KR20170079128A - A Pharmaceutical composition comprising PPAR-β inhibitor for enhancing Anti-cancer effect - Google Patents
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Abstract
The present invention relates to a pharmaceutical composition for enhancing an anti-cancer effect comprising a PPAR-beta (peroxisome proliferator-activated receptor-beta) antagonist. In the present invention, it was confirmed that the increase of the nuclear receptor PPAR-beta in the sorafenib resistant hepatocarcinoma cell line caused reprogramming of glucose and glutamine metabolism by regulating the protein involved in cancer metabolism, The inhibition of PPAR-β has been shown to increase the reactivity to sorapenib and ultimately to overcome tolerance to sorafenib, which may be useful for the effective treatment of liver cancer.
Description
The present invention relates to a pharmaceutical composition for enhancing an anticancer effect comprising a PPAR-beta (peroxisome proliferator-activated receptor-beta) antagonist, and more particularly to a pharmaceutical composition for enhancing anticancer efficacy inhibiting tolerance to Sorafenib, ≪ / RTI >
Cancer is one of the deadliest threats to human health, with about 1.3 million new cancer cases occurring annually in the United States, the second leading cause of death after cardiovascular disease. Currently, surgical treatment, radiation therapy, and chemotherapy are used for the treatment of cancer. Among them, chemotherapy is a method of treating cancer by using an anticancer drug, and methotrexate is added to choriocarcinoma It was used in earnest by obtaining a cure effect. Today, about 60 kinds of various anticancer drugs are used. Recently, as knowledge of cancer development and characteristics of cancer cells is well known, researches on the development of new anticancer drugs are being actively carried out.
Among them, liver cancer is the sixth most common cancer worldwide and is the highest cause of cancer-related deaths. Hepatocellular carcinoma is the primary treatment for hepatocellular carcinoma, but only 30-40% of patients with early diagnosis can undergo surgical treatment. Sorafenib, a multi-kinase inhibitor, has been used as a major therapeutic agent in advanced hepatocellular carcinoma, which can not be operated on, but its clinical survival improvement is insufficient due to tolerance by sorapenib, Efforts are continuing to overcome this by recurrence. Metabolic adaptation studies of cancer cells in metabolic stress conditions, such as nutritional deficiency, hypoxia, and exposure to anticancer drugs, have not been shown to respond to conventional treatments, Which is a new therapeutic strategy. Among them, the corresponding processes, fatty acid synthesis, and increased glutamine metabolism have been reported as important metabolic adaptation mechanisms against external stress.
Under these circumstances, studies on combined chemotherapy using cross-resistance agents with different mechanisms of action have been actively conducted in order to overcome the resistance of cancer cells to anticancer agents. (Korean Patent Publication No. 10-2012-0075978).
DISCLOSURE OF THE INVENTION The present invention was conceived in order to solve the above problems. The present inventors first identified the pathway for acquiring Sorafenib resistance by increasing the expression of PPAR-beta (Peroxisome proliferator-activated receptor-beta) It has been confirmed that the use of an antagonist can inhibit tolerance to sorapenib and effectively inhibit the proliferation of liver cancer cells, and the present invention has been completed on the basis thereof.
Accordingly, an object of the present invention is to provide a pharmaceutical composition for enhancing an anticancer effect comprising, as an active ingredient, a PPAR-beta antagonist, which is used in combination with an anticancer agent, sorapenib.
However, the technical problem to be solved by the present invention is not limited to the above-mentioned problems, and other matters not mentioned can be clearly understood by those skilled in the art from the following description.
In order to achieve the object of the present invention as described above, the present invention provides a medicament for enhancing the anticancer effect comprising, as an active ingredient, a PPAR-beta (peroxisome proliferator-activated receptor-beta) antagonist in combination with sorafenib, Gt;
In one embodiment of the present invention, the PPAR-beta antagonist may be an siRNA comprising the sense sequence of SEQ ID NO: 1 and the antisense sequence of SEQ ID NO: 2 or a compound represented by the following formula (1).
[Chemical Formula 1]
In another embodiment of the present invention, the composition may enhance the anti-cancer effect against liver cancer.
