the present invention may be administered 3 to 7 days later, but is not limited thereto.

[0093] That is, when the pharmaceutical composition is a pharmaceutical composition for combination administration for sequential administration to exhibit a synergistic effect with an anticancer agent, the composition may be such that the composition containing the actin polymerization agent as an active ingredient (“first component”) is administered first and then the anticancer agent (“second component”) is administered, and the reverse order is also possible.

[0094] The actin polymerization agent of the present invention can enhance the efficacy of anticancer agents by changing the composition of lung cancer cells and slowing the growth of alveolar cells. Therefore, in one embodiment of the present invention, the actin polymerization agent was treated simultaneously with the anticancer agent, but this was to confirm the anticancer effect-enhancing activity of the anticancer agent in a state where differentiation into AT1 cells was already induced, alveolar growth was slowed, and the number and activity of lung cancer cells were reduced. Even if the actin polymerization agent was not treated simultaneously, it is clear that the anticancer effect-enhancing activity of the anticancer agent is the same because AT1 cells do not revert back to AT2 cells.

[0095]

[0096] The present invention provides a pharmaceutical composition for preventing or treating cancer, comprising an actin polymerization agent as an active ingredient.

[0097] In the present invention, it was confirmed that treatment with the actin polymerization agent jasplakinolide induced differentiation of AT2 cells, the primary cells of lung cancer cell colonies, into AT1 cells. This effect was confirmed by the change in cell morphology of the lung cancer cell colonies into a morphology characteristic of AT1 cells. Furthermore, this induction of differentiation into AT1 cells can reduce the number and cell activity of AT2 lung cancer cells, thereby producing an anticancer effect.

[0098] In one embodiment of the present invention, the composition may be characterized by at least one selected from the group consisting of, but not limited to:

[0099] a) Change the morphology of cancer cell clusters into the form of wide and flat AT1 cells, induce actin arrangement, and increase cell size;

[0100] b) induce and increase the expression of podoplanin (PDPN), an AT1 cell-specific marker, in cancer cell populations; and

[0101] c) Reduces the cell proliferation rate of cancer cell populations.

[0102] In one embodiment of the present invention, the composition may additionally include an anticancer agent, but is not limited thereto.

[0103] In the present invention, "podoplanin" is a protein that is known to function as a marker of lung damage in lung alveolar cells, renal podocytes, and lymphatic endothelial cells. In the present invention, it was observed that the AT1 cell marker, a unique marker, increased in lung cancer cell populations as AT2 cells were induced to differentiate into AT1 cells by treatment with the composition of the present invention.

[0104] The composition according to the present invention exhibits excellent anticancer effects, and thus can be used as a substance for combination administration with known anticancer agents for the purpose of generating a synergistic effect with the anticancer agent. That is, the composition of the present invention can be used for combination administration with an anticancer agent, thereby enhancing the anticancer effect of the anticancer agent.

[0105] The pharmaceutical composition according to the present invention may be formulated and used in the form of external preparations such as powders, granules, sustained-release granules, enteric-coated granules, liquids, eye drops, ellipsoids, emulsions, suspensions, alcohols, troches, aromatic waters, limonades, tablets, sustained-release tablets, enteric-coated tablets, sublingual tablets, hard capsules, soft capsules, sustained-release capsules, enteric capsules, pills, tinctures, soft extracts, dry extracts, fluid extracts, injections, capsules, irrigation solutions, ointments, lotions, pastes, sprays, inhalants, patches, sterile injection solutions, or aerosols, according to a conventional method, and the external preparations may have formulations such as creams, gels, patches, sprays, ointments, ointments, lotions, liniments, pastes, or cataplasmas.

[0106] Carriers, excipients and diluents that may be included in the pharmaceutical composition according to the present invention include lactose, dextrose, sucrose, oligosaccharides, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil.

[0107] When formulating, it is usually prepared using diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrants, and surfactants.

