KR102197296B1 - Pharmaceutical composition for preventing or treating lung cancer comprising extract of Schoenoplectus triqueter - Google Patents
Pharmaceutical composition for preventing or treating lung cancer comprising extract of Schoenoplectus triqueter Download PDFInfo
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- KR102197296B1 KR102197296B1 KR1020190042096A KR20190042096A KR102197296B1 KR 102197296 B1 KR102197296 B1 KR 102197296B1 KR 1020190042096 A KR1020190042096 A KR 1020190042096A KR 20190042096 A KR20190042096 A KR 20190042096A KR 102197296 B1 KR102197296 B1 KR 102197296B1
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Abstract
본 발명은 세모고랭이의 추출물 또는 이의 분획물을 포함하는 폐암의 예방 또는 치료용 약학 조성물, 식품 조성물, 사료 조성물 및 상기 약학 조성물을 이용하여 폐암을 치료하는 방법에 관한 것이다. 본 발명의 세모고랭이 추출물은 안전하면서도 효과적으로 폐암의 예방 또는 치료효과를 나타냄을 확인하였으므로, 본 발명의 세모고랭이 추출물은 폐암의 예방 또는 치료에 널리 활용될 수 있을 것이다.The present invention relates to a pharmaceutical composition, food composition, feed composition, and a method for treating lung cancer using the pharmaceutical composition for the prevention or treatment of lung cancer comprising an extract or fractions thereof. Since it was confirmed that the trigonolite extract of the present invention exhibits a safe and effective preventive or therapeutic effect on lung cancer, the trigonolite extract of the present invention may be widely used in the prevention or treatment of lung cancer.
Description
본 발명은 세모고랭이의 추출물을 포함하는 폐암의 예방 또는 치료용 약학 조성물에 관한 것으로, 구체적으로 본 발명은 세모고랭이의 추출물 또는 이의 분획물을 포함하는 폐암의 예방 또는 치료용 약학 조성물, 식품 조성물, 사료 조성물 및 상기 약학 조성물을 이용하여 폐암을 치료하는 방법에 관한 것이다.The present invention relates to a pharmaceutical composition for preventing or treating lung cancer comprising an extract of trigonium, specifically, the present invention is a pharmaceutical composition, food composition for preventing or treating lung cancer comprising an extract of trigonium or a fraction thereof , To a method for treating lung cancer using the feed composition and the pharmaceutical composition.
폐에서 기원하는 악성 종양인 폐암은 그 조직형태에 따라 크게 소세포성 폐암(small cell lung cancer)과 비 소세포성 폐암(non-small cell lung cancer)으로 구분된다. 상기 소세포폐암은 발병 조직의 위치에 의해 폐암의 일부로 구분되기는 하나, 다른 폐암과는 임상 경과, 치료법 및 예후 면에서 확연히 구분되는 특징이 있어 상기와 같이 구분하고 있다. 또한, 비소세포폐암은 조직형에 따라 선암, 편평상피세포암 및 대세포암으로 구분된다.Lung cancer, a malignant tumor originating from the lungs, is largely classified into small cell lung cancer and non-small cell lung cancer according to its tissue type. Although the small cell lung cancer is classified as a part of lung cancer by the location of the affected tissue, it is distinguished as described above because it has distinct characteristics in terms of clinical course, treatment, and prognosis from other lung cancers. In addition, non-small cell lung cancer is classified into adenocarcinoma, squamous cell carcinoma, and large cell carcinoma according to the tissue type.
구체적으로, 소세포폐암은 대체적으로 종괴가 크며 회백색을 띠고 기관지벽을 따라 증식하는 것으로 알려져 있는데, 대부분 진단 당시 수술적 절제가 어려울 정도로 진행되어 있는 경우가 많고, 악성도가 강하여 급속히 성장하며, 림프관이나 혈액 순환을 통하여 전신으로 용이하게 전이되는 반면, 화학요법이나 방사선요법에 의하여 현저한 치료효과를 나타내는 것으로 알려져 있다. 상기 소세포폐암이 전이되는 주요 장기로는 뇌, 간, 뼈, 폐, 부신, 신장 등이 보고되었는데, 주로 기도(기관지나 세기관지)에서 처음 발병하는 것으로 알려져 있다.Specifically, small cell lung cancer is generally known to have a large mass, grayish white, and proliferate along the bronchial wall.In most cases, surgical resection is difficult at the time of diagnosis, and it is highly malignant and grows rapidly. While it is easily metastasized to the whole body through blood circulation, it is known to exhibit remarkable therapeutic effects by chemotherapy or radiation therapy. The brain, liver, bones, lungs, adrenal glands, kidneys, and the like have been reported as major organs to which the small cell lung cancer is metastasized, and it is known that it first develops mainly in the airways (bronchi or bronchioles).