In another embodiment of the present invention, the composition may inhibit tolerance to sorapenib.
In another embodiment of the present invention, the composition may be administered simultaneously, separately or sequentially with the anti-cancer agent.
In another embodiment of the present invention, the composition may reduce the expression of one or more genes selected from the group consisting of PDK1, p-PDHelain, and GLS1.
The present invention provides a method of enhancing an anticancer effect or a method of treating cancer comprising the step of administering the pharmaceutical composition to a subject.
The present invention provides the use of a composition comprising a PPAR-beta antagonist to enhance the anti-cancer effect and to treat cancer.
The present invention relates to a pharmaceutical composition for enhancing an anti-cancer effect comprising a PPAR-beta (peroxisome proliferator-activated receptor-beta) antagonist. In the present invention, it was confirmed that the increase of the nuclear receptor PPAR-beta in the sorafenib resistant hepatocarcinoma cell line caused reprogramming of glucose and glutamine metabolism by regulating the protein involved in cancer metabolism, It is expected that the inhibition of PPAR-β will increase the reactivity to sorapenib and ultimately overcome the tolerance to sorafenib, which will be used as a new therapeutic target for advanced liver cancer.
FIG. 1 shows the results of flow cytometry analysis of the death of liver cancer cells following treatment with sorapenib in the sorapenib resistant hepatoma cell line (Huh7-SR cell line).
FIG. 2 shows Western blot analysis of Cleaved caspase-3 and cleaved PARP expression in sorapenib-resistant liver cancer cell line following sorafenib treatment.
FIG. 3 shows the results of Western blotting the expression of PDK1, p-PDHe1α, G6PD, GLS1, nSREBP-1c and PPAR-β according to sorafenib treatment in sorafenib resistant liver cancer cell line.
FIG. 4 shows the results of XF analysis of the change in oxygen consumption rate following sorafenib treatment in sorafenib resistant liver cancer cell lines.
FIG. 5 shows Western blot results of expression of PDK1, p-PDHe1α and GLS1 in a sorapenib resistant liver cancer cell line treated with PPAR-β siRNA.
FIG. 6 shows Western blot results of expression of PDK1, p-PDHe1α and GLS1 in a sorapenib resistant liver cancer cell line treated with the PPAR-β antagonist GSK0660.
FIG. 7 shows the results of XF analysis of changes in oxygen consumption rate in sorafenib resistant liver cancer cell line treated with PPAR-beta antagonist GSK0660.
FIG. 8 shows Western blot results of PDK1, p-PDHe1α, G6PD, GLS1, nSREBP-1c, and PPAR-β expression in sorapenib resistant liver cancer cell lines treated with sorapenib and GSK0660.
FIG. 9 shows the results of flow cytometry analysis of (a) quantitative changes in liver cancer cell numbers and (b) death rate of liver cancer cells in sorapenib resistant liver cancer cell lines treated with sorapenib and GSK0660.
Fig. 10 shows the result of visually observing changes in size of a mass in an animal model derived from sorapenib resistant liver cancer cell line treated with sorapenib and GSK0660. Fig.
Fig. 11 shows the results of quantitative changes in the size of mass in an animal model derived from sorapenib resistant liver cancer cell line treated with sorapenib and GSK0660.
The inventors of the present invention first identified the pathway for acquiring Sorafenib resistance by confirming the increased expression of PPAR-beta (peroxisome proliferator-activated receptor-beta) in the Sorapenib resistant hepatocarcinoma cell line and found that by using PPAR- Phenobin and inhibit the proliferation of hepatic cancer cells. The present invention has been completed on the basis thereof.
Hereinafter, the present invention will be described in detail.
The present invention provides a pharmaceutical composition for use in combination with sorapenib, which comprises a PPAR-beta antagonist as an active ingredient.
