KR20180136679A - Pharmaceutical composition for preventing or treating choriocarcinoma comprising luteolin - Google Patents

Abstract

The present invention relates to a composition comprising luteolin as an active ingredient, and more particularly to a pharmaceutical composition for preventing or treating chorioamnion cancer comprising luteolin as an active ingredient and a pharmaceutical composition for preventing or treating chorioamnion cancer comprising luteolin as an active ingredient, And a health functional food composition for improving health.
The composition comprising ruterol as an active ingredient according to the present invention is extracted from a plant and can minimize toxicity or adverse effects in the body compared with a chemical compound and can inhibit proliferation and migration of chorioallantoic cells, In addition to increasing the number of apoptotic cells, synergistic effects of apoptosis can be obtained when a target inhibitor that inhibits the PI3K / AKT or ERK1 / 2 signal transduction pathway or an anticancer chemotherapeutic agent such as etofoside, cisplatin and paclitaxel It can be used widely in various industries such as bar, life sciences, and medicine.

Description

[0001] The present invention relates to a pharmaceutical composition for preventing or treating chorioamnional cancer,

The present invention relates to a composition comprising luteolin as an active ingredient, and more particularly to a pharmaceutical composition for preventing or treating chorioamnion cancer comprising luteolin as an active ingredient and a pharmaceutical composition for preventing or treating chorioamnion cancer comprising luteolin as an active ingredient, And a health functional food composition for improving health.

Chorionic villi is the most malignant disease of the gestational trophoblastic disease, and most of them develop from reptilia in early pregnancy (VCMak et al. , Carcinogenesis, 2016; L. Duffy et al. , Journal of clinical medicine research, (Soper et al., Gynecol Oncol, 2004) have been reported to be expressed at the rate of one per 20,000 to 40,000 pregnant women, a malignant tumor originating from the trocar. In addition, choriocarcinoma is highly invasive and has been known to frequently migrate to other organs such as the lung and the gland (Geramizadeh and Rad, Indian J Pathol Microbiol, 2012).

A common treatment for chorioamnion cancer is to perform a chemical treatment called EMA-CO. However, 15-25% of patients with choriocarcinoma show resistance and poor prognosis for this chemotherapy (Powles et al., Br J Cancer, 2007). Therefore, in order to overcome the anticancer drug resistance in choriocarcinoma, it is necessary to develop a more effective therapeutic agent.

Flavonoids are found in various plants and are known to exhibit anti-inflammatory and antioxidative effects through intracellular biochemical mechanisms and gene expression regulation (Russo et al ., Biochem Pharmacol, 2012). Luteolin is a flavonoid-based natural plant extract that is extracted from various vegetables such as celery, parsley, and broccoli, and has been studied for growth inhibition and anticancer effects in gastric, prostate, and lung cancer (Lu et al ., J Transl Med, Chiu et al ., Prostate, 2008: Chen et al ., Life Sci, 2013).

On the other hand, it is known that AKT protein has a sub-signaling protein such as P70S6K, GSK3β, mTOR and plays an important role in the survival of cancer cells (Lee et al ., Cancer Biol Med, 2015: Xu et al ., Cell Death Dis ). In particular, mTOR is known to promote lipid biosynthesis, which plays a role as energy storage, cell membrane component, and signal transduction by activating SREBP protein, which regulates intracellular lipid metabolism homeostasis (Menedez and Lupu, Nat Rev Cancer 2007 ), SREBP has been reported to be activated compared to normal cells in various carcinoma cells (Li et al ., Mol Cancer Ther, 2014).

Thus, various pharmacological effects by ruteolin and mTOR-SREBP pathways have been reported, but studies on the effects of mTOR-SREBP pathway on the therapeutic mechanism and survival of chorioamnion cancer using cholecystokinin in chorioallantoic tumors have been reported There is no way.

Accordingly, the present inventors have made intensive efforts to develop a new chorioamnional cancer treatment agent using a natural material-derived substance, and as a result, they have confirmed the cell proliferation, migration inhibition and cell death inducing effect of luteolin using JAR and JEG-3 cells And confirming that ruteolin regulates the signaling pathway around the PI3K / AKT and ERK1 / 2 proteins in the chorioamnion carcinoma cell line, thereby completing the present invention.

