KR20230043064A - Pharmaceutical Composition for Preventing or Treating Cancer Comprising Carnitine Acylcarnitine Carrier Inhibitor and Antitumor Agent - Google Patents

Abstract

The present invention relates to a pharmaceutical composition comprising a carnitine acylcarnitine carrier (CAC) inhibitor and an anticancer agent for preventing or treating cancer, and an anticancer adjuvant. The composition comprising a CAC inhibitor and an anticancer agent according to the present invention significantly reduced the growth of various cancer cells, compared to the single use of the CAC inhibitor or the anticancer agent and it was found that the combined administration of the CAC inhibitor and the anticancer agent had a synergic effect against cancer in a xenografted tumor animal model. Accordingly, the composition can be advantageously utilized as an effective combinational anticancer agent.

Description

Pharmaceutical Composition for Preventing or Treating Cancer Comprising Carnitine Acylcarnitine Carrier Inhibitor and Antitumor Agent}

The present invention relates to a pharmaceutical composition for preventing or treating cancer, including a carnitine acylcarnitine carrier (CAC) inhibitor and an anticancer agent, and to an anticancer adjuvant.

While normal cells can perform regular and elastic proliferation and suppression as needed, cancer cells proliferate indefinitely, which is also called a tumor as a cell mass composed of undifferentiated cells. These cancer cells infiltrate surrounding tissues and metastasize to other organs in the body, causing severe pain and eventually death. Despite advances in medicine, the number of cancer patients in Korea has continuously increased, increasing by about 44% over the past 10 years, and the anticancer drug market has also increased internationally, and has been reported to have a scale of about 100 billion dollars per year. .

Anticancer agents include chemical anticancer agents, which are first-generation anticancer agents, and targeted anticancer agents, which are second-generation anticancer agents. However, the biggest problem in current cancer treatment is the recurrence of cancer, because cancer mutations are diverse, making it difficult to target a specific cancer. Because the cases are unusual. Eventually, most patients die due to metastasis and recurrent cancer even after treatment of the primary cancer. Accordingly, in order to enhance the effect of anticancer agents, a strategy of combining anticancer agents for combined treatment has been proposed.

Metabolic anti-cancer drugs are often referred to as 'curing agents that starve cancer cells' because they inhibit the metabolic process in which cancer cells use energy. Metabolic anti-cancer agents can suppress cancer by targeting cancer cell-specific mitochondrial metabolism, metabolic vulnerability of cancer cells, and energy utilization processes of cancer cells in a state of nutritional deficiency. In addition, at a time when anticancer treatment is experiencing difficulties due to tumor mutation and resistance acquisition, metabolic anticancer drugs that target cancer cell energy metabolism show new possibilities to solve the problem of anticancer drug resistance and cancer recurrence, and overcome anticancer drug resistance. Because of the advantages that can be done, it is proposed that metabolic cancer drugs will show the highest efficiency in combination therapy with other anticancer drugs (Alba Luengo et al ., Cell Chem Biol ., 24(9): 1161-1180, 2017).

On the other hand, omeprazole, a carnitine acylcarnitine carrier (CAC) inhibitor, is a proton-pump inhibitor and is known to be effective in treating gastroesophageal reflux disease, peptic ulcer, erosive esophagitis or eosinophilic esophagitis . Recently, studies have shown that proton pump inhibitors, including omeprazole, inhibit Fatty Acid Synthase (FASN) activity, which helps produce fatty acids, which are the key to cancer cell survival, and induce cancer cell death while minimizing the effects on non-cancer cells. has been published (Walsh et al. , Journal of Experimental & Clinical Cancer Research , 34:93, 2015). Efforts have been made to reduce side effects of chemotherapy and increase anticancer effects by co-administering carnitine acylcarnitine transporters including such omeprazole as an adjuvant.

Accordingly, the present inventors have made diligent efforts to provide a combination anticancer agent capable of significantly inhibiting cancer cells. As a result, when a carnitine acylcarnitine transporter inhibitor and an anticancer agent are treated in combination, the cancer cell inhibitory effect is significantly higher than that when each is treated alone. It was confirmed that it rises, and the present invention was completed.

Accordingly, an object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer comprising a carnitine acylcarnitine transporter inhibitor and an anticancer agent as active ingredients.

Another object of the present invention is to provide an anticancer adjuvant comprising a carnitine acylcarnitine transporter inhibitor and an anticancer agent as active ingredients.

In order to achieve the above purpose,

The present invention provides a pharmaceutical composition for preventing or treating cancer comprising a carnitine acylcarnitine carrier (CAC) inhibitor and an anticancer agent as active ingredients.

In addition, the present invention provides an anticancer adjuvant comprising a carnitine acylcarnitine transporter inhibitor and an anticancer agent as active ingredients.

According to a preferred embodiment of the present invention, the carnitine acylcarnitine transporter inhibitor is composed of Omeprazole (KN510), Lansoprazole (KN511), Pantoprazole (KN512) and pharmaceutically acceptable salts thereof. It may be any one or more selected from the group.

According to another preferred embodiment of the present invention, the anticancer agent is irinotecan, fluorouracil (5-FU), paclitaxel, gemcitabine, cisplatin, and pharmaceuticals thereof. It may be any one or more selected from the group consisting of acceptable salts.

According to another preferred embodiment of the present invention, the carnitine acylcarnitine transporter inhibitor and the anticancer agent may be included in a concentration ratio of 100:0.1 to 1:1, preferably 100:0.1 to 100:10, more preferably It may be included in a concentration ratio of 100:0.5 to 100:5.

According to another preferred embodiment of the present invention, the carnitine acylcarnitine transporter inhibitor and the anticancer agent may be administered sequentially or simultaneously.

According to another preferred embodiment of the present invention, the cancer is any one or more selected from the group consisting of colorectal cancer, lung cancer, stomach cancer, breast cancer, melanoma, leukemia, ovarian cancer, kidney cancer, pancreatic cancer, glioblastoma, and liver cancer. It could be cancer.

According to another preferred embodiment of the present invention, when the anticancer agent is irinotecan or a pharmaceutically acceptable salt thereof, the cancer is colorectal cancer, kidney cancer, liver cancer, glioblastoma, pancreatic cancer, breast cancer or leukemia,

When the anticancer agent is paclitaxel or a pharmaceutically acceptable salt thereof, the cancer is colorectal cancer, glioblastoma, melanoma, pancreatic cancer, gastric cancer, lung cancer or leukemia,

When the anticancer agent is 5-FU (fluorouracil) or a pharmaceutically acceptable salt thereof, the cancer is colorectal cancer, kidney cancer, liver cancer, melanoma, lung cancer or leukemia,

When the anticancer agent is cisplatin or a pharmaceutically acceptable salt thereof, the cancer may be ovarian cancer or leukemia.

The composition comprising the carnitine acylcarnitine transporter inhibitor and the anticancer agent of the present invention not only significantly reduced the growth of various cancer cells compared to the case of using the carnitine acylcarnitine transporter inhibitor or the anticancer agent alone, but also carnitine in a xenograft tumor animal model. The anticancer synergistic effect of the combined administration of an acylcarnitine transporter inhibitor and an anticancer agent was confirmed. Therefore, the composition of the present invention can be usefully utilized as an effective combination anticancer agent.

