WO2019088749A1 - Composition for preventing, ameliorating or treating liver cancer or gastric cancer containing sinensetin as active ingredient - Google Patents

Composition for preventing, ameliorating or treating liver cancer or gastric cancer containing sinensetin as active ingredient Download PDF

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WO2019088749A1
WO2019088749A1 PCT/KR2018/013230 KR2018013230W WO2019088749A1 WO 2019088749 A1 WO2019088749 A1 WO 2019088749A1 KR 2018013230 W KR2018013230 W KR 2018013230W WO 2019088749 A1 WO2019088749 A1 WO 2019088749A1
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cells
composition
sinensetin
active ingredient
liver cancer
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French (fr)
Korean (ko)
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김곤섭
이상준
허정두
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경상대학교산학협력단
한국화학연구원
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Publication of WO2019088749A1 publication Critical patent/WO2019088749A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/116—Heterocyclic compounds
    • A23K20/121—Heterocyclic compounds containing oxygen or sulfur as hetero atom
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A61K31/282—Platinum compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/308—Foods, ingredients or supplements having a functional effect on health having an effect on cancer prevention

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  • the present invention relates to a composition for preventing, ameliorating or treating liver cancer or stomach cancer containing cinnensetin as an active ingredient, and more particularly to a composition for preventing, ameliorating or treating liver cancer or stomach cancer containing cinnensetine or cinnenecetin and cisplatin as an active ingredient Therapeutic and transfection-inhibiting pharmaceutical compositions, functional food compositions and functional feed compositions.
  • Cancer refers to a group of cells that are caused by continuous division and proliferation of abnormal cells by destroying the balance of cell division and death by various causes, and are sometimes referred to as tumors. It usually occurs in more than 100 different parts of the body, including lungs, lymph nodes, bones, and white blood cells, and has a high mortality rate due to metastasis to the surrounding tissues.
  • the highest cancer death rate in Korea in 2015 was gastric cancer in the 30s and liver cancer in the 40s and 50s. Several strategies for treating this are being studied.
  • Cisplatin is an anticancer drug used for the treatment of various types of solid cancer such as stomach cancer, colon cancer, liver cancer and lung cancer. It is the most common substance used alone or in combination with other anticancer drugs for cancer treatment. However, side effects such as vomiting due to cisplatin, diarrhea, cystitis, and renal dysfunction have been reported. Therefore, a new approach is needed for cancer treatment and adjuvant treatment. In this regard, research has been conducted to develop a therapeutic agent having a low side effect and excellent anticancer effect by using natural substances relatively low in toxicity compared to the synthesized substance, and to develop a substance capable of reducing the adverse effects of existing anticancer drugs and increasing their effects.
  • Flavonoids in natural products have two phenyl rings and a heterocyclic ring and have 15 carbon skeletons. Extracts and single components of flavonoids have been reported to have a wide range of pharmacological and biological activities (antiallergic, antiinflammatory, antioxidant, antimicrobial, anti-cancer, etc.). One of the single components of flavonoids, methylated flavone, methylenated flavone, is contained in a large amount in orange oil, and anti-inflammatory and antiviral effects have been reported.
  • the present inventors have studied a method for overcoming the problems of the conventional anticancer drugs by using cinnensetine as one of such flavonoid components. As a result, the present inventors have found that the above- Or stomach cancer cells can be effectively killed and the mobility of these cells can be effectively inhibited. In particular, when used in combination with the existing anticancer drug cisplatin, synergistic effects were shown in the killing effect and the mobility inhibition effect of gastric cancer cells, and it was confirmed that the use of cisplatin could be reduced to reduce the side effects and increase the anti- Thereby completing the invention.
  • a pharmaceutical composition for the prophylaxis or treatment of liver cancer or stomach cancer containing sinensetin or a salt thereof as an active ingredient.
  • composition for preventing or treating liver cancer or stomach cancer of the present invention it is preferable to further contain cisplatin as an active ingredient in addition to the above-mentioned sinensetin or a salt thereof.
  • a functional food composition for preventing, ameliorating or preventing the transplantation of liver cancer or stomach cancer containing sinensetin or a salt thereof as an active ingredient.
  • the functional food composition for preventing, ameliorating or inhibiting metastasis of liver cancer or stomach cancer of the present invention it is preferable to further contain cisplatin as an active ingredient in addition to the above-mentioned sinensetin or a salt thereof.
  • a functional feed composition for preventing, ameliorating or preventing the transplantation of liver cancer or stomach cancer containing sinensetin or a salt thereof as an active ingredient.
  • the functional feed composition for preventing, ameliorating or inhibiting metastasis of liver cancer or gastric cancer it is preferable to further contain cisplatin as an active ingredient in addition to the above-mentioned sinensetin or a salt thereof.
  • a pharmaceutical composition for inhibiting the metastasis of liver cancer or stomach cancer containing sinensetin or a salt thereof as an active ingredient.
  • the pharmaceutical composition for inhibiting metastasis of liver cancer or stomach cancer it is preferable to further contain cisplatin as an active ingredient in addition to the above-mentioned sinensetin or a salt thereof.
  • the composition of the present invention can effectively prevent, ameliorate, or treat liver cancer or stomach cancer by inducing the death of liver cancer cells or stomach cancer cells without significantly affecting normal cells by containing cinnenecetin as an active ingredient, It is possible to effectively inhibit metastasis of liver cancer or stomach cancer by inhibiting mobility.
  • a composition containing cinnensetin as an active ingredient together with cisplatin is more effective in preventing gastric cancer, preventing or ameliorating gastric cancer, and inhibiting metastasis, because of the synergistic effect of the two components, have.
  • FIG. 1 shows the results of experiments on the killing effect of cinnenecetin (Si) on HepG2 cells.
  • Cell viability was measured by MTT assay, and HepG2 cells were treated with 25 ⁇ 100 ⁇ M of cinnenecetin for 24 h and 48 h; #, p ⁇ Thle2 cell control; ## p ⁇ 0.01 vs. Thle2 cell Control; *, p ⁇ HepG2 Cell control; ** p ⁇ HepG2 cell Control; *** p ⁇ HepG2 cell Control.
  • FIG. 2 shows the results of experiments on the killing effect of AGS cells of cinnenecetin (Si). Treatment of cinnenecetin with AGS cells at a concentration of 20-80 ⁇ M for 24 h; * p ⁇ Control; ** p ⁇ Control; *** p ⁇ Control.
  • Fig. 3 shows the results of experiments on the killing effect of AGS cells of cisplatin (Cis). Treatment of AGS cells with cisplatin at a concentration of 0.1-0.3 ⁇ M for 24 h; ** p ⁇ Control.
  • FIG. 4 shows the results of an experiment on the killing effect of AGS cells when cisplatin (Cis) and synenecetin (Si) were treated at the same time.
  • AGS cells were treated with cisplatin at a concentration of 0.1, 0.2 ⁇ M, cinnexetin at 40, 50 ⁇ M for 24 h; ** p ⁇ Control; *** p ⁇ Control;### p ⁇ 0.001 vs. Cis 0.1 [mu] M or Cis 0.2 [mu] M; $$ p ⁇ Si 40 ⁇ M or 50 ⁇ M.
  • FIG. 5 shows the results of an experiment for inhibiting the mobility of HepG2 cells of cinnenecetin (Si). Wound healing assay, analysis of cell area after treatment with cynesetin at 50, 100 ⁇ M for 48 h; *** p ⁇ Control.
  • Fig. 6 shows the results of experiments on the effect of inhibiting the migration of AGS cells of cisplatin (Cis) and cinnenecetin (Si). Cisplatin and cinnenecetin were measured at 24 h after treatment at each concentration; * p ⁇ Control; *** p ⁇ Control;# p ⁇ Cis 0.1 [mu] M or Cis 0.2 [mu] M; $$ p ⁇ Si 40 ⁇ M; $$$ p ⁇ 0.001 vs. Si 40 ⁇ M.
  • composition of the present invention contains sinensetin or a salt thereof as an active ingredient or a composition containing sinensetin or a salt thereof; And cisplatin or a salt thereof as an active ingredient.