It is intended to provide a pharmaceutical composition for preventing or treating chorioamnion cancer comprising ruteroline as an active ingredient.

The present invention also aims to provide a health functional food composition for preventing or ameliorating chorioamnional cancer, which comprises luteolin as an active ingredient.

It is another object of the present invention to provide a method for inhibiting the proliferation and migration ability of a chorionic villus cancer cell line using the pharmaceutical composition or the health functional food composition.

Another object of the present invention is to provide a method for improving the killing effect of a chorionic villus cancer cell line using the pharmaceutical composition or the health functional food composition.

The present invention provides a pharmaceutical composition for the prevention or treatment of chorioamnional cancer, which comprises luteolin as an active ingredient.

The present invention also provides a health functional food composition for preventing or ameliorating chorioamnional cancer comprising luteolin as an active ingredient.

The present invention also provides a method for inhibiting the growth and migration ability of a chorioallcytic cancer cell line using the pharmaceutical composition or the health functional food composition.

The present invention also provides a method for enhancing the killing effect of a chorionic villus cancer cell line using the pharmaceutical composition or the health functional food composition.

The composition comprising ruterol as an active ingredient according to the present invention is extracted from a plant and can minimize toxicity or adverse effects in the body compared with a chemical compound and can inhibit proliferation and migration of chorioallantoic cells, In addition to increasing the number of apoptotic cells, synergistic effects of apoptosis can be obtained when a target inhibitor that inhibits the PI3K / AKT or ERK1 / 2 signal transduction pathway or an anticancer chemotherapeutic agent such as etofoside, cisplatin and paclitaxel It can be used widely in various industries such as bar, life sciences, and medicine.

Fig. 1 shows the results of measuring the effect of ruteolin on the growth of chorionic villus cancer cell lines.
FIG. 2 shows the results of measuring the cell death-inducing effect of chorioallantoic cancer cell line upon treatment with luteolin.
FIG. 3 shows the results of analysis of the phosphorylation pattern of signal transduction material by dose-dependent treatment of luteolin in a chorionic villus cancer cell line.
FIG. 4 shows the result of analysis of the phosphorylation pattern of signal transduction material by time-dependent treatment of luteolin in chorionic villus cancer cell line.
FIG. 5 shows the results of measurement of cell proliferation change patterns by treatment with luteolin and PI3K, ERK1 / 2, and mTOR signal transduction inhibitor in chorionic villus cancer cells.
FIG. 6 shows the results of analysis of signal transduction protein phosphorylation according to treatment with luteolin and PI3K, ERK1 / 2, and mTOR signal transduction inhibitors in chorionic villus cancer cells.
Fig. 7 shows the results of analysis of the expression pattern of SREBP-related gene in chorioallantoic cancer cells by luteolin.
Fig. 8 shows the results of measurement of the expression positions of SREBP1 and SREBP2 in chorioallantoic cancer cells by luteolin.
FIG. 9 shows the results of analysis of the expression of luteolin-induced changes in lipid metabolism-controlling genes in chorionic villus cancer cells.
FIG. 10 shows the treatment efficiency of chorioallantoic cancer using luteolin and conventional chemotherapeutic agents.
FIG. 11 shows the apoptosis mechanism by ruteolin in chorionic villus cancer cells.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In general, the nomenclature used herein is well known and commonly used in the art.

In the present invention, the cell death mechanism of ruteolin in chorioamnion cancer cells was revealed (Fig. 11).

In one aspect, the present invention relates to a pharmaceutical composition for preventing or treating chorioamnion cancer comprising luteolin as an active ingredient.

In another aspect, the present invention relates to a health functional food composition for preventing or ameliorating chorioamnional cancer comprising luteolin as an active ingredient.

The term " composition " as used herein is intended to encompass the products comprising the specified ingredients, as well as any products made directly or indirectly by the combination of the specified ingredients.