[0108] The additives of the tablets, powders, granules, capsules, pills, and troches according to the present invention include excipients such as corn starch, potato starch, wheat starch, lactose, sucrose, glucose, fructose, D-mannitol, precipitated calcium carbonate, synthetic aluminum silicate, calcium hydrogen phosphate, calcium sulfate, sodium chloride, sodium bicarbonate, purified lanolin, microcrystalline cellulose, dextrin, sodium alginate, methylcellulose, sodium carboxymethylcellulose, kaolin, urea, colloidal silica gel, hydroxypropyl starch, hydroxypropyl methylcellulose (HPMC), HPMC 1928, HPMC 2208, HPMC 2906, HPMC 2910, propylene glycol, casein, calcium lactate, and Primogel; Gelatin, gum arabic, ethanol, agar powder, cellulose acetate phthalate, carboxymethylcellulose, calcium carboxymethylcellulose, glucose, purified water, sodium caseinate, glycerin, stearic acid, sodium carboxymethylcellulose, sodium methylcellulose, methylcellulose, microcrystalline cellulose, dextrin, hydroxycellulose, hydroxypropyl starch, hydroxymethylcellulose, refined shellac, starch starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, polyvinyl pyrrolidone, and binders such as hydroxypropyl methylcellulose, corn starch, agar powder, methylcellulose, bentonite, hydroxypropyl starch, sodium carboxymethylcellulose, sodium alginate, Disintegrants such as carboxymethylcellulose calcium, calcium citrate, sodium lauryl sulfate, anhydrous silicic acid, 1-hydroxypropyl cellulose, dextran, ion exchange resin, polyvinyl acetate, formaldehyde-treated casein and gelatin, alginic acid, amylose, guar gum, baking soda, polyvinylpyrrolidone, calcium phosphate, gelled starch, gum arabic, amylopectin, pectin, sodium polyphosphate, ethylcellulose, sucrose, magnesium aluminum silicate, di-sorbitol solution, and light anhydrous silicic acid;Lubricants such as calcium stearate, magnesium stearate, stearic acid, hydrogenated vegetable oil, talc, lycopodium dentata, kaolin, petrolatum, sodium stearate, cacao butter, sodium salicylate, magnesium salicylate, polyethylene glycol (PEG) 4000, PEG 6000, liquid paraffin, hydrogenated soybean oil (Lubri wax), aluminum stearate, zinc stearate, sodium lauryl sulfate, magnesium oxide, macrogol, synthetic aluminum silicate, anhydrous silicic acid, higher fatty acids, higher alcohols, silicone oil, paraffin oil, polyethylene glycol fatty acid ether, starch, sodium chloride, sodium acetate, sodium oleate, dl-leucine, and light anhydrous silicic acid can be used.;

[0109] As additives of the liquid formulation according to the present invention, water, dilute hydrochloric acid, dilute sulfuric acid, sodium citrate, monostearate sucrose, polyoxyethylene sorbitol fatty acid esters (twin esters), polyoxyethylene monoalkyl ethers, lanolin ethers, lanolin esters, acetic acid, hydrochloric acid, ammonia water, ammonium carbonate, potassium hydroxide, sodium hydroxide, prolamine, polyvinylpyrrolidone, ethylcellulose, sodium carboxymethylcellulose, etc. can be used.

[0110] The syrup according to the present invention may include a solution of white sugar, other sugars, or sweeteners, and may also include a fragrance, a coloring agent, a preservative, a stabilizer, a suspending agent, an emulsifier, a viscosity modifier, and the like, as needed.

[0111] Purified water may be used in the emulsion according to the present invention, and emulsifiers, preservatives, stabilizers, fragrances, etc. may be used as needed.

[0112] The suspension according to the present invention may include suspending agents such as acacia, tragacanth, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, sodium alginate, hydroxypropylmethylcellulose (HPMC), HPMC 1828, HPMC 2906, and HPMC 2910, and surfactants, preservatives, stabilizers, colorants, and fragrances may be used as needed.