  • Cynenecetine is a methylated flavone, which is found in a lot of orange oil, and has been reported to have anti-inflammatory and antiviral effects.
  • the present invention provides the use of prevention, improvement or treatment of liver cancer or stomach cancer and the use of inhibiting the metastasis of liver cancer or stomach cancer.
  • cisplatin The chemical structure of cisplatin is represented by the following chemical formula 2. It is used for the treatment of various types of cancer such as stomach cancer, colon cancer, liver cancer, and lung cancer. However, there are side effects such as vomiting, diarrhea, cystitis, and kidney dysfunction.
  • cinnenecetin can kill hepatocellular carcinoma cells or stomach cancer cells without significantly affecting normal cells, and can inhibit the mobility of liver cancer cells or stomach cancer cells.
  • cinnenecetin can be used as an anticancer adjuvant to increase the anticancer effect of cisplatin or as an antitumor agent to increase the suppression effect of metastasis.
  • salts of cinnenecetin in the present invention may be used in the form of salts, such as acid, pharmacologically or pharmacologically acceptable acid addition salts or metal complexes, such as zinc and iron.
  • the pharmaceutical composition of the present invention can be administered orally or parenterally at the time of clinical administration, and can be administered orally or parenterally at the time of parenteral administration, and can be administered intraperitoneally, rectally, subcutaneously, intravenously, intramuscularly, Or intramuscular injection, and may be used in the form of a general pharmaceutical preparation.
  • compositions of the present invention may be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy and biological response modifiers.
  • the daily dosage of the pharmaceutical composition of the present invention may be about 1 to 100 mg / kg on an adult basis per day based on the cinnenecetin or a salt thereof of the present invention contained in the composition, and may be administered once to several times a day
  • the range may vary depending on the patient's weight, age, sex, health condition, diet, time of administration, administration method, excretion rate, and severity of the disease.
  • the cisplatin may be administered at a level that is used for the treatment of existing gastric cancer, and according to the present invention, the combination with cinnenecetine may be administered at a lower level because the anticancer effect is enhanced.
  • the adult standard may be about 1 to 50 mg / kg per day.
  • parenteral administration In practical administration, it may be administered in various formulations of parenteral administration.
  • formulation it may be prepared by using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants and the like.
  • Formulations for parenteral administration may include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations, and suppositories.
  • Propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, etc. may be used as the non-aqueous solvent and suspension agent.
  • the base of suppositories may be witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like.
  • the pharmaceutical composition of the present invention may contain one or more active ingredients showing the same or similar functions in addition to the cinnenecetin or a salt thereof of the present invention or cisplatin.
  • the food composition of the present invention may be a composition based on the effective amount of cinnenecetin or a salt thereof, or a mixture of cisplatin itself or a pharmaceutically acceptable carrier.
  • the food composition of the present invention can be applied to food products such as meat products, fish products, tofu, mushrooms, porridge, noodles such as noodles or noodles, seasonings such as soy sauce, miso, It is considered that food types such as pickles such as pickles, pickles, fruits, vegetables, soymilk, and fermented beverages are possible.
  • the pharmacologically acceptable carrier may also be the pharmaceutically acceptable carrier.
  • the feed composition of the present invention may be a composition based on the effective amount of cinnenecetin or a salt thereof, or a composition obtained by mixing cisplatin itself or a dietary acceptable carrier.
  • the feed composition of the present invention is considered to be in the form of compound feed, pellet, and silage.
  • the compound feed can be prepared by mixing various kinds of general feeds and the above-mentioned cinnenecetin or a salt thereof, or cisplatin.
  • Feeds in the form of a pellet may be prepared by formulating the compound feed into a pelletizer, which may be prepared by fermenting a chrysanthemum and then adding the cinnenecetin or a salt thereof, or cisplatin.
  • Sinensetin was purchased from MedChem Express (MCE, USA) and stocked with DMSO at 10 mM.
  • Dulbecco's Modified Eagles medium (DMEM) used for cell culture was purchased from Hyclone (Logan, UT), and Bronchial Epithelial Cell Growth Medium (BEGM TM ) Bulletkit TM was purchased from Lonza (Switzerland).
  • Penicillin / streptomycin and fetal bovine serum (FBS) added to the medium were purchased from Gibco (Grand Island, NY).
  • MTT 3- [4,5-dimethylthiazol-2-yl] -2,5-diphenyltetrazolium bromide
  • HepG2 cells which are human liver-derived hepatic cancer cells, were cultured in DMEM medium.
  • AGS cells derived from human cells were cultured in RPMI medium supplemented with 10% FBS and 1% penicillin / streptomycin. And cultured in a CO 2 incubator (5% CO 2 , 95% air) at 37 ° C. When the cells were over 80% in the culture dish, the cells were washed with phosphate buffered saline (PBS, pH 7.4) and subcultured with 0.25% trypsin-2.65 mM EDTA. Cynecetin was added to 10 mM of DMSO and treated with 50 ⁇ M and 100 ⁇ M of HepG2 cells. AGS cells were treated with 40 ⁇ M and 50 ⁇ M of cinnenecetin with 0.1 ⁇ M and 0.2 ⁇ M of cisplatin, and the same amount of DMSO was added to the control.
  • HepG2 and AGS cells were plated in 48-well plates at 5 ⁇ 10 4 and incubated for 16 h at 37 ° C in a 5% CO 2 incubator. After the medium was removed, each of the following samples was treated according to the concentration, and the control group was treated with dimethyl sulfoxide (DMSO). Each sample was treated with 50 ⁇ l of MTT (0.05 g / 10 ml; 0.5%) solution (final 0.05% MTT) for 48 hours for HepG2 and for 24 hours for AGS. The cells were reacted for 3 hours in a 5% CO 2 incubator at 37 ° C to reduce MTT. All wells were removed and 500 ul of DMSO was added to each well. The absorbance was measured at 560 nm using an ELISA reader.
  • HepG2 and AGS cells were plated at 2 ⁇ 10 5 in a 12-well plate for cell culture and cultured for 16 hours. The cells were scrunched using a plastic 200ul tip and washed with PBS. After that, the drug was treated at each concentration, and the cells were reacted in CO 2 incubator for each hour. The cell mobility was photographed and the area was measured using the Image J program.
  • HepG2 and AGS cells were plated at 5 ⁇ 10 5 in a 6-well plate and treated with each concentration 16 hours later. After the reaction time of the drug has elapsed, cells were washed once with PBS and cells were collected using typsin-EDTA. Cells were stained with FITC Annexin V Apoptosis Detection Kit I (BD Biosciences, San Jose, Calif.) By flow cytometry using FACS Calibur (BD Biosciences).
  • HepG2 and AGS cells were plated in 6 well plates and flow cytometry was used. HepG2 and AGS cells were collected after each reaction time, and cells were fixed at -20 °C for 1 hour with 70% ethanol. The cells were washed with PBS and reacted with 1 U / ml of RNase A (DNase free) and PBS at 37 ° C for 1 hour, then 5 ug / ml of propidium iodide (PI) And then reacted. 10,000 cells per sample were measured using a FACS Calibur (BD Biosciences, San Jose, Calif.).
  • HepG2 cells treated with cinnenecetin were washed with PBS and incubated with RIPA lysis buffer (50 mM Tris-HCl pH 7.4, 1% NP-40, 0.25% Na-deoxycholate , 150 mM NaCl, 1 mM EDTA) was added to extract whole proteins of the cells.
  • Bicinchoninate (BCA) assay was used to quantitate the protein concentration, electrophoresed on SDS-polyacrylamide gel, and then transferred to the PVDF membrane.
  • BCA horse radish peroxidase (HRP) conjugated secondary antibody was reacted.
  • the antibodies were reacted with ECL kit (Promega, USA) and then measured using Chemidoc instrument (Bio Rad, California, USA).
  • HepG2 a human liver cancer cell
  • MTT assay MTT assay was performed.
  • HepG2 a human liver cancer cell
  • the cancer cell killing activity was confirmed to be about 50% at 50 ⁇ M and 65% at 100 ⁇ M in the group treated with cinnensetin for 48 hours.