In the present invention, the pharmaceutical composition may be characterized by containing a pharmaceutically acceptable carrier, which may be an ion exchange resin, alumina, aluminum stearate, lecithin, serum proteins, buffer substances, water, Characterized in that it is at least one selected from the group consisting of electrolytes, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substrate, polyethylene glycol, sodium carboxymethylcellulose, polyarylate, wax, polyethylene glycol and wool .

In the present invention, the pharmaceutical composition is characterized in that it is formulated for intravenous, intraperitoneal, intramuscular, intraarterial, oral, intracardiac, intramedullary, transdermal, intestinal, subcutaneous, sublingual or topical administration And may further comprise at least one auxiliary selected from the group consisting of a buffer, an antibacterial preservative, a surfactant, an antioxidant, a tonicity adjusting agent, an antiseptic, a thickener and a viscosity modifier, and may further comprise a solution, a suspension, , Gels, and powders. ≪ Desc / Clms Page number 7 >

Suitable dosages of the pharmaceutical compositions of the present invention will vary depending on factors such as the severity of the symptoms, the weight, age, sex, mode of administration, and time of administration of the patient, and the ordinarily skilled physician will, The dose can be easily determined.

In the present invention, the health functional food means a food prepared and processed by using a raw material or a component having a useful function in the human body according to the Health Functional Food Act No. 6722, and the nutrient Refers to foods that are ingested for the purpose of obtaining a beneficial effect in health uses such as control, physiological action, and the like.

The health functional food composition of the present invention may be formulated into a conventional health functional food formulation known in the art and may be formulated into granules, tablets, pills, suspensions, emulsions, syrups, gums, tea, jellies, , An alcoholic beverage and the like, and there is no particular limitation on the kind of the health functional food.

The health functional food composition of the present invention may be in any form suitable for administration to an animal body including the human body, more specifically any form usual for oral administration, for example additives and adjuvants of food or feed, food or feed, Such as powders, granules, powders, granules, powders, powders, powders, powders, powders, powders, powders, powders, powders, powders, powders, Preservatives, and the like, and these components can be used independently or in combination.

In the present invention, it is possible that ruteolin regulates PI3K / AKT and ERK1 / 2 MAPK signal transduction mechanism.

In the present invention, it may be characterized that ruteolin inhibits the activity of the SREBP1 protein.

In the present invention, it may further comprise a target inhibitor that inhibits the PI3K / AKT or ERK1 / 2 signaling pathway.

The composition of the present invention may be administered as an individual therapeutic agent or in combination with another therapeutic agent, and may be administered sequentially or simultaneously with a conventional therapeutic agent.

In the present invention, it may further comprise ethoposide, cisplatin or paclitaxel, but the present invention is not limited thereto and may further include a chemotherapeutic agent used as a chorioamnional cancer therapeutic agent.

In another aspect, the present invention relates to a method for inhibiting the growth and migration ability of a chorionic germ cell line using the pharmaceutical composition or the health functional food composition.

In another aspect, the present invention relates to a method for enhancing the killing effect of a chorionic germ cell line using the pharmaceutical composition or the health functional food composition.

[Example]

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for illustrating the present invention and that the scope of the present invention is not construed as being limited by these embodiments. It is therefore intended that the scope of the invention be defined by the claims appended hereto and their equivalents.

Experimental Method

Experimental animal and cell culture

HTR8 / SVneo, the pregnant choriocarcinoma cell line, and JAR and JEG-3 cells were purchased from the American Type Culture Collection. For cell monolayer culture, RPMI-1640 medium containing 2.05 mM L-Glutaimine 10% fetal bovine serum (FBS) was mixed with HT-8 / SVneo, JAR and MEM medium (JEG-3).

Experimental material

Luteolin, a candidate compound, was purchased from Sigma-Aldrich, Inc. and phospho-AKT, ERK1 / 2, GSK3β, mTOR, P70S6K, P90RSK protein and total AKT were used to confirm the signaling mechanism by luteolin. Antibodies to ERK1 / 2, GSK3?, MTOR, P70S6K and P90RSK were purchased from Cell Signaling Techonology. In addition, PCNA antibody was purchased from Santa Cruz Biotechnology. In addition, PI3K inhibitor LY294002 was purchased from Cell Signaling Technology, ERK1 / 2 inhibitor U0126, and mTOR inhibitor rapamycin were purchased from Enzo Life Science in order to investigate the effect of inhibiting the target signal transduction process. Etoposide, cisplatin and paclitaxel were also purchased from Sigma.