반면, 비소세포폐암은 상술한 바와 같이 선암(adenocarcinoma), 편평상피세포암(squamous cell acrcinoma) 및 대세포암(large-cell carcinoma)으로 구분된다. 먼저, 선암은 폐말초 부위에서 주로 발생하고, 여성 또는 비흡연자에게서도 잘 발생하며, 크기가 작아도 전이가 되어 있는 경우가 많고, 최근 그의 발생 빈도가 증가하는 추세에 있다. 다음으로, 편평상피세포암은 주로 폐 중심부에서 발견되고, 주로 기관지 내강으로 자라 기관지를 막는 증상을 나타내며, 남성에게 흔하고, 흡연과 밀접하게 관련된 것으로 알려져 있다. 끝으로, 대세포암은 폐표면 근처(폐 말초)에서 주로 발생하고, 절반 가량은 큰 기관지에서 발생하며, 전체 폐암의 4 내지 10% 정도를 차지하고, 세포 크기가 대체적으로 크며, 그 중 일부는 빠르게 증식 및 전이되는 경향이 있어 다른 비소세포폐암에 비해 예후가 나쁜 것으로 알려져 있다.On the other hand, non-small cell lung cancer is classified into adenocarcinoma, squamous cell acrcinoma, and large-cell carcinoma as described above. First, adenocarcinoma occurs mainly in the peripheral part of the lungs, it occurs well in women or non-smokers, and there are many cases of metastasis even though the size is small, and the incidence of it has recently increased. Next, squamous cell carcinoma is mainly found in the center of the lungs and mainly grows into the lumen of the bronchi, showing symptoms that block the bronchi, is common in men, and is known to be closely related to smoking. Lastly, large cell carcinoma occurs mainly near the lung surface (peripheral lung), and about half of it occurs in the large bronchi, accounts for about 4 to 10% of all lung cancer, and the cell size is generally large, some of which are It is known to have a poor prognosis compared to other non-small cell lung cancers because it tends to proliferate and metastasize rapidly.
이로 인하여, 이의 진단 또는 치료 방법에 대한 연구가 활발히 이루어지고 있다. 그 예로서, 아트라노린 등을 함유하는 폐암 예방 또는 치료용 조성물(한국 공개특허공보 제10-2017-0089822호), 폐암, 대장암 등 방사선 치료에 대하여 내성을 나타내는 암 치료용 약학 조성물(한국 공개특허공보 제10-2017-0023335호), 대장암 과발현 유전자를 이용하여 대장암을 진단하는 방법(한국 등록특허공보 제10-1007573호) 등이 공지된바 있다. 이같은 폐암이 조기에 진단될 경우에는, 약물치료 및 방사선 치료등을 통해 회복될 수 있으나, 일정 수준으로 병증이 악화된 경우에는 수술을 통해 병변을 제거하고, 약물치료 및 방사선 치료등을 통한 치료를 수행하게 되는데, 아직까지는 폐암의 치료에 사용될 수 있도록 공인된 약물은 이레사 등을 비롯한 몇가지로 제한되어 있어 환자에게 적합한 치료를 수행하기 어렵고, 이들 치료제는 무시할 수 없는 수준의 부작용을 나타낸다는 단점이 있어, 수술 이후의 치료성공율이 저조한 실정이다. 이러한 단점을 극복하기 위하여, 부작용을 줄일 수 있는 복합 천연물로부터 유래된 치료제를 개발하려는 노력이 계속되고 있는데, 이들 천연물 유래 치료제는 치료효과가 우수하지 못하다는 근본적인 단점이 해소되지 않고 있다. For this reason, research on a diagnosis or treatment method thereof has been actively conducted. As an example, a composition for preventing or treating lung cancer containing atlanolin, etc. (Korean Patent Laid-Open Publication No. 10-2017-0089822), a pharmaceutical composition for treating cancer that exhibits resistance to radiation therapy such as lung cancer and colon cancer (Korea Korean Patent Publication No. 10-2017-0023335), a method of diagnosing colorectal cancer using a colon cancer overexpression gene (Korean Patent Publication No. 10-1007573), and the like have been known. If such lung cancer is diagnosed early, it can be recovered through drug treatment and radiation treatment, but if the condition worsens to a certain level, the lesion is removed through surgery, and treatment through drug treatment and radiation treatment is performed. However, it is difficult to perform appropriate treatment for patients, as drugs that have been approved to be used for the treatment of lung cancer are limited to a few, including Iressa, and these treatments have the disadvantage that they exhibit side effects that cannot be ignored. , The treatment success rate after surgery is low. In order to overcome these shortcomings, efforts to develop therapeutic agents derived from complex natural products that can reduce side effects are continuing, and these natural products-derived therapeutic agents have not solved the fundamental disadvantage that the therapeutic effect is not excellent.
이러한 배경하에서, 본 발명자들은 폐암을 보다 안전하면서도 효과적으로 치료하는 방법을 개발하고자 예의 연구노력한 결과, 세모고랭이의 추출물을 사용할 경우, 안전하면서도 효과적으로 폐암을 치료할 수 있음을 확인하고 본 발명을 완성하였다.Under this background, the present inventors have made intensive research efforts to develop a safer and more effective treatment method for lung cancer.As a result, when using an extract of trigonium, it has been confirmed that lung cancer can be safely and effectively treated and completed the present invention.