  • the human normal hepatocyte, Thle2 cells was also treated with cinnenecetin. As a result, it was confirmed that cinnenecetin had a greater effect on liver cancer cells than hepatic normal cells in the group treated for 24 hours and 48 hours (see FIG. 1).
  • Cynenecetin showed AGS cell killing activity in a concentration dependent manner.
  • the cytotoxic effect was about 25% at 60 ⁇ M of cynesecetin and 35% at 80 ⁇ M (see FIG. 2).
  • the cytotoxic effect of cisplatin which is known as an anticancer drug, was examined in AGS cells, and showed a killing effect of about 50% at 0.3 ⁇ M of cisplatin (see FIG. 3).
  • AGS cells were treated with 40 ⁇ M and 50 ⁇ M of cinnenecetine and treated with 0.1 ⁇ M and 0.2 ⁇ M each cisplatin.
  • cell viability was reduced to about 30% in the group treated with 50 ⁇ M of cinnenecetin, although the cell viability was about 90% (see FIG. 4).
  • about 75% cell viability was observed in the group treated with 0.2 ⁇ M of cisplatin alone, but about 50% cell viability was shown when treated with 40 ⁇ M of cinnenecetin (see FIG. 4).
  • cisplatin and cinnenecetin are treated together, cisplatin exhibits a higher apoptotic action in AGS cells, which are human gastric cancer cells.

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Abstract

The present invention relates to a composition for preventing, ameliorating or treating liver cancer or gastric cancer containing sinensetin as an active ingredient. Specifically, the present invention relates to a pharmaceutical composition, a functional food composition and a functional feed composition for preventing, ameliorating or treating liver cancer or gastric cancer and for inhibiting metastasis, containing sinensetin as an active ingredient, or sinensetin and cisplatin as active ingredients. As a result of containing sinensetin as an active ingredient, the composition of the present invention can effectively prevent, ameliorate, or treat liver cancer or gastric cancer by inducing the death of liver cancer cells or gastric cancer cells without significantly affecting normal cells, and can effectively inhibit metastasis of liver cancer or gastric cancer by inhibiting the mobility of liver cancer cells or gastric cancer cells. Particularly, a composition containing sinensetin together with cisplatin as active ingredients has superior effects of killing gastric cancer cells and inhibiting the mobility thereof due to synergy of the two ingredients, and thus can prevent, ameliorate or treat gastric cancer more effectively and inhibit metastasis.

Description

시넨세틴을 유효성분으로 함유하는 간암 또는 위암의 예방, 개선 또는 치료용 조성물Composition for preventing, ameliorating or treating liver cancer or stomach cancer containing cinnenecetin as an active ingredient
본 발명은 시넨세틴을 유효성분으로 함유하는 간암 또는 위암의 예방, 개선 또는 치료용 조성물에 관한 것으로, 구체적으로 시넨세틴을 또는 시넨세틴과 시스플라틴을 유효성분으로 함유하는 간암 또는 위암의 예방, 개선 또는 치료용, 및 전이 억제용 약학적 조성물, 기능성 식품 조성물 및 기능성 사료 조성물에 관한 것이다.The present invention relates to a composition for preventing, ameliorating or treating liver cancer or stomach cancer containing cinnensetin as an active ingredient, and more particularly to a composition for preventing, ameliorating or treating liver cancer or stomach cancer containing cinnensetine or cinnenecetin and cisplatin as an active ingredient Therapeutic and transfection-inhibiting pharmaceutical compositions, functional food compositions and functional feed compositions.
암은 다양한 원인에 의해 세포 분열과 사멸의 균형이 파괴가 되어 비정상적인 세포의 계속적인 분열과 증식에 의해 발생되는 세포의 집단을 의미하며, 종양이라고 불리기도 한다. 일반적으로 폐와 같은 장기, 림프절, 뼈, 백혈구 등 100가지 이상 여러 부위의 신체에서 발병하며, 주변조직으로 이동하는 전이를 통해 높은 사망률을 기록하고 있다. 2015년 대한민국 사망률(인구 10만명당 사망자)이 가장 높은 암은 30대에서는 위암, 40, 50대에서는 간암인 것으로 나타났다. 이를 치료하기 위한 여러 전략들이 연구되고 있다.Cancer refers to a group of cells that are caused by continuous division and proliferation of abnormal cells by destroying the balance of cell division and death by various causes, and are sometimes referred to as tumors. It usually occurs in more than 100 different parts of the body, including lungs, lymph nodes, bones, and white blood cells, and has a high mortality rate due to metastasis to the surrounding tissues. The highest cancer death rate in Korea in 2015 (deaths per 100,000 population) was gastric cancer in the 30s and liver cancer in the 40s and 50s. Several strategies for treating this are being studied.
암 치료를 위한 방사선, 화학적 요법, 수술 등 치료법이 존재하고 있지만 많은 부작용이 보고되고 있다. 시스플라틴(cisplatin)은 위암, 대장암, 간암, 폐암 등 다양한 고형암 치료에 사용되는 항암제이다. 이는 암 치료에 단독적으로 혹은 다른 항암제와 함께 사용되는 가장 보편적인 물질이다. 하지만 시스플라틴에 의한 구토, 설사, 방광염, 신장 기능 저하 등 부작용이 보고되고 있다. 따라서 암 치료제와 보조적인 치료제를 위한 새로운 접근 방법이 필요하다. 이와 관련하여, 독성이 합성된 물질보다 비교적 낮은 천연물을 이용하여 부작용은 적고 항암작용이 뛰어난 치료제를 개발하고 기존의 항암제의 부작용을 줄이며 효과를 높일 수 있는 물질을 개발하기 위한 연구가 이루어지고 있다.There are radiation, chemotherapy, and surgical treatments for cancer treatment, but many side effects have been reported. Cisplatin is an anticancer drug used for the treatment of various types of solid cancer such as stomach cancer, colon cancer, liver cancer and lung cancer. It is the most common substance used alone or in combination with other anticancer drugs for cancer treatment. However, side effects such as vomiting due to cisplatin, diarrhea, cystitis, and renal dysfunction have been reported. Therefore, a new approach is needed for cancer treatment and adjuvant treatment. In this regard, research has been conducted to develop a therapeutic agent having a low side effect and excellent anticancer effect by using natural substances relatively low in toxicity compared to the synthesized substance, and to develop a substance capable of reducing the adverse effects of existing anticancer drugs and increasing their effects.
천연물 중 플라보노이드(flavonoid)는 두개의 페닐 고리(phenyl rings)와 헤테로 사이클릭 고리(heterocyclic ring)로 가지며 15개 탄소 골격 구조를 갖는다. 플라보노이드의 추출물과 단일 성분들은 광범위한 약리학적, 생물학적 활성(항알레르기, 항염증, 항산화물질, 항미생물, 항암 등)을 갖는 것으로 보고되었다. 플라보노이드의 단일 성분중 하나인 시넨세틴은 methylated flavone으로 오렌지 오일에 많이 함유되어 있으며, 항염증, 항바이러스 등의 효능이 보고되고 있다.Flavonoids in natural products have two phenyl rings and a heterocyclic ring and have 15 carbon skeletons. Extracts and single components of flavonoids have been reported to have a wide range of pharmacological and biological activities (antiallergic, antiinflammatory, antioxidant, antimicrobial, anti-cancer, etc.). One of the single components of flavonoids, methylated flavone, methylenated flavone, is contained in a large amount in orange oil, and anti-inflammatory and antiviral effects have been reported.