BrdU  Analysis of cell proliferation ability

To confirm the effect of ruteolin on the proliferative capacity of chorionic villus carcinoma cells, 5 × 10 ³ cells cultured under FBS condition and 100 μl of culture medium were divided into 96 wells, and luteolin was administered in a dose dependent manner (0, 5, 10, 20, 50, and 100 μM), cultured for 48 hours, and then tested according to the manufacturer's manual using a BrdU kit (Cat No: 1167229001, Roche). After a 48 hour incubation, 10 [mu] M BrdU was added to each well and incubated for 2 hours in a 37 [deg.] C / 5% CO ₂ incubator. BrdU was labeled on chorionic villus cancer cells and the cells were fixed. The anti-BrdU-POD solution was incubated at room temperature for 90 minutes and washed three times. Finally, cells were reacted with 100 μl of 3,3 ', 5,5'-tetramethylbenzidine substrate and assayed for their ability to proliferate by measuring absorbance at 370 nm and 492 nm using an ELISA reader.

Immunofluorescence

3 × 10 ⁴ chorioallcytic cancer cells were cultured in a confocal dish (catalog number: 100350, SPL Life Science, Republic of Korea) together with 300 μl of a medium containing 10% FBS, . The cells were treated with 20 μM of ruteolin for 48 hours, then fixed with methanol for 10 minutes, treated with PCNA antibody diluted to 2 μg / ml, and treated with mouse IgG for 16 hours at 4 ° C. Then, goat anti-mouse IgG Alexa 488 (catalog number: A-11001, Invitrogen, Carlsbad, Calif., USA) was used as the secondary antibody after 2 washes with PBS containing 0.1% bovine serum albumin diluted 1: 200 in antibody dilution buffer, and incubated at room temperature for 1 hour. JEG-3 cells were washed with 0.1% BSA-PBS and DAPI staining was performed to observe the nuclei as well as target proteins in JEG-3 cells. After completion of the experiment, cells were observed and photographed using a confocal microscope of LSM710 (Carl Zeiss, Thornwood, NY, USA).

TUNEL  Analysis of apoptosis through reaction

3 × 10 ⁴ chorioallcytic cancer cells were cultured in a confocal dish (catalog number: 100350, SPL Life Science, Republic of Korea) together with 300 μl of a medium containing 10% FBS, And treated with 20 μM of ruteolin for 48 hours. Then, the cells were air-dried and incubated with 4% paraformaldehyde at room temperature for 1 hour to fix the cells. Fixed cells were rinsed once with PBS and incubated on ice for 2 minutes with 0.1% sodium citrate in a solution containing 0.1% Triton X-100. Next, the cells were incubated in a 37 ° C / 5% CO ₂ incubator for 1 hour using a TUNEL staining mixture contained in the In Situ Cell Death Detection Kit, TMR red (Roche). Finally, after rinsing with PBS and staining DAPI, cells were observed and photographed using a confocal microscope LSM710 (Carl Zeiss, Thornwood, NY, USA).

Annexin  V and propidium  Analysis of apoptosis through iodide staining

In order to confirm the killing effect of chitosan cancer cells by ruteolin, experiments were carried out using FITC Annexin V Cell Death Diagnosis Kit I (BD Biosciences). First, 5 × 10 ⁵ cells were cultured in 6 wells, and when the cells were filled in the 70-80% culture dish, they were further cultured in a FBS starvation state for 24 hours. Luteolin was then treated in a dose dependent manner (0, 5, 10, 20 μM) and incubated in a 37 ° C / 5% CO ₂ incubator for 48 hours. Then, the cells were detached from the culture dish using trypsin, washed with PBS, and the cells were slowly mixed using 1 mL of 1 × binding buffer and centrifuged to obtain a cell pellet. Next, cells were suspended in 200 μL of 1 × binding buffer, 100 μL of each was added to a brown 1.5 mL tube, and 5 μL of Annexin V and 5 μL of PI were mixed together and the cells were stained for 15 minutes at room temperature. Then, 400 μL of 1 × binding buffer was added, and the stained solution was transferred to a 5 mL FACS tube. The fluorescence intensity was analyzed using a flow cytometer and the number of dead cells was measured.