Figure 1 shows the treatment of omeprazole (KN510) and/or various anticancer agents (irinotecan, 5-FU, paclitaxel, gemcitabine, cisplatin) alone or in combination with HCT-116 cells and COLO-205 cells, which are colon cancer cell lines. This is data confirming the growth rate of cancer cells. Figure 1a is a drug showing a synergistic anti-cancer effect by combined administration, Figure 1b is data for drugs that did not show a synergistic effect of combined administration.
Figure 2 shows renal cancer (Renal cell Carcinoma) cell lines, CAKI-1 and ACHN cells, when omeprazole (KN510) and / or various anticancer drugs (irinotecan, 5-FU, paclitaxel, gemcitabine, cisplatin) were treated alone or in combination, This is data confirming the growth rate of cancer cells. Figure 2a is a drug showing a synergistic anti-cancer effect by combined administration, Figure 2b is data for drugs that did not show a synergistic effect of combined administration.
Figure 3 shows omeprazole (KN510) and/or various anticancer agents (irinotecan, 5-FU, paclitaxel, gemcitabine, cisplatin) alone or in combination with SK-HEP-1 cells and Huh-7 cells, which are liver cancer cell lines. This is data confirming the growth rate of cancer cells. Figure 3a is a drug showing a synergistic anti-cancer effect by combined administration, Figure 3b is data for drugs that did not show a synergistic effect of combined administration.
Figure 4 shows that omeprazole (KN510) and/or various anticancer agents (irinotecan, 5-FU, paclitaxel, gemcitabine, cisplatin) were treated alone or in combination with U-87 MG cells and T87G cells, which are glioblastoma (GBM) cell lines. This is data confirming the growth rate of cancer cells. Figure 4a is a drug showing a synergistic anti-cancer effect by combined administration, Figure 4b is data for drugs that did not show a synergistic effect of combined administration.
Figure 5 shows the growth rate of cancer cells when omeprazole (KN510) and/or various anticancer drugs (irinotecan, 5-FU, paclitaxel, gemcitabine, cisplatin) were treated alone or in combination with UACC62 cells and UACC257 cells, which are melanoma cell lines. This is confirmed data. Figure 5a is a drug showing a synergistic anti-cancer effect by combined administration, Figure 5b is data for drugs that did not show a synergistic effect of combined administration.
Figure 6 shows that omeprazole (KN510) and/or various anticancer agents (irinotecan, 5-FU, paclitaxel, gemcitabine, cisplatin) were administered alone to MIA PaCa-2 cells and PANC-1 cells, which are pancreatic ductal adenocarcinoma (PDAC) cell lines. Or data confirming the growth rate of cancer cells when treated in combination. Figure 6a is a drug showing a synergistic anti-cancer effect by combined administration, Figure 6b is data for drugs that did not show a synergistic effect of combined administration.
Figure 7 shows the cancer cells when omeprazole (KN510) and/or various anticancer drugs (irinotecan, 5-FU, paclitaxel, gemcitabine, cisplatin) were treated alone or in combination with MKN-28 cells and AGS cells, which are gastric cancer cells. This data confirms the growth rate. Figure 7a is a drug showing a synergistic anti-cancer effect by combined administration, Figure 7b is data for drugs that did not show a synergistic effect of combined administration.
Figure 8 shows omeprazole (KN510) and/or various anticancer agents (irinotecan, 5-FU, paclitaxel, gemcitabine, cisplatin) alone or in combination with ovarian cancer cells, OVCAR-8 cells and SK-OV-3 cells. This is data confirming the growth rate of cancer cells when treated. Figure 8a is a drug showing a synergistic anti-cancer effect by combined administration, Figure 8b is data for drugs that did not show a synergistic effect of combined administration.
Figure 9 shows the growth rate of cancer cells when omeprazole (KN510) and/or various anticancer agents (irinotecan, 5-FU, paclitaxel, gemcitabine, cisplatin) were treated alone or in combination with A549 cells and H23 cells, which are lung cancer cells. This is confirmed data. Figure 9a is a drug showing a synergistic anti-cancer effect by combined administration, Figure 9b is data for drugs that did not show a synergistic effect of combined administration.
10 is a single or combined treatment of omeprazole (KN510) and/or various anticancer agents (irinotecan, 5-FU, paclitaxel, gemcitabine, cisplatin) to MDA-MB-231 cells and MCF-7 cells, which are breast cancer cells. This is data confirming the growth rate of cancer cells. Figure 10a is a drug showing a synergistic anti-cancer effect by combined administration, Figure 10b is data for a drug that did not show a synergistic effect of combined administration.
Figure 11 shows the treatment of PC-3 cells and DU-145 cells, which are prostate cancer cells, with omeprazole (KN510) and/or various anticancer agents (irinotecan, 5-FU, paclitaxel, gemcitabine, cisplatin) alone or in combination. This is data confirming the growth rate of cancer cells. In the case of prostate cancer, no synergistic effect was seen in all combination treatments.
Figure 12 shows the growth rate of cancer cells when omeprazole (KN510) and/or various anticancer agents (irinotecan, 5-FU, paclitaxel, gemcitabine, cisplatin) were treated alone or in combination with SR cells and K562 cells, which are leukemia cells. It is data. Figure 12a is a drug showing a synergistic anti-cancer effect by combined administration, Figure 12b is data for drugs that did not show a synergistic effect of combined administration.
Figure 13 shows (a) when omeprazole (KN510, 50 mg/kg) and irinotecan (20 mg/kg) were treated alone or in combination in a pancreatic cancer xenograft tumor model, and
(b) Data showing changes in tumor tissue size when omeprazole (KN510, 100 mg/kg) and irinotecan (20 mg/kg) were treated alone or in combination in a pancreatic cancer xenograft tumor model.

Hereinafter, the present invention will be described in detail.

In one aspect, the present invention relates to a pharmaceutical composition for preventing or treating cancer comprising a carnitine acylcarnitine carrier (CAC) inhibitor and an anticancer agent as active ingredients.

In another aspect, the present invention relates to an anticancer adjuvant comprising a carnitine acylcarnitine transporter inhibitor and an anticancer agent as active ingredients.

In the present invention, the carnitine acylcarnitine transporter inhibitor is any one selected from the group consisting of omeprazole (KN510), lansoprazole (KN511), pantoprazole (KN512) and pharmaceutically acceptable salts thereof or more, preferably omeprazole or a pharmaceutically acceptable salt thereof.

In the present invention, the anticancer agent may be a metabolic inhibitor or an anticancer agent, preferably irinotecan, fluorouracil (5-FU), paclitaxel, gemcitabine, cisplatin ) and any one or more selected from the group consisting of pharmaceutically acceptable salts thereof.

In the present invention, the carnitine acylcarnitine transporter inhibitor and the anticancer agent may be administered sequentially or simultaneously.

In the present invention, the carnitine acylcarnitine transporter inhibitor and the anticancer agent may be included in a concentration ratio of 100:0.1 to 1:1, preferably 100:0.1 to 100:10, more preferably 100:0.5 to 100:5 concentration ratio may be included.

In the present invention, the cancer may be any one or more cancers selected from the group consisting of colorectal cancer, lung cancer, stomach cancer, breast cancer, melanoma, leukemia, ovarian cancer, kidney cancer, pancreatic cancer, glioblastoma, and liver cancer.