In the present invention, "PPAR-beta antagonist" refers to a substance that inhibits the expression or activity of PPAR-beta, and the effect of VEGF, AKT increase and PTEN decrease in relation to the function of PPAR- , There is no known information regarding the resistance to sorafenib drug. The PPAR-beta antagonist is preferably an siRNA comprising the sense sequence of SEQ ID NO: 1 and the antisense sequence of SEQ ID NO: 2 or a compound represented by the following formula (3 - [[[2-Methoxy-4- (phenylamino) phenyl] amino ] sulfonyl] -2-thiophenecarboxylic acid methyl ester, hereinafter referred to as GSK0660).
[Chemical Formula 1]
On the other hand, "cancer" which is a disease to be treated by the composition of the present invention refers to an aggressive characteristic that the cell ignores normal growth limit and divides and grows, invasive characteristic penetrating into surrounding tissues, And diseases caused by cells with metastatic characteristics that spread to other parts of the body. In the present invention, the type of cancer may be any one selected from the group consisting of pancreatic cancer, stomach cancer, liver cancer, colon cancer, brain cancer, breast cancer, thyroid cancer, bladder cancer, esophageal cancer, uterine cancer, and lung cancer, Preferably liver cancer.
The term "anticancer drug resistance" used in the present invention means that in the treatment of cancer using an anticancer agent, there is no effect from the beginning of the treatment or the cancer treatment effect is initially lost, but the cancer treatment effect is lost during the continuous treatment.
As the anticancer agent used in combination with the composition of the present invention, it may preferably be sorapenem. Currently, a multi-kinase inhibitor, sorapenib, is used as a major therapeutic agent for advanced liver cancer. However, resistance to the treatment with sorapenib in cancer cells is difficult to treat effectively due to the acquisition problem. Accordingly, by administering the composition of the present invention in a simultaneous, separate or sequential manner to sorafenib, the tolerance to sorafenib can be suppressed, thereby further enhancing the cancer treatment effect of sorapenib Respectively.
In one embodiment of the present invention, a Sorapenib-resistant liver cancer cell line was constructed, and the expression of PPAR-beta was confirmed by the pathway of acquiring the Sorapenib resistance in the cell line (see Example 1). In another embodiment of the present invention, when the PPAR-beta antagonist is treated with sorapenib, the expression of the resistance-related factors and the inhibitory effect on the proliferation and death of hepatocellular carcinoma cells in the sorafenib resistant hepatocellular carcinoma cell line are inhibited by sorafenib- The decrease in the size of the masses in the animal model derived from the cell line was confirmed, and thus it could be usefully used as a combined preparation to overcome tolerance to sorafenib.
The pharmaceutical composition according to the present invention may contain a pharmaceutically acceptable carrier in addition to the active ingredient. The pharmacologically acceptable carriers are those conventionally used at the time of formulation and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose But are not limited to, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. Further, in addition to the above components, a lubricant, a wetting agent, a sweetener, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, and the like may be further included.
The pharmaceutical composition of the present invention may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically) depending on the intended method, and the dose may vary depending on the condition and the weight of the patient, The mode of administration, the route of administration, and the time, but may be appropriately selected by those skilled in the art.
The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. In the present invention, the term "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level will depend on the type of disease, severity, The sensitivity to the drug, the time of administration, the route of administration and the rate of release, the duration of the treatment, factors including co-administered drugs, and other factors well known in the medical arts. The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, sequentially or concurrently with conventional therapeutic agents, and may be administered singly or in multiple doses. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without side effects, which can be easily determined by those skilled in the art.
Specifically, the effective amount of the pharmaceutical composition of the present invention may vary depending on the age, sex, condition, body weight, the degree of absorption of the active ingredient in the body, the rate of inactivation and excretion, the type of disease, 100 to 500 mg per kg of body weight may be administered daily or every other day, or one to three divided doses per day. However, the dosage may be varied depending on the route of administration, the severity of obesity, sex, weight, age, etc. Therefore, the dosage is not limited to the scope of the present invention by any means.
In another aspect of the present invention, the present invention provides a method of enhancing an anticancer effect or a method of treating cancer comprising the step of administering the pharmaceutical composition to an individual. The term " individual "as used herein refers to a subject in need of treatment of a disease, and more specifically refers to a mammal such as a human or non-human primate, mouse, dog, cat, horse, do.
Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the following examples.