[0113] The injection according to the present invention includes a solvent such as distilled water for injection, 0.9% sodium chloride injection, Ringer's injection, dextrose injection, dextrose + sodium chloride injection, PEG, lactated Ringer's injection, ethanol, propylene glycol, non-volatile oils - sesame oil, cottonseed oil, peanut oil, soybean oil, corn oil, ethyl oleate, isopropyl myristate, and benzene benzoate; a solubilizing agent such as sodium benzoate, sodium salicylate, sodium acetate, urea, urethane, monoethylacetamide, butazolidine, propylene glycol, tween, nitrile acid amide, hexamine, and dimethylacetamide; a buffer such as weak acids and their salts (acetic acid and sodium acetate), weak bases and their salts (ammonia and ammonium acetate), organic compounds, proteins, albumin, peptone, and gums; It may include isotonic agents such as sodium chloride; stabilizers such as sodium bisulfite (NaHSO3), carbon dioxide gas, sodium metabisulfite (Na2S2O5), sodium sulfite (Na2SO3), nitrogen gas (N2), and ethylenediaminetetraacetic acid; oxidizing agents such as sodium bisulfite 0.1%, sodium formaldehyde sulfoxylate, thiourea, disodium ethylenediaminetetraacetic acid, and acetone sodium bisulfite; analgesics such as benzyl alcohol, chlorobutanol, procaine hydrochloride, glucose, and calcium gluconate; and suspending agents such as sodium cis-methylenediamine, sodium alginate, Tween 80, and aluminum monostearate.

[0114] The suppository according to the present invention comprises cocoa butter, lanolin, withepsol, polyethylene glycol, glycerogelatin, methylcellulose, carboxymethylcellulose, a mixture of stearic acid and oleic acid, Subanal, cottonseed oil, peanut oil, palm oil, cocoa butter + cholesterol, lecithin, ranet wax, glycerol monostearate, Tween or Span, Imhausen, monolene (propylene glycol monostearate), glycerin, Adeps solidus, Buytyrum Tego-G, Cebes Pharma 16, hexalide base 95, Cotomar, Hydroxocote SP, S-70-XXA, S-70-XX75 (S-70-XX95), Mechanisms such as Hydrokote 25, Hydrokote 711, Idropostal, Massa estrarium (A, AS, B, C, D, E, I, T), Massa-MF, Masupol, Masupol-15, Neosupostal-N, Paramound-B, Suposiro (OSI, OSIX, A, B, C, D, H, L), Suppository type IV (AB, B, A, BC, BBG, E, BGF, C, D, 299), Supostal (N, Es), Wecovi (W, R, S, M, Fs), and Tezester triglyceride basis (TG-95, MA, 57) can be used.

[0115] Solid dosage forms for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid dosage forms are prepared by mixing the extract with at least one excipient, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used.

[0116] Liquid preparations for oral administration include suspensions, solutions, emulsions, and syrups. In addition to commonly used simple diluents such as water and liquid paraffin, they may contain various excipients such as wetting agents, sweeteners, flavoring agents, and preservatives. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solvents and suspensions can include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.

[0117] The pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment. The effective dosage level can be determined based on factors including the type and severity of the patient's disease, drug activity, drug sensitivity, administration time, administration route and excretion rate, treatment period, concurrently used drugs, and other factors well known in the medical field.

[0118] The pharmaceutical composition according to the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents. It can be administered sequentially or simultaneously with conventional therapeutic agents, or in single or multiple doses. Taking all of the above factors into account, it is important to administer an amount that achieves maximum efficacy with minimal side effects. This amount can be readily determined by those skilled in the art to which the present invention pertains.

[0119] The pharmaceutical composition of the present invention can be administered to a subject via various routes. All modes of administration are conceivable, including oral ingestion, subcutaneous injection, intraperitoneal administration, intravenous injection, intramuscular injection, intrathecal injection, sublingual administration, buccal mucosal administration, rectal insertion, vaginal insertion, ocular administration, otic administration, nasal administration, inhalation, oral or nasal spraying, dermal administration, and transdermal administration.