When the anticancer agent is irinotecan or a pharmaceutically acceptable salt thereof, the cancer is colorectal cancer, kidney cancer, liver cancer, glioblastoma, pancreatic cancer, breast cancer or leukemia,

When the anticancer agent is paclitaxel or a pharmaceutically acceptable salt thereof, the cancer is colorectal cancer, glioblastoma, melanoma, pancreatic cancer, gastric cancer, lung cancer or leukemia,

When the anticancer agent is 5-FU (fluorouracil) or a pharmaceutically acceptable salt thereof, the cancer is colorectal cancer, kidney cancer, liver cancer, melanoma, lung cancer or leukemia,

When the anticancer agent is cisplatin or a pharmaceutically acceptable salt thereof, the cancer may be ovarian cancer or leukemia.

In a specific embodiment of the present invention, colorectal cancer, kidney cancer, liver cancer, glioblastoma, melanoma, pancreatic cancer, gastric cancer, ovarian cancer, lung cancer, breast cancer, prostate cancer and leukemia-derived cell lines are treated with omeprazole (KN510) and irinotecan as an anticancer agent, When paclitaxel, 5-FU, gemcitabine or cisplatin were co-administered, anticancer agents showing synergistic anticancer effects were selected.

Confirmation of synergistic effect of combined administration of anticancer drugs Cancer Drug colorectal cancer
(Colone Cancer) Positive effect Irinotecan, Paclitaxel, 5-FU Negative effect gemcitabine, cisplatin kidney cancer
(Renal cell carcinoma) Positive effect Irinotecan, 5-FU Negative effect gemcitabine, paclitaxel, cisplatin liver cancer
(Liver Cancer) Positive effect Irinotecan, 5-FU Negative effect gemcitabine, paclitaxel, cisplatin glioblastoma
(GBM) Positive effect Irinotecan, Paclitaxel Negative effect 5-FU, gemcitabine, cisplatin melanoma
(Melanoma) Positive effect Irinotecan, 5-FU, Paclitaxel Negative effect gemcitabine, cisplatin pancreatic cancer
(PDAC) Positive effect Irinotecan, Paclitaxel Negative effect 5-FU, gemcitabine, cisplatin stomach cancer
(Stomach Cancer) Positive effect paclitaxel Negative effect Irinotecan, 5-FU, Gemcitabine, Cisplatin ovarian cancer
(Ovarian Cancer) Positive effect Cisplatin Negative effect Irinotecan, 5-FU, paclitaxel, gemcitabine lung cancer
(Lung Cancer) Positive effect 5-FU, paclitaxel Negative effect Irinotecan, Gemcitabine, Cisplatin breast cancer
(Breast Cancer) Positive effect Irinotecan Negative effect 5-FU, gemcitabine, paclitaxel, cisplatin prostate cancer
(Prostate Cancer) Positive effect - Negative effect Irinotecan, 5-FU, gemcitabine, paclitaxel, cisplatin leukemia
(leukemia) Positive effect Irinotecan, 5-FU, paclitaxel, cisplatin Negative effect gemcitabine

As a result, as shown in Table 1 and FIGS. 1 to 9, in the case of combined administration of omeprazole (KN510) + irinotecan, in colorectal cancer, kidney cancer, liver cancer, glioblastoma, pancreatic cancer, breast cancer and leukemia cell lines,

In the case of combined administration of omeprazole (KN510) + paclitaxel, in colorectal cancer, glioblastoma, melanoma, pancreatic cancer, gastric cancer, lung cancer and leukemia cell lines,

In the case of omeprazole (KN510) + 5-FU combined administration, in colorectal cancer, kidney cancer, liver cancer, melanoma, lung cancer and leukemia cell lines,

In the case of combined administration of omeprazole (KN510) + cisplatin, it was confirmed that the cancer cell killing effect was remarkably increased in ovarian cancer and leukemia cell lines compared to the single administration.

In another specific embodiment of the present invention, in order to confirm the anticancer synergistic effect of the combined administration of omeprazole (KN510) and an anticancer agent in vivo, a pancreatic cancer xenograft tumor model was prepared, and omeprazole (KN510, 50 mg/kg or 100 mg/kg) and irinotecan (20 mg/kg) were administered alone or in combination. As a result, as shown in FIG. 13 , it was confirmed that the tumor size was significantly reduced when omeprazole (KN510) and irinotecan were treated in combination compared to when each was treated alone.

The composition of the present invention may be in various oral or parenteral dosage forms. When formulating the composition, one or more buffers (eg, saline or PBS), antioxidants, bacteriostats, chelating agents (eg, EDTA or glutathione), fillers, bulking agents, binders, adjuvants (eg, aluminum hydroxide), suspending agents, thickening agents, wetting agents, disintegrating agents or surfactants, diluents or excipients.

Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc. These solid preparations include at least one excipient in one or more compounds, such as starch (corn starch, wheat starch, rice starch, potato) including starch, etc.), calcium carbonate, sucrose, lactose, dextrose, sorbitol, mannitol, xylitol, erythritol maltitol, cellulose, methyl cellulose, sodium carboxymethylcellulose and hydroxypropylmethyl -It is prepared by mixing cellulose or gelatin. Tablets or dragees may be obtained, for example, by combining the active ingredient with a solid excipient which is then milled and processed into a mixture of granules after adding suitable auxiliaries.

In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, solutions for oral administration, emulsions, or syrups. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, aromatics, or preservatives may be included. can In addition, cross-linked polyvinylpyrrolidone, agar, alginic acid, or sodium alginate may be added as a disintegrant, and may further include anti-agglomerating agents, lubricants, wetting agents, flavoring agents, emulsifiers, and preservatives. .

Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspension solutions, emulsions, freeze-dried formulations, suppositories, and the like. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents. As a base for suppositories, witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerol, gelatin, and the like may be used.

The composition of the present invention may be administered orally or parenterally, and in the case of parenteral administration, external skin use; It may be formulated according to a method known in the art in the form of an injection for intraperitoneal, rectal, intravenous, intramuscular, subcutaneous, intrauterine, or intracerebral vascular injection.

In the case of the injection, it must be sterilized and must be protected from contamination by microorganisms such as bacteria and fungi. Examples of suitable carriers for injections include, but are not limited to, water, ethanol, polyols (eg, glycerol, propylene glycol, liquid polyethylene glycol, etc.), mixtures thereof, and/or solvents or dispersion media containing vegetable oils. can More preferably, suitable carriers include Hanks' solution, Ringer's solution, phosphate buffered saline (PBS) with triethanolamine or isotonic solutions such as sterile water for injection, 10% ethanol, 40% propylene glycol and 5% dextrose. etc. can be used. In order to protect the injection from microbial contamination, various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid, and thimerosal may be further included. Also, in most cases, the injection may further include an isotonic agent such as sugar or sodium chloride.

The composition of the present invention is administered in a pharmaceutically effective amount. A pharmaceutically effective amount means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level depends on the type of patient's disease, severity, activity of the drug, sensitivity to the drug, and administration time. , the route of administration and excretion rate, the duration of treatment, factors including concomitantly used drugs, and other factors well known in the medical field. The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered single or multiple times. That is, the total effective amount of the composition of the present invention can be administered to the patient in a single dose, or it can be administered by a fractionated treatment protocol in which multiple doses are administered over a long period of time. . Considering all of the above factors, it is important to administer an amount that can obtain the maximum effect with the minimum amount without side effects, which can be easily determined by those skilled in the art.