[Example]
Example 1 Construction of Sorapenib Resistant Liver Cancer Cell Line and Confirmation of Acquisition of Resistance
In this Example, a liver cancer cell line resistant to Sorapenib, which is known to be an active ingredient of a therapeutic agent for liver cancer, was constructed and the present inventors searched for the mechanism of obtaining sorapenib resistance using the cell line. Specifically, the concentration of sorapenib was gradually increased to 10 mM to continuously expose sorapenib to the Huh 7 liver cancer cell line. As shown in FIGS. 1 and 2, the Sorapenib resistant hepatoma cell line (Huh7-SR cell line). In addition, changes in expression of glucose and glutamine metabolism related proteins (PDK1, p-PDHe1α, G6PD, GLS1, nSREBP-1c, and PPAR-β) were observed in the sorafenib resistant liver cancer cell line , And the change of oxygen consumption rate over time was analyzed by XF analysis. At this time, Huh 7 liver cancer cells were used as a control group.
As a result, as shown in Fig. 3, expression of PDK1 and p-PDHe1 alpha involved in the oxidation of keratin acid, GLS1, which plays an important role in glutamine metabolism, and the nuclear receptor PPAR-β were remarkable in the sorafenib resistant liver cancer cell line Respectively. In addition, as shown in FIG. 4, it was confirmed that glutamine oxidation of the sorapenib-resistant liver cancer cell line was increased by increasing the oxygen consumption rate.
These results indicate that the acquisition of resistance to sorapenib in liver cancer cells is closely related to PDK1, p-PDHe1α, GLS1, and PPAR-β.
Example 2. Confirmation of the inhibitory effect of sorapenib on PPAR-beta inhibition
In this example, the role of the nuclear receptor PPAR-β, which is expressed in the sporadic hepatocarcinoma cell line, was investigated. Therefore, the expression of sorapenib resistance-related factors was confirmed by treatment with PPAR-β antagonist, and the effect of the combination of sorapenib and PPAR-β antagonist on the resistance to sorafenib and the proliferation of liver cancer cell line was confirmed.
2-1. Decreased expression of sorafenib resistant factor
PPAR-β siRNA and PPAR-β antagonist GSK0660 were used, and the expression of sorafenib resistance-related factors (PDK1, p-PDHe1α, and GLS1) was confirmed by these treatments, and the oxygen consumption rate Were analyzed by XF analysis. At this time, as a control group, a group not treated with PPAR-beta antagonist was used in the sorafenib resistant liver cancer cell line.
As a result, as shown in Figs. 5 to 7, the expression of PDK1, p-PDHe1 [alpha], and GLS1, which were increased in the filamentous hepatocarcinoma cell line, was reduced in both cases of treatment with PPAR-beta siRNA and GSK0660 5 and 6), it was confirmed that, similarly to the above results, when the PPAR-beta antagonist was treated, the oxidation of glutamine was also reduced (see FIG. 7).
2-2. Sorapenip and PPAR -b < / RTI > antagonist Sorapanib Confirmation of tolerance
The expression of sorafenib resistance factors (PDK1, p-PDHe1α, and GLS1) and the proliferation of hepatocellular carcinoma cells were analyzed by using the PPAR-β antagonist GSK0660 and the combination of sorapenib and GSK0660 in the sorafenib- . As a control group, sorapenib-resistant liver cancer cell line treated with sorapenib alone was used.
As a result, as shown in FIG. 8, it was confirmed that PDK1, p-PDHe1α, and GLS1 expression, which were increased in the endosomes of Sorapenib resistant liver cancer cell lines, were reduced when the combination treatment with GSK0660 was performed. In addition, as shown in Fig. 9, in the case of sorafenib resistant hepatocarcinoma cell line, cell proliferation could not be inhibited by only sorapenib treatment alone, but cell proliferation could be effectively inhibited and killed by the combination treatment with GSK0660 Respectively.