[0120] The pharmaceutical composition of the present invention is determined according to the type of drug as an active ingredient along with various related factors such as the disease to be treated, route of administration, age, sex, weight, and severity of the disease of the patient.

[0121] In the present invention, “subject” means a subject requiring treatment for a disease, and more specifically, a mammal such as a human or non-human primate, mouse, rat, dog, cat, horse, and cow.

[0122] In the present invention, “administration” means providing a predetermined composition of the present invention to a subject by any appropriate method.

[0123] In the present invention, “prevention” means any action that suppresses or delays the onset of a target disease, “treatment” means any action that improves or beneficially changes a target disease and its metabolic abnormality symptoms by administering a pharmaceutical composition according to the present invention, and “improvement” means any action that reduces a parameter related to a target disease, for example, the severity of a symptom, by administering a composition according to the present invention.

[0124]

[0125] The present invention provides a kit for enhancing the anticancer effect of an anticancer agent, including an actin polymerization agent and an instruction manual.

[0126] The present invention provides a kit for combination administration of an anticancer agent or a kit for preventing or treating cancer, comprising an actin polymerization agent and an instruction manual.

[0127] In the present invention, the "kit" refers to a tool that uses the actin polymerization agent of the present invention to enhance the anticancer effect of an anticancer agent, administer the agent in combination with an anticancer agent, or prevent or treat cancer. In addition to the above-mentioned substances, the kit of the present invention may include other components, compositions, solutions, devices, etc. that are typically required for methods of storing and processing them. As a specific example, each component may be applied at least once without limitation in the number of times, there is no limitation on the order in which each substance is applied, and the application of each substance may be performed simultaneously or microscopically.

[0128] In the present invention, the kit may include a container; instructions; and the like. The container may serve to package the substance, and may also serve to store and fix the substance. The material of the container may take the form of, for example, a bottle, a tub, a sachet, an envelope, a tube, an ampoule, and the like, and these may be formed partially or wholly from plastic, glass, paper, foil, wax, and the like. The container may be initially equipped with a completely or partially detachable stopper, which may be part of the container or may be attached to the container by mechanical, adhesive, or other means, and may also be equipped with a stopper for allowing access to the contents by means of a syringe needle. The kit may include an outer package, and the outer package may include instructions for the use of the components.

[0129] Hereinafter, preferred examples are presented to aid in understanding the present invention. However, the following examples are provided solely to facilitate a better understanding of the present invention, and the scope of the present invention is not limited by the following examples.

[0130]

[0131] [Example]

[0132]

[0133] Culture of A549 cells

[0134] A549 (CCL-185) cells were cultured in a 5% CO2, 37°C incubator using Advanced DMEM / F-12 (ThermoFisher Scientific, 12634-010) supplemented with 10% (v / v) FBS and 100 U / mL Penicillin-Streptomycin (ThermoFisher Scientific, 15140122). Cell suspensions were prepared using 0.25% Trypsin-EDTA (ThermoFisher Scientific, 25200-056) and cells were maintained in culture or prepared for testing. For assays using cisplatin, erlotinib, and jasplakinolide, A549 cells were cultured in 96-well plates (SPL Life Sciences, 30096).

[0135]

[0136] Preparation of jasplakinolide and anticancer agents

[0137] Jasplakinolide (Invitrogen, J7437) was prepared as a 1 mM solution using dimethyl sulfoxide (Sigma-Aldrich, D2650) and stored at -80°C.

[0138] Cisplatin (TOCRIS, 2251) was prepared as a 4 mM solution using sterile ddH2O and stored at room temperature. Erlotinib (Aigma-Aldrich, SML2156) was prepared as a 4 mM solution using dimethyl sulfoxide and stored at -20°C.