The preferred dosage of the composition varies depending on the patient's condition, body weight, disease severity, drug form, administration route and period, but can be appropriately selected by those skilled in the art, for example, 0.0001 to 2,000 mg/kg per day, and more Preferably, it may be administered at 0.001 to 2,000 mg/kg. Administration may be administered once a day or divided into several times. However, the scope of the present invention is not limited by the dosage.

The composition of the present invention can be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers.

The anticancer adjuvant of the present invention refers to any form for increasing the anticancer effect of an anticancer agent or suppressing or improving the side effects of an anticancer agent. The anticancer adjuvant of the present invention can be administered in combination with various types of anticancer agents or anticancer adjuvants, and when administered in combination, even if the anticancer agent is administered at a lower level than the dose of a conventional anticancer agent, it can exhibit an equivalent level of anticancer treatment effect, which is safer anticancer treatment can be performed.

The administration route of the anticancer adjuvant may be administered through any general route as long as it can reach the target tissue. The anticancer adjuvant of the present invention may be administered intraperitoneally, intravenously, intramuscularly, subcutaneously, orally, intrapulmonaryly, or intrarectally, as desired, but is not limited thereto. In addition, the anticancer adjuvant may be administered by any device capable of moving active substances to target cells.

The anticancer adjuvant of the present invention may be preferably formulated as an anticancer adjuvant by including one or more pharmaceutically acceptable carriers in addition to the active ingredient for administration. Carriers, excipients or diluents that may be included in the anticancer treatment adjuvant of the present invention include lactose, dextrose, sucrose, 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.

The anti-cancer adjuvant of the present invention may be a formulation for oral or parenteral administration, and the description of the formulation is replaced by a description of the formulation of the pharmaceutical composition.

Hereinafter, the present invention will be described in more detail through examples. These examples are only for exemplifying the present invention, and it is obvious to those skilled in the art that the scope of the present invention is not construed as being limited by these examples.

Confirmation of anticancer activity against colorectal cancer according to combined administration

In the present invention, in order to confirm the effect of the combined treatment of a carnitine acylcarnitine carrier (CAC) inhibitor and an anticancer agent on cancer cell growth, the degree of cancer cell death was confirmed through SRB analysis (Sulforhodamine B colorimetric assay), Cancer cell growth rates were analyzed based on the control group (100%). All experiments were performed in triplicate, and data were presented as average ± standard deviation (SD) values.

First, HCT-116 cells and COLO-205 cells, which are colorectal cancer cell lines, were prepared, and cells were plated at plating densities ranging from 5,000 to 20,000 cells/well depending on the doubling time of each cell line ( 100 μl) was inoculated into a 96-well cell culture plate. After seeding the cells, the plates were incubated for 24 hours before adding the experimental drugs. The concentrations of omeprazole (KN510) and/or anticancer agent were added to each well as follows:

1) control,

2) Omeprazole (KN510) 200μM alone treatment group,

3) Anticancer drugs (irinotecan 2.5 μM, 5-FU 5 μM, paclitaxel 10 nM, gemcitabine 2.5 μM or cisplatin 1 μM) alone treatment group

4) Omeprazole (KN510) 200 μM + anticancer drugs (irinotecan 2.5 μM, 5-FU 5 μM, paclitaxel 10 nM, gemcitabine 2.5 μM or cisplatin 1 μM) combination treatment group

Then, after culturing in a CO ₂ incubator for 48 hours, the analysis was terminated by adding cold trichloroacetic acid (TCA). 50 μl of cold 50% (w/v) TCA (final concentration: 10% TCA) was gently added to fix the cells in situ and incubated at 4° C. for 60 minutes. The supernatant was discarded, the plate was washed 5 times with distilled water and then air dried. A 0.4% (w/v) solution of SRB (Sulforhodamine B) in 1% acetic acid (100 μl) was added to each well, and the plate was left at room temperature for 10 minutes. After staining, the plate was air-dried after washing with 1% acetic acid five times to remove unbound dye. The bound dye was then solubilized with 10 mM trizma base and absorbance was recorded at 515 nm using an automated plate reader.

Colorectal cancer cell line growth rate according to drug treatment Drug HCT-116 COLO-205 average (%) SD average (%) SD Irinotecan Control 100.00 0.00 100.00 4.28 KN510 200 µM 35.30 4.12 25.62 3.47 Irinotecan 2.5 µM 41.85 1.59 59.34 1.93 KN510 200 μM + Irinotecan 2.5 μM 28.03 0.83 18.72 2.56 5-FU Control 100.00 0.00 100.00 4.28 KN510 200 µM 35.30 4.12 25.62 3.47 5-FU 5 µM 41.59 5.20 23.39 2.06 KN510 200 µM +
5-FU 5 µM 17.64 1.87 11.48 1.55 Gemcitabine Control 100.00 0.00 100.00 4.28 KN510 200 µM 35.30 4.12 25.62 3.47 Gemcitabine 2.5 μM 16.32 2.37 22.24 1.93 KN510 200 μM + Gemcitabine 2.5 μM 22.18 1.33 20.09 1.31 Paclitaxel Control 100.00 0.00 100.00 4.28 KN510 200 µM 35.30 4.12 25.62 3.47 Paclitaxel 10 nM 17.70 0.54 14.57 1.34 KN510 200 μM + Paclitaxel 10 nM 7.96 0.65 5.57 3.49 Cisplatin Control 100.00 0.00 100.00 4.28 KN510 200 µM 35.30 4.12 25.62 3.47 Cisplatin 1 μM 100.00 0.00 94.22 4.25 KN510 200 μM + Cisplatin 1 μM 43.27 6.96 25.54 2.15

As a result, as shown in Figure 1 and Table 2, when irinotecan, paclitaxel, or 5-FU was treated in combination with omeprazole (KN510) in colon cancer cell lines, colon cancer cell growth was significantly inhibited compared to the single treatment group. Confirmed.

Confirmation of anticancer activity against renal cancer according to combined administration

Experiments were performed in the same manner as in Example 1 using CAKI-1 and ACHN cells, which are renal cell carcinoma cell lines.

Growth rate of renal cancer cell lines according to drug treatment Drug CAKI-1 ACHN average (%) SD average (%) SD Irinotecan Control 100.00 6.37 100.00 9.42 KN510 200 µM 41.69 2.10 17.28 0.54 Irinotecan 2.5 µM 44.74 10.43 42.20 27.15 KN510 200 μM + Irinotecan 2.5 μM 28.59 2.14 8.71 0.28 5-FU Control 100.00 6.37 100.00 9.42 KN510 200 µM 41.69 2.10 17.28 0.54 5-FU 5 µM 47.91 4.73 48.97 4.47 KN510 200 µM +
5-FU 5 µM 24.21 4.93 7.34 0.78 Gemcitabine Control 100.00 6.37 100.00 9.42 KN510 200 µM 41.69 2.10 17.28 0.54 Gemcitabine 2.5 μM 2.30 1.15 -2.82 0.68 KN510 200 μM + Gemcitabine 2.5 μM 24.15 1.05 3.76 0.35 Paclitaxel Control 100.00 100.00 6.37 100.00 KN510 200 µM 35.30 41.69 2.10 17.28 Paclitaxel 10 nM 17.70 80.81 0.91 59.69 KN510 200 μM + Paclitaxel 10 nM 7.96 42.29 4.19 14.88 Cisplatin Control 100.00 6.37 100.00 9.42 KN510 200 µM 41.69 2.10 17.28 0.54 Cisplatin 1 μM 88.17 4.97 78.57 7.37 KN510 200 μM + Cisplatin 1 μM 56.04 5.94 18.46 1.12

As a result, as shown in FIG. 2 and Table 3, when irinotecan or 5-FU was combined with omeprazole (KN510) in renal cancer cell lines, it was confirmed that renal cancer cell growth was significantly inhibited compared to the single treatment group. .