JC -1 Mitochondria through staining Membrane potential  Measure

Changes in JC-1 mitochondrial membrane potential (MMP) were measured using the mitochondria staining kit (Cat No: CS0390, Sigma-Aldrich). 5 × 10 ⁵ choriocarcinoma cells were cultured in 6 wells, and when the cells were filled in a 70-80% culture dish, they were further cultured for 24 hours in an FBS starvation state. Luteolin was then treated in a dose dependent manner (0, 5, 10, 20 μM) and incubated in a 37 ° C / 5% CO ₂ incubator for 48 hours. Then, cells were detached from the culture dish using trypsin and centrifuged to obtain a cell pellet. Cells were uncoated in JC-1 staining solution and incubated for 20 min in a 37 ° C / 5% CO ₂ incubator. The stained cells were centrifuged again, washed with 1 × JC-1 staining buffer, and analyzed for fluorescence intensity using a flow cytometer.

Protein Expression Analysis ( Western blot )

Chorionic villus cancer cells were treated with a mixture of ruteolin or a cell signal transduction inhibitor, and whole proteins were extracted from chorionic villus carcinoma cells and quantified by Bradford protein assay (Bio-Rad, Hercules, CA, USA). Then, the extracted proteins were denatured at 95 ° C for 5 minutes, electrophoresed using 10% SDS / PAGE gel, transferred to nitrocellulose membrane, incubated with primary antibody and secondary antibody, and then chemiluminescence detection (SuperSignal West Pico, Pierce, Rockford, Ill., USA) reagents, and ChemiDoc EQ system and Quantity One software (Bio-Rad) instrument.

mRNA  Expression analysis ( qPCR )

Chorionic villus cancer cells were treated with 20 μM luteolin and total RNA was extracted using Trizol reagent (Invitrogen). Then, 1 μg of RNA was synthesized using AccuPower RT PreMix (Bioneer, Daejeon, Korea). Gene expression was measured using SYBR Green (Sigma) and the StepOnePlus Real-Time PCR system (Applied Biosystems, Foster City, CA). The PCR conditions were: incubation at 95 ° C. for 3 minutes, followed by 95 ° C. for 30 seconds, 60 ° C. for 30 seconds, and 72 ° C. for 3 minutes. The conditions were normalized based on the amount of GAPDH expression.

Statistical analysis

The mean and standard error were calculated using a statistical analysis system (SAS) statistical program and one-way ANOVA was performed. Significance test was performed at P <0.05 level.

Results and Discussion

Chorionic villus  Analysis of the effects of luteolin on proliferation

In order to analyze the changes of normal pregnancy early stage trophoblast (HTR8 / SVneo) and gestational trophoblast cell line (JAR, JEG-3) by luteolin, luteolin was first administered in a dose dependent manner (0, 5, 10, , 100 [mu] M) for 48 hours. After the cell proliferation pattern was analyzed, it was confirmed that the proliferative capacity of chorionic villus cancer cells was gradually decreased by luteolin (Fig. 1A). However, the viability of HTR8 / SVneo cells, which are normal human cancer cell lines, was not affected by ruteolin. Thereafter, an immunofluorescence technique was performed using an antibody against PCNA, a protein essential for DNA propagation (FIG. 1B). As a result, the expression of PCNA was significantly reduced in the nucleus of chorioalloidal cancer cells treated with 20 μM luteolin for 48 hours compared to the control group, confirming that ruteolin inhibited the proliferation of choriocarcinoma cells Respectively.