[0139]

[0140] Measurement of cell activity

[0141] Cell activity measurements used to compare cell growth rates and confirm the efficacy of anticancer drugs were measured at absorbance at 490 nm using CellTiter 96 AQueous One Solution Cell Proliferation Assay (MTS) (Promega, G3582) and PowerWave XS (BIO-TEK).

[0142]

[0143] Immunofluorescence staining

[0144] After removing the medium and washing with PBS (Phosphate Buffered Saline), the cells were fixed with 4% PFA (paraformaldehyde) for 20 minutes at room temperature. After fixation, the cells were washed three times with PBS and treated with 0.1% Triton X-100 (Biosesang, TR1020-500-00) for 15 minutes at room temperature. After washing with PBS, the sections were blocked with 5% normal goat serum (Vector Laboratories, Inc, S-1000) at room temperature for 1 hour and then treated with the following primary antibodies at 4°C overnight: Podoplanin (1:200, ThermoFisher, MA1-83884), SFTPC (1:100, ThermoFisher Scientific, PA5-102493), TP53 (1:100, Abclonal, A3185), NKX2-1 (1:100, Abclonal, A3292). After washing with PBS, the sections were treated with the following secondary antibodies at room temperature for 1 hour: goat anti-rabbit IgG 488 (1:1000, Invitrogen, A-11008), goat anti-mouse IgG 594 (1:1000, Invitrogen, A-11005). After washing with PBS for 15 minutes at room temperature, the cells were stained with DAPI (Invitrogen, D1306) for 2 minutes at room temperature. Actin staining was performed in the same manner as above, but instead of the antibody, Alexa Fluor 594 Phalloidin (1:400, Invitrogen, A12381) was treated at room temperature for 1 hour, followed by PBS washing and DAPI staining. After staining, the cells were replaced with PBS, and images were taken using Carl Zeiss LSM800 and LSM900 confocal microscopes (Carl Zeiss).

[0145]

[0146] Statistical analysis

[0147] All statistical analyses were performed using GraphPad Prism 8 (GraphPad Software Inc., San Diego, CA, USA) and Microsoft Excel. The bars in each group represent standard deviations, and a two-way ANOVA was used to determine statistical significance. The α value was set to 0.05. The symbols indicating p-values ​​are as follows: *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.

[0148]

[0149] Example 1. Establishment of treatment conditions for anticancer drugs cisplatin and erlotinib and actin polymerization agent jasplakinolide on lung cancer cell lines.

[0150] Example 1-1. Establishment of treatment conditions for anticancer drugs cisplatin and erlotinib against lung cancer cell lines.

[0151] Experiments were conducted to determine the treatment conditions for the anticancer drugs cisplatin and erlotinib on lung cancer cell lines. The experiments included observing the cell death effect and analyzing the activity of surviving cells at various concentrations. Specifically, the A549 lung cancer cell line was prepared and treated with cisplatin and erlotinib at concentrations of 100 nM, 300 nM, 500 nM, 1 μM, 5 μM, 10 μM, 100 μM, and 200 μM, respectively, to determine the anticancer activity.

[0152]

[0153] As a result (cisplatin - Figure 2a, erlotinib - Figure 2b), it was confirmed that both anticancer drugs caused A549 cell death in a concentration-dependent manner.

[0154] Additionally, when the same cell line was treated with cisplatin and erlotinib, the activity of surviving cells was confirmed as shown in Figures 2c and 2d, respectively.

[0155]

[0156] Example 1-2. Establishment of treatment conditions for jasplakinolide, an actin polymerization agent, in lung cancer cell lines.

[0157] Experiments were conducted to determine the treatment conditions for the actin polymerization agent jasplakinolide on lung cancer cell lines. The cell death effect was analyzed when jasplakinolide was treated at concentrations of 50 nM, 100 nM, 500 nM, 1 μM, and 5 μM.