본 발명의 하나의 목적은 세모고랭이 추출물 또는 이의 분획물을 포함하는 폐암의 예방 또는 치료용 약학 조성물을 제공하는 것이다.One object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of lung cancer comprising a triangulum extract or a fraction thereof.
본 발명의 다른 목적은 세모고랭이 추출물 또는 이의 분획물을 포함하는 폐암의 예방 또는 개선용 식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a food composition for preventing or improving lung cancer comprising a triangulum extract or a fraction thereof.
본 발명의 또 다른 목적은 세모고랭이 추출물 또는 이의 분획물을 포함하는 폐암의 예방 또는 개선용 사료 조성물을 제공하는 것이다.Another object of the present invention is to provide a feed composition for preventing or improving lung cancer comprising a triangulum extract or a fraction thereof.
본 발명의 또 다른 목적은 상기 약학 조성물을 이용하여 폐암을 치료하는 방법을 제공하는 것이다.Another object of the present invention is to provide a method of treating lung cancer using the pharmaceutical composition.
상술한 목적을 달성하기 위한 본 발명의 일 실시양태는 세모고랭이의 추출물 또는 이의 분획물을 포함하는 폐암의 예방 또는 치료용 약학 조성물을 제공한다.One embodiment of the present invention for achieving the above object provides a pharmaceutical composition for the prevention or treatment of lung cancer comprising an extract of trigonolite or a fraction thereof.
본 발명의 용어 "세모고랭이(Schoenoplectus triqueter)"란, 외떡잎식물 벼목 사초과의 여러해살이풀을 의미하는데, 다음과 같은 특징을 갖는다고 알려져 있다: 물가에서 자란다. 땅속줄기가 옆으로 뻗으면서 마디에서 녹색의 원줄기가 1개씩 자라서 높이 50∼100 cm로 된다. 잎은 퇴화하고 잎집으로 되어 원줄기를 감싸며 원대는 삼각형이다. 포는 1개가 원줄기와 연속되어 원줄기같이 보인다. 꽃은 7∼10월에 핀다. 작은이삭은 타원형에서 달걀모양이고 1∼3개씩 모여 달리며 전체가 산방상으로 된다. 비늘조각은 긴 타원형이며 막질(膜質:얇은 종이처럼 반투명한 것)이고 길이 4 mm 내외이다. 열매는 수과(瘦果)이며 달걀을 거꾸로 세운 모양이고 렌즈형이며 갈색으로 성숙한다. 암술머리는 2개이고, 화피갈래조각은 가시와 같이 생기며 3∼5개이다. 한국을 비롯한 아시아와 유럽에 분포한다.The term " Schoenoplectus triqueter " of the present invention refers to a perennial plant of the monocotyledonous plant sedgeaceae, which is known to have the following characteristics: It grows near water. As the subterranean stem extends to the side, a green main stem grows one at a time from the node and becomes 50-100 cm high. Leaves degenerate and form a sheath, enclosing the main stem, and the circle is triangular. One bract is contiguous with the main stem and looks like a main stem. Flowers bloom from July to October. Small ears are oval to egg-shaped, 1 to 3 are gathered and run, and the whole becomes corymb. Scale fragments are long oval, membranous (膜質: translucent like thin paper), about 4 mm long. The fruit is a fruit, the shape of an egg upside down, lenticular, and mature brown. There are 2 pistil heads, and the forked flower pieces are like thorns, and there are 3 to 5 pieces. It is distributed in Asia and Europe, including Korea.
본 발명에 있어서, 상기 세모고랭이는 상업적으로 판매되는 것을 구입하여 사용하거나, 자연에서 채취 또는 재배된 것을 사용할 수 있으나, 이에 제한되지 않는다.In the present invention, the triangular gorengi may be purchased and used commercially, or may be harvested or grown in nature, but is not limited thereto.
본 발명의 용어, "추출물"이란, 목적하는 물질을 다양한 용매에 침지한 다음, 상온 또는 가온상태에서 일정시간 동안 추출하여 수득한 액상성분, 상기 액상성분으로부터 용매를 제거하여 수득한 고형분 등의 결과물을 의미한다. 뿐만 아니라, 상기 결과물에 더하여, 상기 결과물의 희석액, 이들의 농축액, 이들의 조정제물, 정제물 등을 모두 포함하는 것으로 포괄적으로 해석될 수 있다. 이에 따라, 본 발명에서 제공하는 세모고랭이 추출물은 세모고랭이를 추출 처리하여 얻어지는 추출액, 상기 추출액의 희석액이나 농축액, 상기 추출액을 건조하여 얻어지는 건조물, 상기 추출액의 조정제물이나 정제물, 또는 이들의 혼합물 등, 추출액 자체 및 추출액을 이용하여 형성 가능한 모든 제형의 추출물을 포함하는 것으로 해석될 수 있다. The term "extract" of the present invention refers to a liquid component obtained by immersing a target substance in various solvents and then extracting it for a certain period of time at room temperature or warming state, and a resultant product such as a solid component obtained by removing the solvent from the liquid component. Means. In addition, in addition to the resulting product, it can be comprehensively interpreted as including all of the diluted solution of the resultant, the concentrate thereof, the preparation thereof, and the purified product. Accordingly, the triangulum extract provided in the present invention is an extract obtained by extracting trigonium, a dilution or concentrate of the extract, a dried product obtained by drying the extract, a preparation or purified product of the extract, or It can be interpreted as including a mixture, the extract itself, and extracts of all formulations that can be formed using the extract.