Confirmation of anticancer activity against liver cancer according to combined administration

Experiments were performed in the same manner as in Example 1 using SK-HEP-1 cells and Huh-7 cells, which are liver cancer cell lines.

Growth rate of liver cancer cell lines according to drug treatment Drug SK-HEP-1 Huh7 average (%) SD average (%) SD Irinotecan Control 100.00 5.23 100.00 0.87 KN510 200 µM 20.20 1.16 9.69 1.05 Irinotecan 2.5 µM 47.04 2.55 42.82 3.26 KN510 200 μM + Irinotecan 2.5 μM 18.87 1.48 6.08 0.46 5-FU Control 100.00 5.23 100.00 0.87 KN510 200 µM 20.20 1.16 9.69 1.05 5-FU 5 µM 61.32 2.05 42.30 3.17 KN510 200 µM +
5-FU 5 µM 16.82 1.72 3.41 1.12 Gemcitabine Control 100.00 5.23 100.00 0.87 KN510 200 µM 20.20 1.16 9.69 1.05 Gemcitabine 2.5 μM 21.64 1.06 22.98 0.90 KN510 200 μM + Gemcitabine 2.5 μM 25.22 0.15 13.39 1.45 Paclitaxel Control 100.00 5.23 100.00 0.87 KN510 200 µM 20.20 1.16 9.69 1.05 Paclitaxel 10 nM 32.17 0.45 32.69 0.30 KN510 200 μM + Paclitaxel 10 nM 12.22 1.21 13.00 0.37 Cisplatin Control 100.00 5.23 100.00 0.87 KN510 200 µM 20.20 1.16 9.69 1.05 Cisplatin 1 μM 91.86 3.39 53.37 3.46 KN510 200 μM + Cisplatin 1 μM 27.27 1.43 13.94 4.06

As a result, as shown in FIG. 3 and Table 4, when irinotecan or 5-FU was combined with omeprazole (KN510) in liver cancer cell lines, it was confirmed that cancer cell growth was significantly inhibited compared to the single treatment group.

Confirmation of anticancer activity against glioblastoma according to combined administration

Experiments were performed in the same manner as in Example 1 using U-87 MG cells and T87G cells, which are glioblastoma (GBM) cell lines.

Growth rate of glioblastoma cell line according to drug treatment Drug U-87 MG T87G average (%) SD average (%) SD Irinotecan Control 100.00 0.00 100.00 6.14 KN510 200 µM 57.73 8.05 24.31 3.03 Irinotecan 2.5 µM 15.59 1.99 41.16 2.36 KN510 200 μM + Irinotecan 2.5 μM 8.39 0.37 10.86 0.20 5-FU Control 100.00 0.00 100.00 1.62 KN510 200 µM 57.73 8.05 32.53 2.08 5-FU 5 µM 9.93 0.65 76.71 4.27 KN510 200 µM +
5-FU 5 µM 9.06 0.67 26.25 5.21 Gemcitabine Control 100.00 0.00 100.00 5.01 KN510 200 µM 57.73 8.05 26.29 7.05 Gemcitabine 2.5 μM 1.52 0.48 35.87 3.75 KN510 200 μM + Gemcitabine 2.5 μM 4.14 0.40 25.06 3.93 Paclitaxel Control 100.00 0.00 100.00 2.49 KN510 200 µM 57.73 8.05 19.25 2.23 Paclitaxel 10 nM 31.96 8.18 4.35 3.36 KN510 200 μM + Paclitaxel 10 nM 22.60 5.56 -25.20 5.74 Cisplatin Control 100.00 0.00 100.00 3.32 KN510 200 µM 57.73 8.05 37.94 2.30 Cisplatin 1 μM 93.66 0.00 90.80 2.86 KN510 200 μM + Cisplatin 1 μM 74.04 15.63 36.15 1.71

As a result, as shown in Figure 4 and Table 5, when irinotecan or paclitaxel and omeprazole (KN510) were treated in combination with glioblastoma cell lines, it was confirmed that glioblastoma cell growth was significantly inhibited compared to the single treatment group.

Confirmation of anticancer activity against melanoma according to combined administration

Experiments were performed in the same manner as in Example 1 using UACC62 cells and UACC257 cells, which are melanoma cell lines.

Growth rate of melanoma cell lines according to drug treatment Drug UACC62 UACC257 average (%) SD average (%) SD Irinotecan Control 100.00 13.71 100.00 7.53 KN510 200 µM 24.68 26.65 4.33 3.12 Irinotecan 2.5 µM -35.63 3.35 21.87 4.51 KN510 200 μM + Irinotecan 2.5 μM -66.29 3.21 -7.67 3.38 5-FU Control 100.00 11.32 100.00 7.91 KN510 200 µM 24.68 26.65 10.97 0.99 5-FU 5 µM 52.14 16.66 62.17 1.60 KN510 200 µM +
5-FU 5 µM 7.45 2.01 6.76 1.38 Gemcitabine Control 100.00 6.02 100.00 5.75 KN510 200 µM 42.31 12.05 3.31 1.32 Gemcitabine 2.5 μM 53.65 12.13 30.97 2.01 KN510 200 μM + Gemcitabine 2.5 μM 55.00 6.80 7.58 1.60 Paclitaxel Control 100.00 14.85 100.00 0.60 KN510 200 µM 38.66 5.04 3.31 0.57 Paclitaxel 10 nM 48.36 6.74 35.43 2.84 KN510 200 μM + Paclitaxel 10 nM 22.68 6.40 -9.72 1.46 Cisplatin Control 100.00 9.07 100.00 7.92 KN510 200 µM 57.65 5.41 3.10 0.26 Cisplatin 1 μM 62.76 6.38 76.16 5.77 KN510 200 μM + Cisplatin 1 μM 42.18 7.15 4.46 0.98

As a result, as shown in FIG. 5 and Table 6, when irinotecan, 5-FU or paclitaxel were treated in combination with omeprazole (KN510) in melanoma cell lines, melanoma cell growth was significantly inhibited compared to the single treatment group. Confirmed.

Confirmation of anticancer activity against pancreatic cancer according to combined administration

Experiments were performed in the same manner as in Example 1 using MIA PaCa-2 cells and PANC-1 cells, which are pancreatic ductal adenocarcinoma (PDAC) cell lines.