By luteolin Chorionic villus  Death inducing effect

In order to analyze the induction effect of ruteolin on chorioamnional cancer cells, TUNEL assay was performed after incubation of 20 μM luteolin for 48 hours in chorionic villus cancer cells. As a result, DNA fragmentation hardly occurred in the chorionic villus cancer cells of the control group, but it was confirmed that the DNA fragmentation was increased by treatment with luteolin (FIG. 2A). In addition, the number of chorionic villus cells that underwent apoptosis through chorionic villus staining with Annexin V and PI was measured by FACS, and it was 488% (JAR), 703% (JEG -3) (Fig. 2B, 2C). In addition, when the depolarization of mitochondria was measured by FACS after JC-1 staining, it was found that 146.6% (JAR) and 677% (JEG-3) of mitochondria (Fig. 2D, 2E). It was confirmed that ruteolin induces apoptosis through DNA fragmentation and mitochondrial membrane potential change from chorionic villus cancer cells.

By luteolin Chorionic villus cancer cells  Analysis of regulation of my signal transduction mechanism

The phosphorylation pattern of ERK1 / 2 MAPK and AKT associated with proliferation was determined by luteolin dose-dependent (Fig. 3) to confirm the signaling mechanism of cell proliferation inhibition and cell death induced by luteolin in chorioallcytic cancer cells Western blot analysis. As a result, luteolin dose - dependently suppressed phosphorylation of AKT and P70S6K in chorioallcytic cancer cells, and phosphorylation of ERK1 / 2 was dose - dependently induced by luteolin. In addition, the phosphorylation pattern of GSK3β and P90RSK by luteolin showed a tendency to be different between the two villous cancer cells. In addition, phos- phorylation of AKT, GSK3β, and ERK1 / 2 by time-dependent treatment of choroidal cancer cells with luteolin resulted in inactivation of the AKT signaling pathway and activation of the ERK1 / 2 mechanism, (Fig. 4).

Through luteolin and signal transduction inhibitors Chorionic villus  Analysis of proliferation change pattern

To investigate the effect of ruteolin-regulated signaling molecules on the proliferation of chorionic villus cells, 20 μM of LY294002 (PI3K inhibitor), 10 μM of U0126 (ERK1 / 2 inhibitor) or 10 μM of rapamycin (mTOR inhibitor) And treated with luteolin 20 μM. In JAR cells, it was confirmed that the effect of inhibiting cell proliferation was enhanced when the combination treatment with luteolin or a signal transduction protein inhibitor was performed more than when treated with luteolin or a signal transduction protein inhibitor alone (Fig. 5A). However, in the case of JEG-3 cells, it was confirmed that cell proliferation was more inhibited when U0126 and luteolin were coadministered than when they were treated alone (Fig. 5B). These results suggest that PI3K / AKT and ERK1 / 2 signaling pathways are closely related to the antiproliferative effect of luteolin on chorionic villus carcinoma cells, suggesting that they mediate different intracellular mechanisms in the two choroidal cancer cells do.

With luteolin AKT , ERK1 / 2 signaling pathway inhibitor mixture JEG -3 Analysis of intracellular signaling substance phosphorylation pattern

In order to determine the precise cellular mechanism of the antioxidant effect of cholangiocarcinoma cells, LY294002, U0126, or rapamycin were first incubated in chorionic villus carcinoma cells for 1 hour, and the signal transduction pathway was stopped. Luteolin 20 μM was then treated The phosphorylation pattern of AKT, GSK3β and ERK1 / 2 was confirmed. As a result, the phosphorylation of AKT reduced by luteolin was not restored by ERK1 / 2 or mTOR inhibition (Fig. 6A). When JEG-3 cells specifically treated all signal transduction inhibitors with luteolin Lt; RTI ID = 0.0 &gt; (Fig. 6B). &Lt; / RTI &gt; In addition, when LY294002 in chorionic villus cancer cells was treated with luteolin, it was confirmed that phosphorylation of ERK1 / 2 was enhanced more than that of luteolin alone (Fig. 6C). These results imply that the effect of luteolin on chimeric cancer cells is related to the inactivation of the PI3K / AKT signaling pathway and the activation of the ERK1 / 2 signaling pathway.