[0158]

[0159] As a result (Fig. 2e), when treated with 100 nM jasplakinolide, the A549 cell line did not die, but cell death caused by jasplakinolide was observed at 500 nM or higher. Accordingly, 50 nM and 100 nM jasplakinolide were used in the following experiments.

[0160]

[0161] Example 2. Confirmation of AT1 cell differentiation activity following jasplakinolide treatment.

[0162] Since lung cancer cells are composed primarily of AT2 cells among alveolar cells, we investigated whether treatment with jasplakinolide would alter the composition of lung cancer cell lines by differentiating AT2 cells into AT1 cells. First, we confirmed the increase in AT1 cells due to jasplakinolide, which promotes actin production, through morphological analysis. Furthermore, for further confirmation, we analyzed changes in expression markers and cell growth rates.

[0163]

[0164] First (Fig. 3a), in the A549 cell colony treated with jasplakinolide, cells with a wide, flat shape, characteristic of AT1 cells, were observed, unlike the small, cuboidal cells characteristic of AT2 cells, which are the original composition. In addition, the actin arrangement characteristic of AT1 cells was also observed in the lung cancer cell line. In addition, it was confirmed that the higher the concentration of jasplakinolide, the more cells with these AT1 cell-specific properties were observed, and the size of each cell was also formed larger.

[0165]

[0166] In addition (Fig. 3b), we observed changes in expression markers within the A549 cell population treated with jasplakinolide. The A549 cell line is originally an AT2 cell line, so it expresses the AT2 marker protein SFTPC, but when treated with jasplakinolide, it was confirmed that the AT1 cell marker protein podoplanin (PDPN) was expressed. Therefore, it was confirmed that jasplakinolide not only induces morphological changes similar to AT1 cells by promoting actin production in AT2 cells, but also induces the expression of AT1 cell-specific marker proteins.

[0167]

[0168] Finally (Fig. 3c), the cell proliferation rate of lung cancer cells treated with jasplakinolide was analyzed to confirm the differentiation activity into AT1 cells, which is accompanied by a decrease in AT2 cells exhibiting stem cell potential and self-renewal capacity. As a result, it was confirmed that the overall cell proliferation rate of lung adenocarcinoma cell populations induced by jasplakinolide treatment was slowed down by promoting actin production and inducing conversion to AT1 cells.

[0169]

[0170] These results suggest that the actin polymerization agent jasplakinolide promotes actin production, thereby converting AT2 cells into AT1 cells, thereby reducing lung cancer cells and resulting in an anticancer effect.

[0171]

[0172] Example 3. Confirmation of enhanced anticancer effect of anticancer drug after 3 days of differentiation into AT1 cells following jasplakinolide treatment.

[0173] According to the experimental protocol of Figure 4, it was confirmed whether the anticancer effect of the anticancer drug was enhanced when differentiation into AT1 cells was induced for 3 days by administering jasplakinolide before anticancer drug treatment.

[0174]

[0175] Example 3-1. Confirmation of a decrease in the number of lung adenocarcinoma cells

[0176] According to Figure 4, lung adenocarcinoma cells that were induced to differentiate into AT1 cells by treatment with jasplakinolide for 3 days were treated with the anticancer drugs cisplatin and erlotinib together with jasplakinolide. Each anticancer drug was treated for 1 day.

[0177]

[0178] As a result (Fig. 5a), it was confirmed that the number of lung cancer cells in the group pre-treated with jasplakinolide was significantly reduced compared to the group treated with only the anticancer drug, and this reduction effect was found to be independent of the type of anticancer drug.

[0179]

[0180] Example 3-2. Confirmation of the effect of reducing lung adenocarcinoma cell activity.

[0181] The anticancer activity of the anticancer agent was measured against the same lung adenocarcinoma cell line as in Example 3-1. The anticancer activity was measured by the cell death effect, and the cell death effect was analyzed by cell viability assay using CellTiter 96 AQueous One Solution Cell Proliferation Assay (MTS).