본 발명자는 이러한 플라보노이드 성분 중 하나인 시넨세틴을 이용하여 상기와 같은 기존 항암제의 문제점을 극복할 수 있는 방법에 관하여 연구하였으며, 이의 결과, 상기 시넨세틴이 정상세포에는 큰 영향을 미치지 않으면서 간암세포 또는 위암세포를 효과적으로 사멸시킬 수 있고, 또한 이들 세포의 이동성을 효과적으로 억제할 수 있음을 확인하였다. 특히 기존 항암제인 시스플라틴과 함께 사용할 경우 위암세포에 대한 사멸 효과와 이동성 억제 효과에서 시너지 효과를 나타내어 시스플라틴의 사용량을 줄여 부작용을 줄이면서 동시에 항암 효과 및 암전이 억제 효과를 증가시킬 수 있음을 확인하고 본 발명을 완성하게 되었다.The present inventors have studied a method for overcoming the problems of the conventional anticancer drugs by using cinnensetine as one of such flavonoid components. As a result, the present inventors have found that the above- Or stomach cancer cells can be effectively killed and the mobility of these cells can be effectively inhibited. In particular, when used in combination with the existing anticancer drug cisplatin, synergistic effects were shown in the killing effect and the mobility inhibition effect of gastric cancer cells, and it was confirmed that the use of cisplatin could be reduced to reduce the side effects and increase the anti- Thereby completing the invention.
따라서 본 발명의 주된 목적은 천연물질 물질을 이용하는 부작용이 적고 암의 예방, 개선 또는 치료 효과가 우수한 조성물을 제공하는데 있다.Accordingly, it is a main object of the present invention to provide a composition having few side effects using a natural substance and excellent in prevention, improvement or therapeutic effect of cancer.
본 발명의 다른 목적은 천연물질 물질을 이용하는 암의 전이 억제 효과가 우수한 조성물을 제공하는데 있다.It is another object of the present invention to provide a composition having a superior effect of inhibiting cancer metastasis using a natural substance substance.
본 발명의 한 양태에 따르면, 본 발명은 시넨세틴(sinensetin) 또는 이의 염을 유효성분으로 함유하는 간암 또는 위암의 예방 또는 치료용 약학적 조성물을 제공한다.According to one aspect of the present invention, there is provided a pharmaceutical composition for the prophylaxis or treatment of liver cancer or stomach cancer containing sinensetin or a salt thereof as an active ingredient.
본 발명의 간암 또는 위암의 예방 또는 치료용 약학적 조성물에 있어서, 상기 시넨세틴(sinensetin) 또는 이의 염 이외에 시스플라틴(cisplatin)을 유효성분으로 더 함유하는 것이 바람직하다.In the pharmaceutical composition for preventing or treating liver cancer or stomach cancer of the present invention, it is preferable to further contain cisplatin as an active ingredient in addition to the above-mentioned sinensetin or a salt thereof.
본 발명의 다른 양태에 따르면, 본 발명은 시넨세틴(sinensetin) 또는 이의 염을 유효성분으로 함유하는 간암 또는 위암의 예방, 개선 또는 전이 억제용 기능성 식품 조성물을 제공한다.According to another aspect of the present invention, there is provided a functional food composition for preventing, ameliorating or preventing the transplantation of liver cancer or stomach cancer containing sinensetin or a salt thereof as an active ingredient.
본 발명의 간암 또는 위암의 예방, 개선 또는 전이 억제용 기능성 식품 조성물에 있어서, 상기 시넨세틴(sinensetin) 또는 이의 염 이외에 시스플라틴(cisplatin)을 유효성분으로 더 함유하는 것이 바람직하다.In the functional food composition for preventing, ameliorating or inhibiting metastasis of liver cancer or stomach cancer of the present invention, it is preferable to further contain cisplatin as an active ingredient in addition to the above-mentioned sinensetin or a salt thereof.
본 발명의 또 다른 양태에 따르면, 본 발명은 시넨세틴(sinensetin) 또는 이의 염을 유효성분으로 함유하는 간암 또는 위암의 예방, 개선 또는 전이 억제용 기능성 사료 조성물을 제공한다.According to another aspect of the present invention, there is provided a functional feed composition for preventing, ameliorating or preventing the transplantation of liver cancer or stomach cancer containing sinensetin or a salt thereof as an active ingredient.
본 발명의 간암 또는 위암의 예방, 개선 또는 전이 억제용 기능성 사료 조성물에 있어서, 상기 시넨세틴(sinensetin) 또는 이의 염 이외에 시스플라틴(cisplatin)을 유효성분으로 더 함유하는 것이 바람직하다.In the functional feed composition for preventing, ameliorating or inhibiting metastasis of liver cancer or gastric cancer according to the present invention, it is preferable to further contain cisplatin as an active ingredient in addition to the above-mentioned sinensetin or a salt thereof.
본 발명의 또 다른 양태에 따르면, 본 발명은 시넨세틴(sinensetin) 또는 이의 염을 유효성분으로 함유하는 간암 또는 위암의 전이 억제용 약학적 조성물을 제공한다.According to still another aspect of the present invention, there is provided a pharmaceutical composition for inhibiting the metastasis of liver cancer or stomach cancer containing sinensetin or a salt thereof as an active ingredient.
본 발명의 간암 또는 위암의 전이 억제용 약학적 조성물에 있어서, 상기 시넨세틴(sinensetin) 또는 이의 염 이외에 시스플라틴(cisplatin)을 유효성분으로 더 함유하는 것이 바람직하다.In the pharmaceutical composition for inhibiting metastasis of liver cancer or stomach cancer according to the present invention, it is preferable to further contain cisplatin as an active ingredient in addition to the above-mentioned sinensetin or a salt thereof.
본 발명의 조성물은 유효성분으로 시넨세틴을 함유하여 정상세포에는 큰 영향을 미치지 않고 간암세포 또는 위암세포의 사멸을 유도하여 간암 또는 위암을 효과적으로 예방, 개선 또는 치료할 수 있고, 간암세포 또는 위암세포의 이동성을 억제하여 간암 또는 위암의 전이를 효과적으로 억제할 수 있다. 특히 시스플라틴과 함께 시넨세틴을 유효성분으로 함유하는 조성물은 두 가지 성분의 시너지로 인해 위암세포 사멸 효과와 이동성 억제 효과가 보다 우수하므로 보다 효과적으로 위암을 예방, 개선 또는 치료할 수 있고, 전이를 억제할 수 있다.The composition of the present invention can effectively prevent, ameliorate, or treat liver cancer or stomach cancer by inducing the death of liver cancer cells or stomach cancer cells without significantly affecting normal cells by containing cinnenecetin as an active ingredient, It is possible to effectively inhibit metastasis of liver cancer or stomach cancer by inhibiting mobility. In particular, a composition containing cinnensetin as an active ingredient together with cisplatin is more effective in preventing gastric cancer, preventing or ameliorating gastric cancer, and inhibiting metastasis, because of the synergistic effect of the two components, have.
도 1은 시넨세틴(Si)의 HepG2 세포의 사멸 효과를 실험한 결과이다. Cell viability를 MTT assay 방법으로 측정, HepG2 세포에 시넨세틴을 25 ~ 100μM 농도로 24h, 48h 처리; #, p<0.05 vs. Thle2 cell control; ##p<0.01 vs. Thle2 cell Control; *,p<0.05 vs. HepG2 Cell control; **p<0.01 vs. HepG2 cell Control; ***p<0.001 vs. HepG2 cell Control.FIG. 1 shows the results of experiments on the killing effect of cinnenecetin (Si) on HepG2 cells. Cell viability was measured by MTT assay, and HepG2 cells were treated with 25 ~ 100 μM of cinnenecetin for 24 h and 48 h; #, p < Thle2 cell control; ## p <0.01 vs. Thle2 cell Control; *, p < HepG2 Cell control; ** p < HepG2 cell Control; *** p < HepG2 cell Control.
도 2는 시넨세틴(Si)의 AGS 세포의 사멸 효과를 실험한 결과이다. AGS 세포에 시넨세틴을 20 ~ 80μM 농도로 24h 처리; *p<0.05 vs. Control; **p<0.01 vs. Control; ***p<0.001 vs. Control.FIG. 2 shows the results of experiments on the killing effect of AGS cells of cinnenecetin (Si). Treatment of cinnenecetin with AGS cells at a concentration of 20-80 μM for 24 h; * p <Control; ** p <Control; *** p < Control.
도 3은 시스플라틴(Cis)의 AGS 세포의 사멸 효과를 실험한 결과이다. AGS 세포에 시스플라틴을 0.1 ~ 0.3μM 농도로 24h 처리; **p<0.01 vs. Control.Fig. 3 shows the results of experiments on the killing effect of AGS cells of cisplatin (Cis). Treatment of AGS cells with cisplatin at a concentration of 0.1-0.3 μM for 24 h; ** p < Control.