본 발명의 세모고랭이 추출물에 있어서, 상기 혼합물을 추출하는 방법은 특별히 제한되지 않으며, 당해 기술 분야에서 통상적으로 사용하는 방법에 따라 추출할 수 있다. 상기 추출 방법의 비제한적인 예로는, 열수 추출법, 초음파 추출법, 여과법, 환류 추출법 등을 들 수 있으며, 이들은 단독으로 수행되거나 2종 이상의 방법을 병용하여 수행될 수 있다.In the triangulum extract of the present invention, a method of extracting the mixture is not particularly limited, and may be extracted according to a method commonly used in the art. Non-limiting examples of the extraction method include a hot water extraction method, an ultrasonic extraction method, a filtration method, a reflux extraction method, and the like, and these may be performed alone or in combination of two or more methods.
본 발명에서 상기 추출에 사용되는 용매의 종류는 특별히 제한되지 않으며, 당해 기술 분야에서 공지된 임의의 용매를 사용할 수 있다. 상기 추출 용매의 비제한적인 예로는 물, 알코올 또는 이들의 혼합 용매 등을 들 수 있고, 이들은 단독으로 사용되거나 1종 이상 혼합하여 사용될 수 있으며, 구체적으로 알코올이 사용될 수 있는데, 주로 탄소수 1 내지 4의 알코올을 사용할 수 있다.In the present invention, the type of solvent used for the extraction is not particularly limited, and any solvent known in the art may be used. Non-limiting examples of the extraction solvent may include water, alcohol, or a mixed solvent thereof, and these may be used alone or in combination of one or more, and specifically alcohol may be used, mainly having 1 to 4 carbon atoms. You can use the alcohol.
본 발명의 용어, "분획물"은 여러 다양한 구성 성분들을 포함하는 혼합물로부터 특정 성분 또는 특정 성분 그룹을 분리하기 위하여 분획을 수행하여 얻어진 결과물을 의미한다.As used herein, the term "fraction" means a result obtained by performing fractionation in order to separate a specific component or a specific group of components from a mixture containing several different constituents.
본 발명에서 상기 분획물을 얻는 분획 방법은 특별히 제한되지 않으며, 당해 기술 분야에서 통상적으로 사용하는 방법에 따라 수행될 수 있다. 상기 분획 방법의 비제한적인 예로는, 다양한 용매를 처리하여 수행하는 용매 분획법, 일정한 분자량 컷-오프 값을 갖는 한외 여과막을 통과시켜 수행하는 한외여과 분획법, 다양한 크로마토그래피(크기, 전하, 소수성 또는 친화성에 따른 분리를 위해 제작된 것)를 수행하는 크로마토그래피 분획법, 및 이들의 조합 등이 있다. 구체적으로, 본 발명의 세모고랭이를 추출하여 얻은 추출물에 소정의 용매를 처리하여 상기 추출물로부터 분획물을 얻는 방법을 들 수 있다.The fractionation method for obtaining the fraction in the present invention is not particularly limited, and may be performed according to a method commonly used in the art. Non-limiting examples of the fractionation method include a solvent fractionation method performed by treating various solvents, an ultrafiltration fractionation method performed by passing an ultrafiltration membrane having a constant molecular weight cut-off value, and various chromatography (size, charge, hydrophobicity). Or a chromatographic fractionation method for performing separation according to affinity), and combinations thereof. Specifically, there may be mentioned a method of obtaining a fraction from the extract by treating the extract obtained by extracting the triangulum of the present invention with a predetermined solvent.
본 발명에서 상기 분획물을 얻는 데 사용되는 분획 용매의 종류는 특별히 제한되지 않으며, 당해 기술 분야에서 공지된 임의의 용매를 사용할 수 있다. 상기 분획 용매의 비제한적인 예로는 물, 탄소수 1 내지 4의 알코올 등의 극성 용매; 헥산(Hexan), 에틸 아세테이트(Ethyl acetate), 클로로포름(Chloroform), 디클로로메탄(Dichloromethane) 등의 비극성 용매; 또는 이들의 혼합용매 등을 들 수 있다. 이들은 단독으로 사용되거나 1종 이상 혼합하여 사용될 수 있지만, 이에 제한되는 것은 아니다.In the present invention, the type of fractionation solvent used to obtain the fraction is not particularly limited, and any solvent known in the art may be used. Non-limiting examples of the fractionation solvent include polar solvents such as water and alcohols having 1 to 4 carbon atoms; Non-polar solvents such as hexane, ethyl acetate, chloroform, and dichloromethane; Or a mixed solvent of these, etc. are mentioned. These may be used alone or in combination of one or more, but are not limited thereto.