[0182]

[0183] As a result (Fig. 5b), compared to the case treated with only an anticancer drug, when jasplakinolide was pretreated, differentiation into AT1 cells was induced by actin amplification, resulting in a 30% decrease in cell activity. This remarkable increase in anticancer activity was confirmed to be statistically significant. In particular, in the case of erlotinib, a significant level of effect was observed across the entire concentration range, confirming that an excellent anticancer activity enhancement effect could be achieved with only a 3-day differentiation induction period into AT1 cells.

[0184]

[0185] Example 4. Confirmation of the anticancer activity enhancement effect of anticancer drugs after 7 days of differentiation into AT1 cells following jasplakinolide treatment.

[0186] When AT1 cell differentiation was induced for 7 days by administering jasplakinolide before anticancer treatment according to the experimental protocol of Fig. 6a, the anticancer activity enhancement effect of the anticancer drug was confirmed.

[0187]

[0188] Example 4-1. Confirmation of a decrease in the number of lung adenocarcinoma cells

[0189] According to Fig. 6a, AT1 cell differentiation was induced by treatment with jasplakinolide for 7 days, and the anticancer drugs cisplatin and erlotinib were each treated together with jasplakinolide. Each anticancer drug was treated for 2 days.

[0190]

[0191] As a result (Fig. 6b), the number of lung cancer cells in the group pretreated with jasplakinolide was significantly reduced compared to the group treated with only the anticancer agent in both cases of cisplatin and erlotinib treatment, and it was confirmed that this result corresponds to the experimental result of Example 3-1.

[0192]

[0193] Example 4-2. Confirmation of decreased lung adenocarcinoma cell activity

[0194] The anticancer activity of the anticancer agent was measured against lung adenocarcinoma cell lines using the same method as in Example 3-2. The anticancer activity was measured by the cell death effect, and the cell death effect was measured by cell viability assay using CellTiter 96 AQueous One Solution Cell Proliferation Assay (MTS).

[0195]

[0196] As a result (Fig. 6c), compared to the cases treated with cisplatin and erlotinib, respectively, the activity of lung adenocarcinoma cells was reduced by approximately 40% and 60% when pretreated with jasplakinolide, respectively, indicating a significant increase in anticancer activity, which was confirmed to be statistically significant. In particular, when the differentiation induction period into AT1 cells was set from 3 to 7 days, the anticancer activity enhancement effect was further amplified, confirming that the anticancer activity enhancement effect was affected by the AT1 cell differentiation period by jasplakinolide and was proportional to the treatment period of jasplakinolide.

[0197]

[0198] Example 4-3. Checking marker changes

[0199] Marker expression changes were analyzed for the same lung adenocarcinoma cell line as in Example 4-1.

[0200]

[0201] As a result (Fig. 6d), when cisplatin and erlotinib were treated alone, TP53, a major marker associated with AT1 cell transformation, and NKX2-1, a cancer cell marker, were found to be highly expressed. On the other hand, when jasplakinolide was treated before anticancer drug administration, which resulted in high efficiency death of lung adenocarcinoma cells, the expression levels of both TP53 and NKX2-1 were found to be significantly reduced.

[0202]

[0203] The foregoing description of the present invention is provided for illustrative purposes only. Those skilled in the art will readily appreciate that the present invention can be readily modified into other specific forms without altering the technical spirit or essential characteristics of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive.

[0204] According to a pharmaceutical composition for enhancing the anticancer effect of an anticancer agent containing an actin polymerization agent as an active ingredient, the composition exhibits an anticancer effect by inducing differentiation of AT2 cells, which are the main cells of a lung cancer cell population, into AT1 cells, thereby reducing the number and cell activity of lung cancer cells. In addition, it was confirmed that when the actin polymerization agent was pretreated to induce differentiation into AT1 cells and then the anticancer agent was treated, the sensitivity of the anticancer agent significantly increased. Therefore, the present invention can be usefully utilized as an excellent lung cancer treatment agent or a composition for enhancing the anticancer activity of an anticancer agent for lung cancer, and its industrial applicability is recognized.