도 4는 시스플라틴(Cis)과 시넨세틴(Si)을 동시에 처리하였을 때 AGS 세포의 사멸 효과를 실험한 결과이다. AGS 세포에 시스플라틴은 0.1, 0.2μM 농도로, 시넨세틴은 40, 50μM로 24h 처리; **p<0.01 vs. Control; ***p<0.001 vs. Control; ###p<0.001 vs. Cis 0.1μM 또는 Cis 0.2μM; $$p<0.01 vs. Si 40μM 또는 50μM.FIG. 4 shows the results of an experiment on the killing effect of AGS cells when cisplatin (Cis) and synenecetin (Si) were treated at the same time. AGS cells were treated with cisplatin at a concentration of 0.1, 0.2 μM, cinnexetin at 40, 50 μM for 24 h; ** p <Control; *** p <Control;### p <0.001 vs. Cis 0.1 [mu] M or Cis 0.2 [mu] M; $$ p < Si 40 μM or 50 μM.
도 5는 시넨세틴(Si)의 HepG2 세포의 이동성 억제 효과를 실험한 결과이다. Wound healing assay를 통해 실시, 시넨세틴을 50, 100μM 농도로 48h 처리 한 후 세포의 면적 분석; ***p<0.001 vs. Control.FIG. 5 shows the results of an experiment for inhibiting the mobility of HepG2 cells of cinnenecetin (Si). Wound healing assay, analysis of cell area after treatment with cynesetin at 50, 100 μM for 48 h; *** p < Control.
도 6은 시스플라틴(Cis)과 시넨세틴(Si)의 AGS 세포의 이동성 억제 효과를 실험한 결과이다. 시스플라틴과 시넨세틴은 각 농도로 24h 처리 후 면적 측정; *p<0.05 vs. Control; ***p<0.001 vs. Control; #p<0.05 vs. Cis 0.1μM 또는 Cis 0.2μM; $$p<0.01 vs. Si 40μM; $$$p<0.001 vs. Si 40μM.Fig. 6 shows the results of experiments on the effect of inhibiting the migration of AGS cells of cisplatin (Cis) and cinnenecetin (Si). Cisplatin and cinnenecetin were measured at 24 h after treatment at each concentration; * p <Control; *** p <Control;# p < Cis 0.1 [mu] M or Cis 0.2 [mu] M; $$ p < Si 40 μM; $$$ p <0.001 vs. Si 40 μM.
본 발명의 조성물은 시넨세틴(sinensetin) 또는 이의 염을 유효성분으로 함유하거나 시넨세틴(sinensetin) 또는 이의 염; 및 시스플라틴(cisplatin) 또는 이의 염;을 유효성분으로 함유하는 것을 특징으로 한다.The composition of the present invention contains sinensetin or a salt thereof as an active ingredient or a composition containing sinensetin or a salt thereof; And cisplatin or a salt thereof as an active ingredient.
시넨세틴의 화학구조는 다음 화학식 1과 같다. 시넨세틴은 methylated flavone으로 오렌지 오일에 많이 함유되어 있으며, 항염증, 항바이러스 등의 효능이 보고되고 있다. 본 발명에서 새로운 생리활성을 밝힘으로써 간암 또는 위암의 예방, 개선 또는 치료의 용도와 간암 또는 위암의 전이 억제의 용도를 제공하게 된 것이다.The chemical structure of cinnenecetin is shown in the following chemical formula 1. Cynenecetine is a methylated flavone, which is found in a lot of orange oil, and has been reported to have anti-inflammatory and antiviral effects. In the present invention, by disclosing a new physiological activity, the present invention provides the use of prevention, improvement or treatment of liver cancer or stomach cancer and the use of inhibiting the metastasis of liver cancer or stomach cancer.
[화학식 1][Chemical Formula 1]
Figure PCTKR2018013230-appb-I000001
Figure PCTKR2018013230-appb-I000001
시스플라틴의 화학구조는 다음 화학식 2와 같다. 백금원자에 2개의 염소와 암모니아가 배위한 항암작용을 나타내는 화합물로 위암, 대장암, 간암, 폐암 등 다양한 고형암 치료에 사용되고 있으나, 구토, 설사, 방광염, 신장 기능 저하 등 부작용이 있다.The chemical structure of cisplatin is represented by the following chemical formula 2. It is used for the treatment of various types of cancer such as stomach cancer, colon cancer, liver cancer, and lung cancer. However, there are side effects such as vomiting, diarrhea, cystitis, and kidney dysfunction.
[화학식 2](2)
Figure PCTKR2018013230-appb-I000002
Figure PCTKR2018013230-appb-I000002
본 발명에 따르면, 시넨세틴은 정상세포에는 큰 영향을 미치지 않으면서 간암세포 또는 위암세포를 사멸시킬 수 있고, 간암세포 또는 위암세포의 이동성을 억제할 수 있다.According to the present invention, cinnenecetin can kill hepatocellular carcinoma cells or stomach cancer cells without significantly affecting normal cells, and can inhibit the mobility of liver cancer cells or stomach cancer cells.
또한 시넨세틴을 시스플라틴과 함께 사용하면 위암세포의 사멸 효과와 이동성 억제 효과에서 시너지 효과를 발휘할 수 있다.In addition, when cinnenecetin is used together with cisplatin, the synergistic effect can be exhibited in the killing effect and the mobility inhibition effect of gastric cancer cells.
이러한 효과를 바탕으로 시넨세틴은 시스플라틴의 항암효과를 증가시키기 위한 항암보조제 또는 암전이 억제효과를 증가시키기 위한 암전이 억제 보조제로도 사용될 수 있다.Based on these effects, cinnenecetin can be used as an anticancer adjuvant to increase the anticancer effect of cisplatin or as an antitumor agent to increase the suppression effect of metastasis.
본 발명에서 시넨세틴의 염은 약학적, 식품학적 또는 사료학적으로 허용이 가능한 산부가염 또는 금속 복합체, 예를 들어 아연, 철 등과 같은 염의 형태로도 사용할 수 있을 것으로 판단된다.It is believed that the salts of cinnenecetin in the present invention may be used in the form of salts, such as acid, pharmacologically or pharmacologically acceptable acid addition salts or metal complexes, such as zinc and iron.
본 발명의 약학적 조성물은 임상 투여 시에 경구 또는 비경구로 투여가 가능하며 비경구 투여시 복강내주사, 직장내주사, 피하주사, 정맥주사, 근육내주사, 자궁내 경막주사, 뇌혈관내 주사 또는 흉부내 주사에 의해 투여될 수 있고, 일반적인 의약품 제제의 형태로 사용될 수 있을 것으로 판단된다.The pharmaceutical composition of the present invention can be administered orally or parenterally at the time of clinical administration, and can be administered orally or parenterally at the time of parenteral administration, and can be administered intraperitoneally, rectally, subcutaneously, intravenously, intramuscularly, Or intramuscular injection, and may be used in the form of a general pharmaceutical preparation.
본 발명의 약학적 조성물은 단독으로, 또는 수술, 방사선 치료, 호르몬 치료, 화학 치료 및 생물학적 반응 조절제를 사용하는 방법들과 병용하여 사용할 수 있을 것으로 판단된다.The pharmaceutical compositions of the present invention may be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy and biological response modifiers.