또한, 상기 추출물 또는 분획물은 추출 후 건조 분말 형태로 제조되어 사용될 수 있지만, 이제 제한되는 것은 아니다.In addition, the extract or fraction may be prepared and used in a dry powder form after extraction, but is not limited thereto.
본 발명의 용어, "예방"은 상기 추출물을 포함하는 조성물의 투여로 폐암을 억제 또는 지연시키는 모든 행위를 의미한다. The term "prevention" of the present invention refers to all actions of inhibiting or delaying lung cancer by administration of a composition comprising the extract.
본 발명의 용어, "치료"는 상기 추출물을 포함하는 조성물의 투여로 폐암의 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다.The term "treatment" of the present invention refers to any action in which symptoms of lung cancer are improved or beneficially changed by administration of a composition comprising the extract.
본 발명의 약학 조성물은 조성물 총 중량에 대하여 상기 추출물을 0.001 내지 80, 구체적으로 0.001 내지 70, 더욱 구체적으로 0.001 내지 60 중량%로 포함할 수 있으나, 이에 제한되지 않는다.The pharmaceutical composition of the present invention may include 0.001 to 80, specifically 0.001 to 70, more specifically 0.001 to 60% by weight of the extract based on the total weight of the composition, but is not limited thereto.
또한, 상기 약학 조성물은 약학 조성물의 제조에 통상적으로 사용하는 약학적으로 허용가능한 담체, 부형제 또는 희석제를 추가로 포함할 수 있고, 상기 담체는 비자연적 담체(non-naturally occuring carrier)를 포함할 수 있다. 상기 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다.In addition, the pharmaceutical composition may further include a pharmaceutically acceptable carrier, excipient, or diluent commonly used in the manufacture of pharmaceutical compositions, and the carrier may include a non-naturally occurring carrier. have. Examples of the carrier, excipient and diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline Cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oils.
또한, 상기 약학 조성물은 각각 통상의 방법에 따라 정제, 환제, 산제, 과립제, 캡슐제, 현탁제, 내용액제, 유제, 시럽제, 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 경피흡수제, 겔제, 로션제, 연고제, 크림제, 첩부제, 카타플라스마제, 페이스트제, 스프레이, 피부 유화액, 피부 현탁액, 경피 전달성 패치, 약물 함유 붕대 또는 좌제의 형태로 제형화하여 사용할 수 있다. 구체적으로, 제형화할 경우 통상 사용하는 충진제, 중량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. 경구투여를 위한 고형제제로는 정제, 환제, 산제, 과립제, 캡슐제 등을 포함하지만, 이에 제한되지 않는다. 이러한 고형제제는 적어도 하나 이상의 부형제, 예를 들면, 전분, 칼슘 카보네이트, 수크로오스, 락토오스, 젤라틴 등을 섞어 조제될 수 있다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제 등도 사용될 수 있다. 경구를 위한 액상물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등을 첨가하여 조제될 수 있다. 비경구 투여를 위한 제제는 멸균된 수용액, 비수성 용제, 현탁제, 유제, 동결건조 제제 및 좌제를 포함한다. 비수성 용제 및 현탁제로는 프로필렌 글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 오일, 에틸올레이트와 같은 주사가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔, 마크로골, 트윈 61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있다.In addition, the pharmaceutical compositions are each tablet, pill, powder, granule, capsule, suspension, solution, emulsion, syrup, sterilized aqueous solution, non-aqueous solvent, suspension, emulsion, freeze-dried, transdermal, respectively, according to a conventional method. It can be formulated and used in the form of absorbents, gels, lotions, ointments, creams, patches, cataplasmas, pastes, sprays, skin emulsions, skin suspensions, transdermal delivery patches, drug-containing bandages or suppositories. Specifically, when formulated, it may be prepared using diluents or excipients such as fillers, weight agents, binders, wetting agents, disintegrants, surfactants, etc. that are commonly used. Solid preparations for oral administration include, but are not limited to, tablets, pills, powders, granules, capsules, and the like. These solid preparations may be prepared by mixing at least one or more excipients, for example starch, calcium carbonate, sucrose, lactose, gelatin, and the like. In addition, in addition to simple excipients, lubricants such as magnesium stearate and talc may be used. It can be prepared by adding various excipients, such as wetting agents, sweetening agents, fragrances, preservatives, and the like, in addition to oral liquids and liquid paraffin. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations, and suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyloleate, and the like may be used. As a base for suppositories, Witepsol, Macrogol, Tween 61, cacao butter, laurin paper, glycerogelatin, and the like can be used.