Luteo Olin Chorionic villus cancer cells  of mine SREBP  Influence on mediating lipid metabolism

SREBP1 , SREBP2 , and SREBP2 , which regulate lipid metabolism homeostasis by extracting RNA from ruteolin- treated chorioamnion cancer cells to determine whether ruteolin participates in the lipogenic mechanism mediated by the PI3K / AKT / mTOR signaling mechanism in chorionic villus cancer cells, Expression at the mRNA level of SCAP was confirmed (Fig. 7A). As a result, mRNA expression of SREBP1 , SREBP2 , and SCAP was decreased when 20 μM of ruteolin was treated. In addition, it was confirmed that mRNA expression of mTOR was decreased and the expression of SREBP1 was decreased and that the expression of SREBP2 protein was not influenced by luteolin dose-dependently (Fig. 7B-D).

In addition, intracellular expression of SREBP1 and SREBP2 was re-verified by immunofluorescence using antibodies (Fig. 8). SREBP induced lipid biosynthesis-related genes ( FASN , ACACA , PPARγ , DBI , SCD, HMGCR , HMGCS1 , FDFT1 , MVK , and SQLE ) at the mRNA level was regulated by luteolin (Fig. 9). As a result, it was confirmed that the expression of most genes was significantly reduced by luteolin.

By luteolin and chemotherapy Chorionic villus  Comparative analysis of proliferation pattern

To compare the anti-proliferative effects of etoposide, cisplatin, paclitaxel and luteolin used in the treatment of chorioamnion cancer, each combination of chemotherapy and luteolin was used (Fig. 10). As a result, JAR cells were found to have enhanced anti-proliferative effect when treated with ethoposide or luteolin alone, while anti-proliferative effect of ethoposide and paclitaxel was enhanced in JEG-3 cells compared with JAR cells And that it was resistant to cisplatin. However, it was confirmed that the anti - proliferative effect of each combination of chemotherapy with luteolin was enhanced. These results indicate that ruteolin is highly likely to be developed as a treatment for chorioamnion cancer or as an adjuvant treatment for existing chemotherapy.

While the present invention has been particularly shown and described with reference to specific embodiments thereof, those skilled in the art will readily appreciate that many modifications are possible in the exemplary embodiments without materially departing from the novel teachings and advantages of this invention. something to do. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (12)

A pharmaceutical composition for the prevention or treatment of chorioamnional cancer, comprising luteolin as an active ingredient. The method according to claim 1,
Wherein said ruteolin regulates PI3K / AKT and ERK1 / 2 MAPK signal transduction mechanism. The method according to claim 1,
The pharmaceutical composition for preventing or treating chorioamnional cancer, wherein the ruteolin inhibits the activity of the SREBP1 protein. The method according to claim 1,
A target inhibitor that inhibits the PI3K / AKT or ERK1 / 2 MAPK signaling pathway. The method according to claim 1,
A pharmaceutical composition for the prevention or treatment of chorioamnional cancer, which further comprises etofoside, cisplatin or paclitaxel. A health functional food composition for preventing or ameliorating choriocarcinoma comprising luteolin as an active ingredient. The method according to claim 6,
Wherein said ruteolin regulates PI3K / AKT and ERK1 / 2 MAPK signal transduction mechanism. The method according to claim 6,
Wherein said ruteolin inhibits the activity of the SREBP1 protein. The method according to claim 6,
PI3K / AKT or ERK1 / 2 signal transduction pathway. &Lt; RTI ID = 0.0 &gt; 25. &lt; / RTI &gt; The method according to claim 6,
Wherein the composition further comprises etofoside, cisplatin or paclitaxel. A pharmaceutical composition for preventing or treating chorioamnional cancer according to any one of claims 1 to 5 or a health functional food composition for preventing or treating chorion cell cancer according to any one of claims 6 to 10, And a method of inhibiting migration ability. A pharmaceutical composition for preventing or treating ovarian cancer of the chorioallantoic cancer according to any one of claims 1 to 5 or a health functional food composition for preventing or treating chorioamnional cancer according to any one of claims 6 to 10, Of the killing effect.

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