본 발명 약학적 조성물의 일일 투여량은 조성물에 함유된 본 발명의 시넨세틴 또는 이의 염을 기준으로 성인 기준 하루에 약 1 내지 100㎎/㎏일 수 있으며, 하루 1회 내지 수회 나누어 투여될 수 있으나 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설율 및 질환의 중증도 등에 따라 그 범위가 다양할 것이다. 시스플라틴은 기존 위암의 치료에 사용되는 수준으로 투여될 수 있으며, 본 발명에 따르면 시넨세틴과의 조합으로 인해 항암효과가 높아지기 때문에 보다 낮은 수준으로도 투여될 수 있을 것이다. 예를 들어, 성인 기준 하루에 약 1 내지 50㎎/㎏일 수 있다.The daily dosage of the pharmaceutical composition of the present invention may be about 1 to 100 mg / kg on an adult basis per day based on the cinnenecetin or a salt thereof of the present invention contained in the composition, and may be administered once to several times a day The range may vary depending on the patient's weight, age, sex, health condition, diet, time of administration, administration method, excretion rate, and severity of the disease. The cisplatin may be administered at a level that is used for the treatment of existing gastric cancer, and according to the present invention, the combination with cinnenecetine may be administered at a lower level because the anticancer effect is enhanced. For example, the adult standard may be about 1 to 50 mg / kg per day.
실제 임상 투여 시에 비경구의 여러 가지 제형으로 투여될 수 있는데, 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제할 수 있을 것이다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제가 포함될 수 있을 것이다. 비수성용제, 현탁용제로는 프로필렌글리콜(Propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있을 것이다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있을 것이다.In practical administration, it may be administered in various formulations of parenteral administration. In the case of formulation, it may be prepared by using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants and the like. Formulations for parenteral administration may include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations, and suppositories. Propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, etc. may be used as the non-aqueous solvent and suspension agent. The base of suppositories may be witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like.
본 발명의 약학적 조성물은 본 발명의 시넨세틴 또는 이의 염, 또는 시스플라틴에 추가로 동일 또는 유사한 기능을 나타내는 유효성분을 1종 이상 함유할 수 있을 것이다.The pharmaceutical composition of the present invention may contain one or more active ingredients showing the same or similar functions in addition to the cinnenecetin or a salt thereof of the present invention or cisplatin.
본 발명의 식품 조성물은 상기 유효량을 기준으로 시넨세틴 또는 이의 염, 또는 시스플라틴 그 자체 또는 식품학적으로 허용된 담체와 혼합한 조성물일 수 있다. 본 발명의 식품 조성물은 식육가공품, 어육제품, 두부, 묵, 죽, 라면이나 국수 등의 면류, 간장, 된장, 고추장, 혼합장 등의 조미식품, 소스, 과자, 발효유나 치즈 등의 유가공품, 김치나 장아찌 등의 절임식품, 과실, 채소, 두유, 발효음료 등의 음료수의 식품 형태가 가능할 것으로 판단된다. 또한 식품학적으로 허용된 담체는 상기 약학적으로 허용된 담체도 사용할 수 있을 것이다.The food composition of the present invention may be a composition based on the effective amount of cinnenecetin or a salt thereof, or a mixture of cisplatin itself or a pharmaceutically acceptable carrier. The food composition of the present invention can be applied to food products such as meat products, fish products, tofu, mushrooms, porridge, noodles such as noodles or noodles, seasonings such as soy sauce, miso, It is considered that food types such as pickles such as pickles, pickles, fruits, vegetables, soymilk, and fermented beverages are possible. The pharmacologically acceptable carrier may also be the pharmaceutically acceptable carrier.
본 발명의 사료 조성물은 상기 유효량을 기준으로 시넨세틴 또는 이의 염, 또는 시스플라틴 그 자체 또는 사료학적으로 허용된 담체와 혼합한 조성물일 수 있다. 본 발명의 사료 조성물은 배합사료, 펠렛형태 및 사일레지 등의 형태가 가능할 것으로 판단된다. 상기 배합사료는 여러 종류의 일반사료와 상기 시넨세틴 또는 이의 염, 또는 시스플라틴과 혼합하여 제조될 수 있다. 펠렛 형태의 사료는 상기 배합사료를 펠렛기로 제형화하여 제조될 수 있으며, 사일레지는 청예사료를 발효한 다음 상기 시넨세틴 또는 이의 염, 또는 시스플라틴을 첨가하는 방법으로 제조될 수 있을 것이다.The feed composition of the present invention may be a composition based on the effective amount of cinnenecetin or a salt thereof, or a composition obtained by mixing cisplatin itself or a dietary acceptable carrier. The feed composition of the present invention is considered to be in the form of compound feed, pellet, and silage. The compound feed can be prepared by mixing various kinds of general feeds and the above-mentioned cinnenecetin or a salt thereof, or cisplatin. Feeds in the form of a pellet may be prepared by formulating the compound feed into a pelletizer, which may be prepared by fermenting a chrysanthemum and then adding the cinnenecetin or a salt thereof, or cisplatin.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하기로 한다. 이들 실시예는 단지 본 발명을 예시하기 위한 것이므로, 본 발명의 범위가 이들 실시예에 의해 제한되는 것으로 해석되지는 않는다.Hereinafter, the present invention will be described in more detail with reference to Examples. These embodiments are only for illustrating the present invention, and thus the scope of the present invention is not construed as being limited by these embodiments.
[실시예][Example]
1. 재료 및 방법1. Materials and Methods
1-1. 시약1-1. reagent
시넨세틴(sinensetin)은 MedChem Express(MCE, USA)를 통해 구입하여 DMSO를 이용해 10mM로 stock을 만들어 사용하였다. 세포 배양에 이용된 Dulbecco's Modified Eagles medium(DMEM)은 Hyclone(Logan, UT)에서, Bronchial Epithelial Cell Growth Medium(BEGMTM) BulletkitTM은 Lonza(Switzerland)로부터 구매하였다. 배지에 첨가한 penicillin/streptomycin과 fetal bovine serum(FBS)은 Gibco(Grand Island, NY)사를 통해 구입하였다. 세포 사멸을 측정을 위해 사용된 MTT(3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide)는 Sigma-Aldrich(St. Louis, MO)사의 제품을 사용하였다.Sinensetin was purchased from MedChem Express (MCE, USA) and stocked with DMSO at 10 mM. Dulbecco's Modified Eagles medium (DMEM) used for cell culture was purchased from Hyclone (Logan, UT), and Bronchial Epithelial Cell Growth Medium (BEGM ™ ) Bulletkit ™ was purchased from Lonza (Switzerland). Penicillin / streptomycin and fetal bovine serum (FBS) added to the medium were purchased from Gibco (Grand Island, NY). MTT (3- [4,5-dimethylthiazol-2-yl] -2,5-diphenyltetrazolium bromide) used for the measurement of apoptosis was purchased from Sigma-Aldrich (St. Louis, Mo.).
1-2. 세포 배양과 시료 처리1-2. Cell culture and sample treatment
인간의 간에서 유래한 간암 세포인 HepG2 세포는 DMEM 배지에, 인간의 위에서 유래한 암세포인 AGS 세포는 RPMI 배지에 10% FBS, 1% penicillin/streptomycin을 첨가한 세포 배양액을 사용하였다. 37℃의 CO2 배양기(5% CO2, 95% air)에 배양하였다. 세포가 배양 접시에 80% 이상을 차지하면 phosphate buffered saline(PBS, pH 7.4)로 세포를 세척한 후 0.25% trypsin-2.65mM EDTA로 계대 배양을 실시하였다. 시넨세틴을 DMSO를 이용해 10mM로 만든 후 HepG2 세포에 50μM, 100μM로 처리하였고, AGS 세포는 cisplatin 0.1μM, 0.2μM과 함께 40μM, 50μM의 시넨세틴을 처리하였고, 대조군은 동량의 DMSO를 첨가하였다.HepG2 cells, which are human liver-derived hepatic cancer cells, were cultured in DMEM medium. AGS cells derived from human cells were cultured in RPMI medium supplemented with 10% FBS and 1% penicillin / streptomycin. And cultured in a CO 2 incubator (5% CO 2 , 95% air) at 37 ° C. When the cells were over 80% in the culture dish, the cells were washed with phosphate buffered saline (PBS, pH 7.4) and subcultured with 0.25% trypsin-2.65 mM EDTA. Cynecetin was added to 10 mM of DMSO and treated with 50 μM and 100 μM of HepG2 cells. AGS cells were treated with 40 μM and 50 μM of cinnenecetin with 0.1 μM and 0.2 μM of cisplatin, and the same amount of DMSO was added to the control.