본 발명의 일 실시예에 의하면, 정상세포에는 독성을 나타내지 않으면서도 폐암세포를 사멸시키고(도 1), 폐암세포의 증식능을 억제하며(도 2), 폐암세포의 침투능을 억제하고(도 3), 폐암세포의 이주능을 억제하며(도 4), 폐암세포로부터 유래된 카스파제-3의 활성을 촉진시키고(도 5), 폐암세포의 사멸을 억제하고, 증식을 촉진하는 단백질의 수준을 감소시키며(도 6), 폐암의 발병에 관여하는 것으로 알려진 STAT3 단백질의 인산화(도 7 및 10), DNA 결합활성(도 8) 및 전이활성(도 9)을 억제함을 확인하였다.According to an embodiment of the present invention, it kills lung cancer cells without showing toxicity to normal cells (FIG. 1), inhibits the proliferative ability of lung cancer cells (FIG. 2), and inhibits the penetration ability of lung cancer cells (FIG. 3). , Suppresses the migration ability of lung cancer cells (Fig. 4), promotes the activity of caspase-3 derived from lung cancer cells (Fig. 5), inhibits the death of lung cancer cells, and reduces the level of protein that promotes proliferation 6), it was confirmed that phosphorylation of STAT3 protein known to be involved in the onset of lung cancer (FIGS. 7 and 10), DNA binding activity (FIG. 8) and metastatic activity (FIG. 9) were inhibited.
따라서, 본 발명에서 제공하는 세모고랭이 추출물은 폐암의 예방 또는 치료에 효과적으로 사용될 수 있을 것이다.Therefore, the trigonium extract provided by the present invention may be effectively used in the prevention or treatment of lung cancer.
본 발명의 다른 실시양태는 상기 약학 조성물을 인간을 제외한 폐암 의심 개체에 투여하는 단계를 포함하는 폐암의 치료방법을 제공한다.Another embodiment of the present invention provides a method for treating lung cancer comprising administering the pharmaceutical composition to an individual suspected of lung cancer other than humans.
이때, 상기 용어 "세모고랭이", "추출물", "분획물", "예방" 및 "치료"의 정의는 상기에서 서술한 바와 같다.At this time, the definitions of the terms "trigonose", "extract", "fraction", "prevention" and "treatment" are as described above.
본 발명의 용어, "투여"는 적절한 방법으로 개체에게 상기 추출물을 포함하는 조성물을 도입하는 행위를 의미한다.The term "administration" of the present invention refers to the act of introducing a composition comprising the extract to an individual by an appropriate method.
본 발명의 용어, "개체"는 폐암이 발병하였거나 발병할 수 있는 인간을 포함한 쥐, 생쥐, 가축 등의 모든 동물을 의미한다. 구체적인 예로, 인간을 포함한 포유동물일 수 있다.As used herein, the term "individual" refers to all animals such as rats, mice, and livestock, including humans who have or may develop lung cancer. As a specific example, it may be a mammal including a human.
본 발명의 약학 조성물은 약학적으로 유효한 양으로 투여한다. 상기 용어, "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 개체 종류 및 중증도, 연령, 성별, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료 기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 예를 들면, 상기 세모고랭이 추출물은 1일 0.01 내지 500 mg/kg으로, 구체적으로 10 내지 100 mg/kg의 용량으로 투여할 수 있으며, 상기 투여는 하루에 한 번 또는 수회 나누어 투여할 수도 있다. The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. The term "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is the type and severity of the subject, age, sex, activity of the drug, Sensitivity to drugs, time of administration, route of administration and rate of excretion, duration of treatment, factors including drugs used concurrently, and other factors well known in the medical field. For example, the triangulum extract may be administered at a dose of 0.01 to 500 mg/kg per day, specifically 10 to 100 mg/kg, and the administration may be administered once or several times a day. .
상기 약학 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있다. 그리고 단일 또는 다중 투여될 수 있다. 상기 요소를 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 당업자에 의해 용이하게 결정될 수 있다.The pharmaceutical composition may be administered as an individual therapeutic agent or administered in combination with other therapeutic agents, and may be administered sequentially or simultaneously with a conventional therapeutic agent. And can be administered single or multiple. It is important to administer an amount capable of obtaining the maximum effect in a minimum amount without side effects in consideration of all the above factors, and can be easily determined by a person skilled in the art.
또한, 상기 약학 조성물은 목적하는 방법에 따라 경구 투여하거나 비경구 투여(예를 들어, 정맥 내, 피하, 복강 내 또는 국소에 적용)할 수 있으며, 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 시간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다.In addition, the pharmaceutical composition may be administered orally or parenterally (for example, intravenous, subcutaneous, intraperitoneal or topical application) according to a desired method, and the dosage may be the patient's condition and weight, the degree of disease , It depends on the drug form, administration route and time, but may be appropriately selected by those skilled in the art.
본 발명의 또 다른 실시양태는 세모고랭이 추출물 또는 이의 분획물을 포함하는 폐암의 예방 또는 개선용 식품 조성물을 제공한다.Another embodiment of the present invention provides a food composition for preventing or improving lung cancer comprising a triangulum extract or a fraction thereof.
이때, 상기 용어 "세모고랭이", "추출물", "분획물" 및 "예방"의 정의는 상기에서 서술한 바와 같다.At this time, the definitions of the terms "trigonose", "extract", "fraction" and "prevention" are as described above.
본 발명의 용어, "개선"은 상기 추출물을 포함하는 조성물의 투여로 치료되는 상태와 관련된 파라미터, 예를 들면 증상의 정도를 적어도 감소시키는 모든 행위를 의미한다.The term "improvement" of the present invention means any action of at least reducing the severity of a parameter, such as a symptom, related to the condition to be treated by administration of a composition comprising the extract.