Growth rate of pancreatic cancer cell lines according to drug treatment Drug MIA PaCa-2 PANC-1 average (%) SD average (%) SD Irinotecan Control 100.00 7.34 100.00 22.49 KN510 200 µM 32.79 3.42 41.83 7.26 Irinotecan 2.5 µM 46.19 1.11 60.53 13.72 KN510 200 μM + Irinotecan 2.5 μM 21.52 1.85 34.26 2.95 5-FU Control 100.00 1.18 100.00 2.30 KN510 200 µM 28.98 1.98 35.97 4.43 5-FU 5 µM 74.96 1.74 55.46 3.77 KN510 200 µM +
5-FU 5 µM 26.00 0.39 35.83 1.47 Gemcitabine Control 100.00 3.73 100.00 2.95 KN510 200 µM 31.47 1.19 42.34 4.93 Gemcitabine 2.5 μM 65.63 2.31 33.37 5.34 KN510 200 μM + Gemcitabine 2.5 μM 33.13 4.01 30.54 3.47 Paclitaxel Control 100.00 3.87 100.00 4.12 KN510 200 µM 31.14 0.42 43.15 1.26 Paclitaxel 10 nM 26.38 1.11 16.55 2.77 KN510 200 μM + Paclitaxel 10 nM 15.70 0.99 9.19 2.42 Cisplatin Control 100.00 13.65 100.00 4.41 KN510 200 µM 29.69 2.40 47.19 4.68 Cisplatin 1 μM 90.59 0.89 94.56 3.57 KN510 200 μM + Cisplatin 1 μM 61.28 4.04 79.97 6.06

As a result, as shown in FIG. 6 and Table 7, when irinotecan or paclitaxel was treated in combination with omeprazole (KN510) in pancreatic cancer cell lines, it was confirmed that pancreatic cancer cell growth was significantly inhibited compared to the single treatment group.

Confirmation of anticancer activity against gastric cancer according to combined administration

Experiments were performed in the same manner as in Example 1 using MKN-28 cells and AGS cells, which are stomach cancer cells.

Gastric cancer cell line growth rate according to drug treatment Drug MKN-28 AGS average (%) SD average (%) SD Irinotecan Control 100.00 20.30 100.00 4.46 KN510 200 µM 6.43 2.05 18.91 8.02 Irinotecan 2.5 µM 76.83 9.49 55.52 13.81 KN510 200 μM + Irinotecan 2.5 μM 55.18 9.80 56.96 6.93 5-FU Control 100.00 8.65 100.00 3.33 KN510 200 µM 7.24 1.63 26.39 1.38 5-FU 5 µM 60.79 3.44 35.40 4.19 KN510 200 µM +
5-FU 5 µM 21.48 0.64 13.76 2.30 Gemcitabine Control 100.00 4.01 100.00 6.24 KN510 200 µM 11.00 4.87 33.79 7.31 Gemcitabine 2.5 μM 42.83 2.27 10.93 2.22 KN510 200 μM + Gemcitabine 2.5 μM 21.30 2.13 23.57 6.38 Paclitaxel Control 100.00 2.38 100.00 2.74 KN510 200 µM 9.27 1.77 31.90 4.56 Paclitaxel 10 nM 27.71 2.65 18.60 3.22 KN510 200 μM + Paclitaxel 10 nM -2.12 4.81 -16.72 6.11 Cisplatin Control 100.00 11.90 100.00 5.83 KN510 200 µM 10.82 4.62 33.59 3.07 Cisplatin 1 μM 75.14 3.02 87.44 5.24 KN510 200 μM + Cisplatin 1 μM 58.68 1.12 83.29 8.81

As a result, as shown in FIG. 7 and Table 8, when gastric cancer cell lines were treated with paclitaxel in combination with omeprazole (KN510), it was confirmed that gastric cancer cell growth was significantly inhibited compared to the single treatment group.

Confirmation of anticancer activity against ovarian cancer according to combined administration

Experiments were performed in the same manner as in Example 1 using OVCAR-8 cells and SK-OV-3 cells, which are ovarian cancer cells.

Ovarian cancer cell line growth rate according to drug treatment Drug OVCAR-8 SK-OV-3 average (%) SD average (%) SD Irinotecan Control 100.00 4.08 100.00 9.21 KN510 200 µM 38.65 1.20 58.31 14.83 Irinotecan 2.5 µM 4.70 3.77 19.77 10.58 KN510 200 μM + Irinotecan 2.5 μM 1.10 0.15 17.31 9.38 5-FU Control 100.00 4.08 100.00 9.21 KN510 200 µM 30.64 0.95 39.56 5.65 5-FU 5 µM 27.12 4.09 24.31 2.12 KN510 200 µM +
5-FU 5 µM 19.09 4.52 23.67 1.57 Gemcitabine Control 100.00 4.08 100.00 9.21 KN510 200 µM 30.64 0.95 39.56 5.65 Gemcitabine 2.5 μM -14.25 2.69 36.98 15.83 KN510 200 μM + Gemcitabine 2.5 μM -12.40 4.68 30.64 15.27 Paclitaxel Control 100.00 4.08 100.00 9.21 KN510 200 µM 38.65 1.20 58.31 14.83 Paclitaxel 10 nM 12.64 0.76 32.33 0.59 KN510 200 μM + Paclitaxel 10 nM 4.52 0.92 22.03 6.08 Cisplatin Control 100.00 4.08 100.00 9.21 KN510 200 µM 30.64 0.95 39.56 5.65 Cisplatin 1 μM 51.47 7.35 43.19 8.23 KN510 200 μM + Cisplatin 1 μM 17.37 0.58 21.61 4.66

As a result, as shown in FIG. 8 and Table 9, when cisplatin and omeprazole (KN510) were treated in combination with ovarian cancer cell lines, it was confirmed that ovarian cancer cell growth was significantly inhibited compared to the single treatment group.

Confirmation of anticancer activity against lung cancer according to combined administration

Experiments were performed in the same manner as in Example 1 using A549 cells and H23 cells, which are lung cancer cells.

Growth rate of lung cancer cell lines according to drug treatment Drug A549 H23 average (%) SD average (%) SD Irinotecan Control 100.00 2.54 100.00 30.63 KN510 200 µM 10.47 1.34 5.67 4.03 Irinotecan 2.5 µM 16.54 2.40 39.98 2.97 KN510 200 μM + Irinotecan 2.5 μM 12.55 2.04 -56.49 4.06 5-FU Control 100.00 2.54 100.00 30.63 KN510 200 µM 10.47 1.34 6.15 0.39 5-FU 5 µM 27.36 7.34 73.30 3.93 KN510 200 µM +
5-FU 5 µM -5.26 6.50 -9.52 6.03 Gemcitabine Control 100.00 2.54 100.00 30.63 KN510 200 µM 10.47 1.34 1.80 4.82 Gemcitabine 2.5 μM -16.60 2.09 -23.44 6.96 KN510 200 μM + Gemcitabine 2.5 μM 2.22 1.80 -8.03 4.93 Paclitaxel Control 100.00 2.54 100.00 30.63 KN510 200 µM 10.47 1.34 -10.74 1.26 Paclitaxel 10 nM 22.67 7.09 24.94 1.49 KN510 200 μM + Paclitaxel 10 nM -0.10 3.37 -38.28 1.78 Cisplatin Control 100.00 2.54 100.00 30.63 KN510 200 µM 10.47 1.34 2.18 4.84 Cisplatin 1 μM 99.46 2.12 92.69 29.47 KN510 200 μM + Cisplatin 1 μM 39.29 2.61 13.41 1.62

As a result, as shown in FIG. 9 and Table 10, when 5-FU or paclitaxel was combined with omeprazole (KN510) in lung cancer cell lines, it was confirmed that lung cancer cell growth was significantly inhibited compared to the single treatment group.