1-3. 세포사멸능 측정(MTT assay)1-3. Measurement of cytotoxicity (MTT assay)
HepG2와 AGS 세포를 48 well plate에 5X104로 분주하여 37℃의 5% CO2 배양기에서 16시간 배양하였다. 그 후 배지를 제거한 후 다음 각 시료를 농도에 맞게 처리하였고, 대조군은 Dimethyl sulfoxide(DMSO)를 처리하였다. 각 시료를 HepG2는 48시간, AGS는 24시간을 처리한 후 MTT(0.05g/10ml; 0.5%) 용액을 50ul(최종 0.05% MTT)씩 처리하였다. 3시간 동안 37℃의 5% CO2 배양기에서 MTT가 환원되도록 반응하였다. 모든 well의 배지를 제거하고 각 well에 DMSO 500ul씩 첨가한 후 ELISA reader를 이용해 흡광도 560nm에서 측정하였다.HepG2 and AGS cells were plated in 48-well plates at 5 × 10 4 and incubated for 16 h at 37 ° C in a 5% CO 2 incubator. After the medium was removed, each of the following samples was treated according to the concentration, and the control group was treated with dimethyl sulfoxide (DMSO). Each sample was treated with 50 μl of MTT (0.05 g / 10 ml; 0.5%) solution (final 0.05% MTT) for 48 hours for HepG2 and for 24 hours for AGS. The cells were reacted for 3 hours in a 5% CO 2 incubator at 37 ° C to reduce MTT. All wells were removed and 500 ul of DMSO was added to each well. The absorbance was measured at 560 nm using an ELISA reader.
1-4. 세포 이동성 실험(Migration assay)1-4. Migration assay
세포 배양용 12 well plate에 HepG2와 AGS 세포를 2X105로 분주한 후 16시간 동안 배양하였다. 플라스틱 200ul tip을 이용하여 세포에 scratch를 형성한 후 PBS로 세척하였다. 그 후 농도별로 약물을 처리하고 CO2 배양기에서 각 시간별로 반응시킨 후 세포이동성을 사진 촬영 후, Image J 프로그램을 이용해 면적을 측정하였다.HepG2 and AGS cells were plated at 2 × 10 5 in a 12-well plate for cell culture and cultured for 16 hours. The cells were scrunched using a plastic 200ul tip and washed with PBS. After that, the drug was treated at each concentration, and the cells were reacted in CO 2 incubator for each hour. The cell mobility was photographed and the area was measured using the Image J program.
1-5. 세포사멸 측정(Annexin V 측정)1-5. Cell death (Annexin V measurement)
HepG2와 AGS 세포를 6 well plate에 5X105로 분주한 후 16시간 후에 각 농도로 약물을 처리하였다. 약물의 반응시간이 경과한 후 PBS로 세포를 1번 세척한 후 typsin-EDTA를 사용해 세포를 수집하였다. 세포에 FITC Annexin V Apoptosis Detection KitⅠ(BD Biosciences, San Jose, CA)를 이용해 염색된 세포를 FACS Calibur(BD Biosciences)를 사용하여 flow cytometry 방법으로 측정하였다.HepG2 and AGS cells were plated at 5 × 10 5 in a 6-well plate and treated with each concentration 16 hours later. After the reaction time of the drug has elapsed, cells were washed once with PBS and cells were collected using typsin-EDTA. Cells were stained with FITC Annexin V Apoptosis Detection Kit I (BD Biosciences, San Jose, Calif.) By flow cytometry using FACS Calibur (BD Biosciences).
1-6. 세포주기 분석(PI staining)1-6. Cell cycle analysis (PI staining)
HepG2와 AGS 세포를 6 well plate에 분주한 후 flow cytometry 방법을 이용하였다. 각 농도별 시료를 처리하고 반응시간이 지난 후에 HepG2와 AGS세포를 수집하여 70% ethanol을 사용해 1시간 동안 -20℃에서 세포를 고정시켰다. 고정된 세포를 PBS를 이용해 세척한 후 1U/ml의 RNase A(DNase free)와 PBS를 이용해 37℃에서 1시간 동안 반응시킨 후 5ug/ml의 propidium iodide(PI)를 첨가하고 15분 동안 4℃에서 차광한 후 반응시켰다. 각 샘플 당 10000개의 세포를 FACS Calibur(BD Biosciences, San Jose, CA)를 사용하여 측정하였다.HepG2 and AGS cells were plated in 6 well plates and flow cytometry was used. HepG2 and AGS cells were collected after each reaction time, and cells were fixed at -20 ℃ for 1 hour with 70% ethanol. The cells were washed with PBS and reacted with 1 U / ml of RNase A (DNase free) and PBS at 37 ° C for 1 hour, then 5 ug / ml of propidium iodide (PI) And then reacted. 10,000 cells per sample were measured using a FACS Calibur (BD Biosciences, San Jose, Calif.).
1-7. 단백질 발현 실험(Western blot analysis)1-7. Protein expression experiments (Western blot analysis)
단백질의 발현을 확인하기 위해 시넨세틴을 처리한 HepG2 세포를 PBS로 세척한 후, protease inhibitor cocktail을 첨가한 RIPA lysis buffer(50mM Tris-Hcl pH7.4, 1% NP-40, 0.25% Na-deoxycholate, 150mM NaCl, 1mM EDTA)을 첨가하여 세포의 전체 단백질을 추출하였다. Bicinchoninate(BCA) assay를 이용해 단백질의 농도를 정량화하여 SDS-polyacrylamide gel에 전기영동한 후 단백질은 PVDF membrane에 이동시켰다. Membrane에 비 특이적인 항체의 결합 방지를 위해 5% skim milk에 1시간 동안 두었고, 1차 항체를 부착한 후 4℃에 overnight후 horse radish peroxide(HRP)가 부착된 2차 항체를 반응시켰다. 부착된 항체를 ECL kit(Promega, USA)를 반응시킨 후 Chemidoc 기기(Bio Rad, California, USA)를 이용해 측정하였다.HepG2 cells treated with cinnenecetin were washed with PBS and incubated with RIPA lysis buffer (50 mM Tris-HCl pH 7.4, 1% NP-40, 0.25% Na-deoxycholate , 150 mM NaCl, 1 mM EDTA) was added to extract whole proteins of the cells. Bicinchoninate (BCA) assay was used to quantitate the protein concentration, electrophoresed on SDS-polyacrylamide gel, and then transferred to the PVDF membrane. To prevent the binding of nonspecific antibodies to membranes, the cells were incubated in 5% skim milk for 1 hour. After incubation at 4 ° C with primary antibody, horse radish peroxidase (HRP) conjugated secondary antibody was reacted. The antibodies were reacted with ECL kit (Promega, USA) and then measured using Chemidoc instrument (Bio Rad, California, USA).
1-8. 통계처리1-8. Statistical processing
모든 실험 결과는 적어도 3번 이상 반복 실험하였고, 그 결과를 평균±표준편차로 나타내었다. 각 실험 결과의 통계적 유의성 검토는 시료가 포함되지 않는 대조군과 비교하여 Student's t-test에 의해 판정되었으며 P 값이 0.05 미만일 경우 통계적으로 유의하다고 판단하였다.All experimental results were repeated at least 3 times and the results were expressed as mean ± standard deviation. The statistical significance of each test result was determined by Student's t-test as compared to the control group without sample and statistically significant when the P value was less than 0.05.