본 발명의 용어, "식품"은 육류, 소시지, 빵, 초콜릿, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알코올음료, 비타민 복합제, 건강 기능 식품 및 건강 식품 등이 있으며, 통상적인 의미에서의 식품을 모두 포함한다.As used herein, the term "food" refers to meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages , Vitamin complexes, health functional foods and health foods, and all foods in the usual sense are included.
본 발명의 식품 조성물은 일상적으로 섭취가능한 세모고랭이로부터 유래되었기 때문에 높은 폐암 개선 효과를 기대할 수 있으므로, 건강 증진 목적으로 매우 유용하게 사용될 수 있다.Since the food composition of the present invention is derived from triangulum that can be consumed on a daily basis, high lung cancer improvement effects can be expected, and thus can be very usefully used for health promotion purposes.
상기 건강 기능(성) 식품(functional food)이란, 특정보건용 식품(food for special health use, FoSHU)과 동일한 용어로, 영양 공급 외에도 생체조절기능이 효율적으로 나타나도록 가공된 의학, 의료효과가 높은 식품을 의미한다. 여기서 '기능(성)'이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건용도에 유용한 효과를 얻는 것을 의미한다. 본 발명의 식품은 당 업계에서 통상적으로 사용되는 방법에 의하여 제조가능하며, 상기 제조시에는 당 업계에서 통상적으로 첨가하는 원료 및 성분을 첨가하여 제조할 수 있다. 또한, 상기 식품의 제형은 식품으로 인정되는 제형이면 제한없이 제조될 수 있다. The health function (functional food) is the same term as food for special health use (FoSHU).In addition to nutritional supply, the term "functional food" refers to medicine that is processed so that the bioregulatory function is effectively displayed. Means food. Here, the term'function (sex)' means to control nutrients for the structure and function of the human body or to obtain useful effects for health purposes such as physiological actions. The food product of the present invention can be prepared by a method commonly used in the art, and during the production, raw materials and ingredients commonly added in the art may be added to prepare it. In addition, the formulation of the food may be prepared without limitation as long as it is a formulation recognized as a food.
본 발명의 식품용 조성물은 다양한 형태의 제형으로 제조될 수 있으며, 일반 약품과는 달리 천연물을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용 등이 없는 장점이 있고, 휴대성이 뛰어나므로, 본 발명의 식품은 폐암의 개선 효과를 증진시키기 위한 보조제로 섭취가 가능하다.The food composition of the present invention can be prepared in various forms, and unlike general drugs, it has the advantage of not having side effects that may occur when taking drugs for a long time using natural substances as raw materials, and is excellent in portability. The food of the present invention can be ingested as an adjuvant for enhancing the effect of improving lung cancer.
상기 건강 식품(health food)은 일반식품에 비해 적극적인 건강유지나 증진 효과를 가지는 식품을 의미하고, 건강보조식품(health supplement food)은 건강보조 목적의 식품을 의미한다. 경우에 따라, 건강 기능 식품, 건강식품, 건강보조식품의 용어는 호용된다.The health food refers to a food having an active health maintenance or promotion effect compared to a general food, and a health supplement food refers to a food for health supplement purposes. In some cases, the terms health functional food, health food, and health supplement are used interchangeably.
구체적으로, 상기 건강 기능 식품은 본 발명의 화합물을 음료, 차류, 향신료, 껌, 과자류 등의 식품 소재에 첨가하거나, 캡슐화, 분말화, 현탁액 등으로 제조한 식품으로, 이를 섭취할 경우 건강상 특정한 효과를 가져오는 것을 의미하나, 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용이 없는 장점이 있다.Specifically, the health functional food is a food prepared by adding the compound of the present invention to food materials such as beverages, teas, spices, gums, confectionery, or encapsulating, powdering, and suspending. It means bringing about an effect, but unlike general drugs, it has the advantage of having no side effects that may occur when taking the drug for a long time by using food as a raw material.
상기 식품 조성물은 생리학적으로 허용 가능한 담체를 추가로 포함할 수 있는데, 담체의 종류는 특별히 제한되지 않으며 당해 기술 분야에서 통상적으로 사용되는 담체라면 어느 것이든 사용할 수 있다.The food composition may further include a physiologically acceptable carrier, the kind of carrier is not particularly limited, and any carrier commonly used in the art may be used.
또한, 상기 식품 조성물은 식품 조성물에 통상 사용되어 냄새, 맛, 시각 등을 향상시킬 수 있는 추가 성분을 포함할 수 있다. 예들 들어, 비타민 A, C, D, E, B1, B2, B6, B12, 니아신(niacin), 비오틴(biotin), 폴레이트(folate), 판토텐산(panthotenic acid) 등을 포함할 수 있다. 또한, 아연(Zn), 철(Fe), 칼슘(Ca), 크롬(Cr), 마그네슘(Mg), 망간(Mn), 구리(Cu), 크륨(Cr) 등의 미네랄; 및 라이신, 트립토판, 시스테인, 발린 등의 아미노산을 포함할 수 있다. In addition, the food composition may include additional ingredients that are commonly used in food compositions to improve smell, taste, vision, and the like. For example, vitamins A, C, D, E, B1, B2, B6, B12, niacin, biotin, folate, panthotenic acid, and the like may be included. In addition, minerals such as zinc (Zn), iron (Fe), calcium (Ca), chromium (Cr), magnesium (Mg), manganese (Mn), copper (Cu), and chromium (Cr); And amino acids such as lysine, tryptophan, cysteine, and valine.