EXAMPLE 3 Confirmation of Sorafenib Resistance-Inhibitory Effect Using Animal Model
In this Example, the effect of the combination treatment of sorapenib with PPAR-beta antagonist on the resistance to sorapenib and the proliferation of hepatocellular carcinoma cell line was confirmed in vivo using an animal model derived from sorapenib resistant hepatocellular carcinoma cell line (Xenograft). Specifically, sorapenib resistant hepatocellular carcinoma cells were injected into mice to induce sorapenib resistant hepatocellular carcinoma, and subsequently, sorapenib and PPAR-beta antagonist were combined, and then the size change of the formed mass was measured. At this time, as the comparative control group, a group treated with sorapenib alone was used in the animal model derived from the sorapenib resistant liver cancer cell line.
As a result, as shown in Fig. 10 and Fig. 11, when the combination treatment with GSK0660 was performed, it was confirmed that the size of the mass formed by the Sorapenib resistant hepatocellular carcinoma cell line was significantly reduced as compared with the control group.
The above results show that the combination of sorafenib and PPAR-beta antagonist (PPAR-beta siRNA, GSK0660) in an animal model derived from liver cancer cell line or liver cancer cell line, which was not effective only by treatment with sorapenib, , Suggesting that the inhibition of PPAR-β may increase susceptibility to sorafenib to inhibit tolerance to sorafenib and improve the efficacy of sorafenib in the treatment of liver cancer.
It will be understood by those skilled in the art that the foregoing description of the present invention is for illustrative purposes only and that those of ordinary skill in the art can readily understand that various changes and modifications may be made without departing from the spirit or essential characteristics of the present invention. will be. It is therefore to be understood that the above-described embodiments are illustrative in all aspects and not restrictive.
<110> Kyungpook National University Industry-Academic Cooperation Foundation
KYUNGPOOK NATIONAL UNIVERSITY HOSPITAL
<120> A pharmaceutical composition comprising a PPAR-beta inhibitor for
enhancing Anti-cancer effect
<130> 2015-0363-KR-MP15-179
<160> 2
<170> KoPatentin 3.0
<210> 1
<211> 19
<212> DNA
<213> Artificial Sequence
<220>
<223> siPPAR-beta_sense
<400> 1
guccuuccau cuucacacu 19
<210> 2
<211> 19
<212> DNA
<213> Artificial Sequence
<220>
<223> siPPAR-beta_antisense
<400> 2
Claims (7)
Wherein the composition comprises PPAR-beta (peroxisome proliferator-activated receptor-beta) antagonist as an active ingredient, and the anticancer agent is sorafenib.
[Chemical Formula 1]
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| Publication number | Priority date | Publication date | Assignee | Title |
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| KR20210065064A (en) * | 2019-11-26 | 2021-06-03 | 주식회사 노브메타헬스 | Pharmaceutical Composition for Enhancing Anti-Cancer Effect Comprising ERRγ Inhibitor as an Active Ingredient |
| CN116898919A (en) * | 2023-07-06 | 2023-10-20 | 宁波科瑞特动物药业有限公司 | Animal insect repellent and preparation method thereof |
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| KR102431651B1 (en) | 2019-11-26 | 2022-08-12 | 경북대학교 산학협력단 | Novel PPARδ antagonist and Pharmaceutical composition for enhancing anti-cancer effect comprising the same |
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| Lihong Xu, et al. Cancer Res. 2006 Dec 15 * |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| KR20210065064A (en) * | 2019-11-26 | 2021-06-03 | 주식회사 노브메타헬스 | Pharmaceutical Composition for Enhancing Anti-Cancer Effect Comprising ERRγ Inhibitor as an Active Ingredient |
| WO2021107644A1 (en) * | 2019-11-26 | 2021-06-03 | 주식회사 노브메타헬스 | USE OF COMPOSITION FOR ENHANCING ANTICANCER EFFECT, COMPRISING ERRγ INHIBITOR AS ACTIVE INGREDIENT |
| CN114980897A (en) * | 2019-11-26 | 2022-08-30 | 诺麦塔制药有限公司 | Use of composition comprising estrogen-related receptor gamma inhibitor for enhancing anticancer effect as active ingredient |
| CN116898919A (en) * | 2023-07-06 | 2023-10-20 | 宁波科瑞特动物药业有限公司 | Animal insect repellent and preparation method thereof |
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