Confirmation of anticancer activity against breast cancer according to combined administration

Experiments were performed in the same manner as in Example 1 using MDA-MB-231 cells and MCF-7 cells, which are breast cancer cells.

Breast cancer cell line growth rate according to drug treatment Drug MDA-MB-231 MCF-7 average (%) SD average (%) SD Irinotecan Control 100.00 3.64 100.00 3.00 KN510 200 µM 38.54 2.86 31.67 2.29 Irinotecan 2.5 µM 38.50 2.35 12.39 0.43 KN510 200 μM + Irinotecan 2.5 μM 2.16 1.61 1.17 0.46 5-FU Control 100.00 4.02 100.00 3.00 KN510 200 µM 38.54 2.49 31.67 2.29 5-FU 5 µM 74.97 6.07 28.09 1.10 KN510 200 µM +
5-FU 5 µM 33.01 0.34 19.68 2.71 Gemcitabine Control 100.00 3.64 100.00 3.00 KN510 200 µM 38.54 2.86 31.67 2.29 Gemcitabine 2.5 μM 44.28 5.36 22.28 2.83 KN510 200 μM + Gemcitabine 2.5 μM 28.38 1.81 14.58 0.38 Paclitaxel Control 100.00 3.64 100.00 3.00 KN510 200 µM 38.54 2.86 31.67 2.29 Paclitaxel 10 nM 55.05 1.99 35.62 2.16 KN510 200 μM + Paclitaxel 10 nM 33.01 1.28 14.58 1.42 Cisplatin Control 100.00 3.64 100.00 3.00 KN510 200 µM 38.54 2.86 31.67 2.29 Cisplatin 1 μM 91.19 1.10 94.58 0.74 KN510 200 μM + Cisplatin 1 μM 37.93 1.81 30.16 1.36

As a result, as shown in FIG. 10 and Table 11, when breast cancer cell lines were treated with irinotecan in combination with omeprazole (KN510), it was confirmed that breast cancer cell growth was significantly inhibited compared to the single treatment group.

Confirmation of anticancer activity against prostate cancer according to combined administration

Experiments were performed in the same manner as in Example 1 using PC-3 cells and DU-145 cells, which are prostate cancer cells.

Prostate cancer cell line growth rate according to drug treatment Drug PC-3 DU-145 average (%) SD average (%) SD Irinotecan Control 100.00 2.99 100.00 3.16 KN510 200 µM 12.70 0.86 43.66 6.14 Irinotecan 2.5 µM 33.84 0.51 -17.79 1.02 KN510 200 μM + Irinotecan 2.5 μM 7.18 0.31 -0.15 3.99 5-FU Control 100.00 2.99 100.00 3.16 KN510 200 µM 12.70 0.86 43.66 6.14 5-FU 5 µM 55.19 1.14 71.75 2.11 KN510 200 µM +
5-FU 5 µM 7.72 1.04 30.29 1.99 Gemcitabine Control 100.00 2.99 100.00 3.16 KN510 200 µM 12.70 0.86 43.66 6.14 Gemcitabine 2.5 μM 32.17 0.91 0.24 0.01 KN510 200 μM + Gemcitabine 2.5 μM 8.95 0.46 0.36 0.01 Paclitaxel Control 100.00 2.99 100.00 3.16 KN510 200 µM 12.70 0.86 43.66 6.14 Paclitaxel 10 nM 32.49 2.10 57.24 2.82 KN510 200 μM + Paclitaxel 10 nM 4.88 0.79 25.86 1.86 Cisplatin Control 100.00 2.99 100.00 3.16 KN510 200 µM 12.70 0.86 43.66 6.14 Cisplatin 1 μM 82.60 3.31 99.32 4.79 KN510 200 μM + Cisplatin 1 μM 10.67 0.13 46.57 1.30

As a result, as shown in FIG. 11 and Table 12, it was confirmed that there was no synergistic effect for combined administration in the case of prostate cancer.

Confirmation of anticancer activity against leukemia according to combined administration

Experiments were performed in the same manner as in Example 1 using SR cells and K562 cells, which are leukemia cells.

Growth rate of leukemia cell lines according to drug treatment Drug SR K562 average (%) SD average (%) SD Irinotecan Control 100.00 1.54 100.00 2.57 KN510 200 µM 42.75 2.22 34.61 1.78 Irinotecan 2.5 µM 6.26 5.50 46.54 5.27 KN510 200 μM + Irinotecan 2.5 μM 1.93 15.73 9.61 3.20 5-FU Control 100.00 1.54 100.00 2.57 KN510 200 µM 42.75 2.22 34.61 1.78 5-FU 5 µM 96.15 1.84 99.83 4.16 KN510 200 µM +
5-FU 5 µM 22.63 4.01 26.44 2.19 Gemcitabine Control 100.00 1.54 100.00 2.57 KN510 200 µM 42.75 2.22 34.61 1.78 Gemcitabine 2.5 μM 53.15 2.31 53.51 6.69 KN510 200 μM + Gemcitabine 2.5 μM 32.99 8.98 25.22 4.36 Paclitaxel Control 100.00 1.54 100.00 2.57 KN510 200 µM 42.75 2.22 34.61 1.78 Paclitaxel 10 nM 94.83 6.35 59.27 3.01 KN510 200 μM + Paclitaxel 10 nM 0.71 7.95 12.44 1.65 Cisplatin Control 100.00 1.54 100.00 2.57 KN510 200 µM 42.75 2.22 34.61 1.78 Cisplatin 1 μM 93.52 2.99 102.62 1.83 KN510 200 μM + Cisplatin 1 μM 30.20 1.23 31.86 0.26

As a result, as shown in FIG. 12 and Table 13, when irinotecan, 5-FU, paclitaxel or cisplatin were treated in combination with omeprazole (KN510) in leukemia cell lines, leukemia cell growth was significantly inhibited compared to the single treatment group. Confirmed.

Confirmation of anticancer activity by co-administration of omeprazole (KN510) and irinotecan in a xenograft tumor model

In the present invention, in order to confirm the anticancer synergistic effect of the combined administration of omeprazole (KN510) and irinotecan in vivo, a pancreatic cancer xenograft tumor model was prepared and the drug was administered.

This experiment was reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of the National Cancer Center Laboratory, and the National Cancer Center Laboratory, which follows the Laboratory Animal Resources Guide (protocol: ncc-19-494). It is accredited by AAALAC International.

Specifically, 6-8 week old Balb/c nude mice (Orient, Korea) were subcutaneously inoculated with MIA PaCa-2 cells (1 × 10 ⁷ ) in 100 μl PBS using a 1 ml syringe, and the tumor size was 100 Upon reaching mm 3 , the mice were randomly divided into 4 groups so that there were 4 mice per group as follows, and then drugs were administered as shown in Table 14 below.

In addition, the experiment was performed by dividing omeprazole (KN510) into a case where it was administered at a concentration of 50 mg/kg and a case where it was administered at a concentration of 100 mg/kg.