2. 결과2. Results
2-1. 시넨세틴의 HepG2 세포 사멸 유도2-1. Induction of HepG2 cell death of cinnenecetin
플라보노이드 단일 성분 중 하나인 시넨세틴이 인간 간암 세포인 HepG2 사멸 작용을 확인하기 위해 시간과 농도 별로 처리한 후 MTT assay를 실시하였다. 인간의 간암세포인 HepG2에서는 24시간과 48시간 시넨세틴을 농도 별로 처리한 그룹에서 시간과 농도 의존적으로 세포사멸 작용이 나타났다. 대조군과 비교하였을 때, 시넨세틴을 48시간 처리한 그룹에서 50μM에서 약 50%, 100μM에서 65%로 암세포 사멸 작용을 확인하였다. 또한, 간암 세포 외 정상세포에도 영향을 미치는지 확인하기 위해 인간의 정상 간세포인 Thle2 세포에도 시넨세틴을 처리하였다. 그 결과, 24시간과 48시간 처리한 그룹에서 시넨세틴이 간 정상세포보다 간암 세포에 더 큰 영향을 미치는 것을 확인할 수 있었다(도 1 참조).One of the flavonoids, cinnexetin, was treated with time and concentration to determine the death of HepG2, a human liver cancer cell, and MTT assay was performed. HepG2, a human liver cancer cell, showed apoptosis in a time - and concentration - dependent manner in groups treated with 24 hours and 48 hours of cinnenecetine. When compared with the control group, the cancer cell killing activity was confirmed to be about 50% at 50 μM and 65% at 100 μM in the group treated with cinnensetin for 48 hours. In addition, in order to confirm whether it affects extrahepatic extra-cellular cells, the human normal hepatocyte, Thle2 cells, was also treated with cinnenecetin. As a result, it was confirmed that cinnenecetin had a greater effect on liver cancer cells than hepatic normal cells in the group treated for 24 hours and 48 hours (see FIG. 1).
2-2. 시넨세틴의 위암세포에서 세포 사멸 작용 효과2-2. Effect of Cynenecetin on Cell Death in Gastric Cancer Cells
인간의 위암 세포인 AGS 세포 사멸을 하는지 알아보기 위해 24시간 동안 시넨세틴을 다양한 농도로 처리한 후 MTT assay를 통해 확인하였다. 시넨세틴은 농도 의존적으로 AGS 세포 사멸 작용을 나타냈다. DMSO를 처리한 대조군과 비교하였을 때, 시넨세틴 60μM에서 약 25%, 80μM에서 35%의 세포 사멸 효과를 나타냈다(도 2 참조). 또한 기존의 항암제로 알려진 시스플라틴(cisplatin)의 세포사멸 작용을 AGS 세포에서 알아본 결과, 시스플라틴 0.3μM에서 약 50%의 사멸 효과를 나타냈다(도 3 참조).To determine whether AGS cells die in human gastric cancer cells, various concentrations of cinnenecetin were treated for 24 hours and then assayed by MTT assay. Cynenecetin showed AGS cell killing activity in a concentration dependent manner. When compared to the control group treated with DMSO, the cytotoxic effect was about 25% at 60 μM of cynesecetin and 35% at 80 μM (see FIG. 2). In addition, the cytotoxic effect of cisplatin, which is known as an anticancer drug, was examined in AGS cells, and showed a killing effect of about 50% at 0.3 μM of cisplatin (see FIG. 3).
2-3. 시넨세틴과 시스플라틴의 조합에 의한 세포 사멸 효과 증가2-3. Increased cell killing effect by combination of cinnenecetin and cisplatin
AGS 세포에 시넨세틴을 40μM과 50μM을 처리한 그룹에 각 시스플라틴을 0.1μM과 0.2μM로 처리하였다. 시스플라틴을 0.1μM만 처리했을 때, cell viability가 약 90%이지만, 시넨세틴 50μM과 함께 처리한 그룹에서 cell viability가 약 30%로 감소하였다(도 4 참조). 또한, 시스플라틴을 0.2μM만 처리한 그룹에서 약 75%의 cell viability가 나타났지만, 시넨세틴 40μM과 함께 처리했을 경우 약 50%의 cell viability로 나타났다(도 4 참조). 이를 통해, 시스플라틴과 시넨세틴을 같이 처리하였을 때, 시스플라틴은 인간의 위암 세포인 AGS 세포에서 더 높은 세포사멸 작용을 보인다.AGS cells were treated with 40 μM and 50 μM of cinnenecetine and treated with 0.1 μM and 0.2 μM each cisplatin. When treated with 0.1 μM of cisplatin alone, cell viability was reduced to about 30% in the group treated with 50 μM of cinnenecetin, although the cell viability was about 90% (see FIG. 4). In addition, about 75% cell viability was observed in the group treated with 0.2 μM of cisplatin alone, but about 50% cell viability was shown when treated with 40 μM of cinnenecetin (see FIG. 4). Thus, when cisplatin and cinnenecetin are treated together, cisplatin exhibits a higher apoptotic action in AGS cells, which are human gastric cancer cells.
2-4. 시넨세틴의 HepG2와 AGS 세포 이동 효과 확인2-4. Identification of HepG2 and AGS cell migration effect of cinnenecetin
시넨세틴이 HepG2 세포 이동성에 어떠한 영향을 미치는지 알아보기 위해 cell migration assay(wound healing assay)를 실시하였다. HepG2에 시넨세틴을 48h동안 50μM과 100μM로 처리한 후 세포의 이동 면적을 측정한 결과, 대조군에 비해 50μM에서 약 50%, 100μM에서 30%의 이동성을 보였다. 이를 통해, HepG2 세포는 농도 의존적으로 시넨세틴에 의해 세포의 이동성이 저해됨을 확인하였다(도 5 참조). AGS 세포의 경우, 시넨세틴과 시스플라틴은 각각 대조군에 비해 세포의 이동성을 저해하였지만, 시넨세틴과 시스플라틴의 조합이 더 큰 이동성 억제 효과를 나타내었다(도 6 참조).Cell migration assay (wound healing assay) was performed to investigate the effect of cinnenecetin on HepG2 cell mobility. When HepG2 was treated with 50 μM and 100 μM of Sinensetin for 48 h, the cell migration area was 50% at 50 μM and 30% at 100 μM, compared with the control. As a result, it was confirmed that the mobility of the cells was inhibited by cinnenecetin in a concentration-dependent manner of HepG2 cells (see FIG. 5). In the case of AGS cells, cinnenecetin and cisplatin inhibited cell mobility compared to the control, respectively, but the combination of cinnenecetin and cisplatin showed greater mobility inhibition (see FIG. 6).

Claims (8)

  1. 시넨세틴(sinensetin) 또는 이의 염을 유효성분으로 함유하는 간암 또는 위암의 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for the prophylaxis or treatment of liver cancer or stomach cancer containing sinensetin or a salt thereof as an active ingredient.
  2. 제 1항에 있어서,The method according to claim 1,
    상기 조성물은 시스플라틴(cisplatin)을 유효성분으로 더 함유하는 것을 특징으로 하는 조성물.Wherein the composition further comprises cisplatin as an active ingredient.
  3. 시넨세틴(sinensetin) 또는 이의 염을 유효성분으로 함유하는 간암 또는 위암의 예방, 개선 또는 전이 억제용 기능성 식품 조성물.A functional food composition for the prevention, amelioration or inhibition of metastasis of liver cancer or stomach cancer containing sinensetin or a salt thereof as an active ingredient.
  4. 제 3항에 있어서,The method of claim 3,
    상기 조성물은 시스플라틴(cisplatin)을 유효성분으로 더 함유하는 것을 특징으로 하는 조성물.Wherein the composition further comprises cisplatin as an active ingredient.
  5. 시넨세틴(sinensetin) 또는 이의 염을 유효성분으로 함유하는 간암 또는 위암의 예방, 개선 또는 전이 억제용 기능성 사료 조성물.A functional feed composition for the prevention, amelioration or inhibition of metastasis of hepatoma or stomach cancer containing sinensetin or a salt thereof as an active ingredient.
  6. 제 5항에 있어서,6. The method of claim 5,
    상기 조성물은 시스플라틴(cisplatin)을 유효성분으로 더 함유하는 것을 특징으로 하는 조성물.Wherein the composition further comprises cisplatin as an active ingredient.
  7. 시넨세틴(sinensetin) 또는 이의 염을 유효성분으로 함유하는 간암 또는 위암의 전이 억제용 약학적 조성물.A pharmaceutical composition for inhibiting the metastasis of liver cancer or stomach cancer containing sinensetin or a salt thereof as an active ingredient.
  8. 제 7항에 있어서,8. The method of claim 7,
    상기 조성물은 시스플라틴(cisplatin)을 유효성분으로 더 함유하는 것을 특징으로 하는 조성물.Wherein the composition further comprises cisplatin as an active ingredient.
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