Claims

1. A pharmaceutical composition for enhancing the anticancer effect of an anticancer agent, comprising an actin polymerization agent as an active ingredient.

2. In paragraph 1, A pharmaceutical composition, wherein the actin polymerization agent is any one selected from the group consisting of jasplakinolide, phalloidin, cytochalasin, and Arp2 / 3 complex activators.

3. In paragraph 1, A pharmaceutical composition that induces differentiation from AT2 cells (alveolar type 2 cells) into AT1 cells (alveolar type 1 cells).

4. In paragraph 1, A pharmaceutical composition, wherein the composition increases the sensitivity of an anticancer agent.

5. In paragraph 1, A pharmaceutical composition wherein the anticancer agent is a mitotic inhibitor or an EGFR inhibitor.

6. In paragraph 5, A pharmaceutical composition, wherein the above-mentioned mitotic inhibitor is any one selected from the group consisting of cisplatin, doxorubicib, 5-FU (5-flurouracil), dactinomycin, and docetaxel.

7. In paragraph 5, A pharmaceutical composition, wherein the EGFR inhibitor is any one selected from the group consisting of erlotinib, gefitinib, lapatinib, vadetanib, neratinib, osimertinib, cetuximab, pantimumab, and necitumumab.

8. In paragraph 1, A pharmaceutical composition, wherein the cancer is any one selected from the group consisting of adenocarcinoma, squamous cell lung cancer, large cell lung cancer, and small cell lung cancer.

9. In paragraph 1, A pharmaceutical composition, wherein the composition reduces at least one of the number or activity of cancer cells.

10. In paragraph 1, A pharmaceutical composition, wherein the composition reduces the expression of one or more markers selected from the group consisting of: a) AT1 cell transformation-related marker TP53; and b) Cancer cell marker NKX2-1.

11. In paragraph 1, A pharmaceutical composition wherein the above composition is formulated separately with the above anticancer agent and administered sequentially.

12. In paragraph 11, A pharmaceutical composition, wherein the composition is administered before the anticancer agent.

13. A pharmaceutical composition for combined administration with an anticancer agent, comprising an actin polymerization agent as an active ingredient.

14. In paragraph 13, A pharmaceutical composition wherein the above composition is formulated separately with the above anticancer agent and administered sequentially.

15. In paragraph 14, A pharmaceutical composition, wherein the composition is administered before the anticancer agent.

16. A pharmaceutical composition for preventing or treating cancer, comprising an actin polymerization agent as an active ingredient.

17. In paragraph 16, A pharmaceutical composition characterized in that the composition comprises at least one selected from the group consisting of: a) Change the morphology of cancer cell clusters into the form of wide and flat AT1 cells, induce actin arrangement, and increase cell size; b) induce and increase the expression of podoplanin (PDPN), an AT1 cell-specific marker, in cancer cell populations; and c) Reduces the cell proliferation rate of cancer cell populations.

18. In paragraph 16, A pharmaceutical composition, wherein the composition further comprises an anticancer agent.

19. A kit for enhancing the anticancer effect of an anticancer agent, including an actin polymerization agent and an instruction manual.

20. A method for enhancing anticancer effect, a method for administering anticancer drugs in combination, or a method for preventing or treating cancer, comprising a step of administering a pharmaceutically effective amount of a composition containing an actin polymerization agent as an active ingredient to a subject in need thereof.

21. Use of a composition containing an actin polymerization agent as an active ingredient for enhancing the anticancer effect, use of combined administration with an anticancer agent, or use of preventing or treating cancer.

22. A composition comprising an actin polymerization agent as an active ingredient for manufacturing a preparation for enhancing anticancer effect, a preparation for combined administration of anticancer drugs, or a preparation for preventing or treating cancer.

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