1) Control group (solvent treatment)

2) Omeprazole (KN510) alone treatment group (50 mg/kg or 100 mg/kg, P.O injection),

3) Irinotecan alone treatment group (20 mg/kg, I.P injection),

4) Omeprazole (KN510) (50 mg/kg or 100 mg/kg) + Irinotecan (20 mg/kg/) combination treatment group

drug administration conditions Cell line MIA PaCa-2 Mice BALB/c-nu (Orient) N (Head) 4 Drug delivery KN510:PO/ 5days/week
Irinotecan: IP/ 1days/week Treatment on/off On (5) Off (2) Week 4 drug dose KN510; 50 mg/kg/ 300 μL or 100 mg/kg/ 300 μL
Irinotecan: 20 mg/kg/ 100 µl Drug vehicle KN510; 5% DMSO + 10% Kolliphor + 85% PBS (PO)
Irinotecan; 100% DW (IP)

Primary tumor size was measured weekly using calipers. Tumor volume was calculated using Equation 1 below, and data were presented as mouse tumor volume average ± standard deviation (SD) values for each group.

[Equation 1]

V = (A × B ² )/2 (V = volume (mm ³ ), A = long diameter, B = short diameter)

Tumor volume (mm ³ ) when omeprazole (KN510) is administered at 50 mg/kg Drug 2 weeks 3 weeks 4 weeks 5 weeks average SD average SD average SD average SD Control 143.54 20.72 593.43 267.26 835.78 303.81 1102.18 406.45 KN510 50 mg/kg 143.01 26.83 675.69 344.08 965.63 294.97 1296.93 458.10 Irinotecan 20 mg/kg 142.65 25.59 538.05 146.81 641.74 159.22 838.70 231.10 KN510 50 mg/kg+ Irinotecan 20 mg/kg 138.13 43.68 382.56 278.28 351.85 221.68 314.19 329.91

Tumor volume (mm ³ ) when omeprazole (KN510) 100 mg/kg was administered Drug 2 weeks 3 weeks 4 weeks 5 weeks average SD average SD average SD average SD Control 98.14 9.05 412.10 74.88 907.60 174.78 1361.54 409.43 KN510 100 mg/kg 93.96 36.90 229.95 59.83 469.90 219.87 843.25 371.66 Irinotecan 20 mg/kg 89.18 18.51 271.99 114.54 487.26 312.91 551.75 349.83 KN510 100 mg/kg+ Irinotecan 20 mg/kg 93.62 24.28 172.67 59.91 350.35 176.91 303.99 231.96

As a result, as shown in FIG. 13 and Table 15 and Table 16, when omeprazole (KN510) and irinotecan were co-administered, it was confirmed that the tumor size was significantly reduced compared to the single treatment group.

Claims (14)

A pharmaceutical composition for preventing or treating cancer, comprising a carnitine acylcarnitine carrier (CAC) inhibitor and an anticancer agent as active ingredients.
According to claim 1,
Characterized in that the carnitine acylcarnitine transporter inhibitor is at least one selected from the group consisting of omeprazole (KN510), lansoprazole (KN511), pantoprazole (KN512) and pharmaceutically acceptable salts thereof , A pharmaceutical composition for preventing or treating cancer.
According to claim 1,
The anticancer agent is any one selected from the group consisting of irinotecan, fluorouracil (5-FU), paclitaxel, gemcitabine, cisplatin, and pharmaceutically acceptable salts thereof Characterized in that the above, a pharmaceutical composition for preventing or treating cancer.
According to claim 1,
The carnitine acylcarnitine transporter inhibitor and the anticancer agent are contained in a concentration ratio of 100: 0.1 to 1: 1, characterized in that, a pharmaceutical composition for preventing or treating cancer.
According to claim 1,
A pharmaceutical composition for preventing or treating cancer, characterized in that the carnitine acylcarnitine transporter inhibitor and the anticancer agent are administered sequentially or simultaneously.
According to claim 1,
The cancer is characterized in that any one or more cancers selected from the group consisting of colorectal cancer, lung cancer, stomach cancer, breast cancer, melanoma, leukemia, ovarian cancer, kidney cancer, pancreatic cancer, glioblastoma and liver cancer, pharmaceutical for preventing or treating cancer enemy composition.
According to claim 1,
When the anticancer agent is irinotecan or a pharmaceutically acceptable salt thereof, the cancer is colorectal cancer, kidney cancer, liver cancer, glioblastoma, pancreatic cancer, breast cancer or leukemia,
When the anticancer agent is paclitaxel or a pharmaceutically acceptable salt thereof, the cancer is colorectal cancer, glioblastoma, melanoma, pancreatic cancer, gastric cancer, lung cancer or leukemia,
When the anticancer agent is 5-FU (fluorouracil) or a pharmaceutically acceptable salt thereof, the cancer is colorectal cancer, kidney cancer, liver cancer, melanoma, lung cancer or leukemia,
When the anticancer agent is cisplatin or a pharmaceutically acceptable salt thereof, the cancer is characterized in that ovarian cancer or leukemia, a pharmaceutical composition for preventing or treating cancer.
An anticancer adjuvant comprising a carnitine acylcarnitine carrier (CAC) inhibitor and an anticancer agent as active ingredients.
According to claim 8,
Characterized in that the carnitine acylcarnitine transporter inhibitor is at least one selected from the group consisting of omeprazole (KN510), lansoprazole (KN511), pantoprazole (KN512) and pharmaceutically acceptable salts thereof , anti-cancer adjuvants.
According to claim 8,
The anticancer agent is any one selected from the group consisting of irinotecan, fluorouracil (5-FU), paclitaxel, gemcitabine, cisplatin, and pharmaceutically acceptable salts thereof An anticancer adjuvant characterized by the above.
According to claim 8,
The anticancer adjuvant comprising the carnitine acylcarnitine transporter inhibitor and the anticancer agent at a concentration ratio of 100:0.1 to 1:1.
According to claim 8,
An anticancer adjuvant, characterized in that the carnitine acylcarnitine transporter inhibitor and the anticancer agent are administered sequentially or simultaneously.
According to claim 8,
The cancer is characterized in that any one or more cancers selected from the group consisting of colorectal cancer, lung cancer, gastric cancer, breast cancer, melanoma, leukemia, ovarian cancer, kidney cancer, pancreatic cancer, glioblastoma and liver cancer, anticancer adjuvant.
According to claim 8,
When the anticancer agent is irinotecan or a pharmaceutically acceptable salt thereof, the cancer is colorectal cancer, kidney cancer, liver cancer, glioblastoma, pancreatic cancer, breast cancer or leukemia,
When the anticancer agent is paclitaxel or a pharmaceutically acceptable salt thereof, the cancer is colorectal cancer, glioblastoma, melanoma, pancreatic cancer, gastric cancer, lung cancer or leukemia,
When the anticancer agent is 5-FU (fluorouracil) or a pharmaceutically acceptable salt thereof, the cancer is colorectal cancer, kidney cancer, liver cancer, melanoma, lung cancer or leukemia,
When the anticancer agent is cisplatin or a pharmaceutically acceptable salt thereof, the cancer is ovarian cancer or leukemia, characterized in that, an anticancer adjuvant.

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