또한, 상기 식품 조성물은 방부제(소르빈산 칼륨, 벤조산나트륨, 살리실산, 데히드로초산나트륨 등), 살균제(표백분과 고도 표백분, 차아염소산나트륨 등), 산화방지제(부틸히드록시아니졸(BHA), 부틸히드록시톨류엔(BHT) 등), 착색제(타르색소 등), 발색제(아질산 나트륨, 아초산 나트륨 등), 표백제(아황산나트륨), 조미료(MSG 글루타민산나트륨 등), 감미료(둘신, 사이클레메이트, 사카린, 나트륨 등), 향료(바닐린, 락톤류 등), 팽창제(명반, D-주석산수소칼륨 등), 강화제, 유화제, 증점제(호료), 피막제, 검기초제, 거품억제제, 용제, 개량제 등의 식품 첨가물(food additives)을 포함할 수 있다. 상기 첨가물은 식품의 종류에 따라 선별되고 적절한 양으로 사용될 수 있다.In addition, the food composition includes preservatives (potassium sorbate, sodium benzoate, salicylic acid, sodium dehydroacetate, etc.), disinfectants (bleaching and highly bleaching, sodium hypochlorite, etc.), antioxidants (butylhydroxyanisole (BHA), butylhydride, etc.) Oxytoleuene (BHT), etc.), coloring agent (tar color, etc.), coloring agent (sodium nitrite, sodium nitrite, etc.), bleach (sodium sulfite), seasoning (MSG sodium glutamate, etc.), sweetener (dulsin, cyclamate, saccharin, etc.) , Sodium, etc.), flavorings (vanillin, lactones, etc.), expanding agents (alum, D-potassium hydrogen stannate, etc.), reinforcing agents, emulsifying agents, thickening agents (thickening agents), coating agents, gum base agents, foam inhibitors, solvents, improving agents It may contain food additives. The additive may be selected according to the type of food and used in an appropriate amount.
본 발명의 식품 조성물의 일 예로 건강음료 조성물로 사용될 수 있으며, 이 경우 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로 함유할 수 있다. 상술한 천연 탄수화물은 포도당, 과당과 같은 모노사카라이드; 말토스, 슈크로스와 같은 디사카라이드; 덱스트린, 사이클로덱스트린과 같은 폴리사카라이드; 자일리톨, 소르비톨, 에리트리톨 등의 당알콜일 수 있다. 감미제는 타우마틴, 스테비아 추출물과 같은 천연 감미제; 사카린, 아스파르탐과 같은 합성 감미제 등을 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 건강음료 조성물 100 ml 당 일반적으로 약 0.01 ~ 0.04 g, 구체적으로 약 0.02 ~ 0.03 g이 될 수 있다.As an example of the food composition of the present invention, it may be used as a health drink composition, and in this case, it may contain various flavoring agents or natural carbohydrates, etc. as an additional ingredient, such as a conventional beverage. The natural carbohydrates described above include monosaccharides such as glucose and fructose; Disaccharides such as maltose and sucrose; Polysaccharides such as dextrin and cyclodextrin; It may be a sugar alcohol such as xylitol, sorbitol, and erythritol. Sweeteners include natural sweeteners such as taumatin and stevia extract; Synthetic sweeteners such as saccharin and aspartame can be used. The ratio of the natural carbohydrate may be generally about 0.01 ~ 0.04 g, specifically about 0.02 ~ 0.03 g per 100 ml of the health beverage composition of the present invention.
상기 외에 건강음료 조성물은 여러 가지 영양제, 비타민, 전해질, 풍미제, 착색제, 펙트산, 펙트산의 염, 알긴산, 알긴산의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올 또는 탄산화제 등을 함유할 수 있다. 그 밖에 천연 과일주스, 과일주스 음료, 또는 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 혼합하여 사용할 수 있다. 이러한 첨가제의 비율은 크게 중요하진 않지만 본 발명의 건강음료 조성물 100 중량부당 0.01 ~ 0.1 중량부의 범위에서 선택되는 것이 일반적이다.In addition to the above, health beverage compositions include various nutrients, vitamins, electrolytes, flavoring agents, colorants, pectic acid, salts of pectic acid, alginic acid, salts of alginic acid, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, It may contain alcohol or a carbonation agent. In addition, it may contain flesh for the manufacture of natural fruit juice, fruit juice beverage, or vegetable beverage. These ingredients may be used independently or in combination. Although the ratio of these additives is not very important, it is generally selected from 0.01 to 0.1 parts by weight per 100 parts by weight of the health beverage composition of the present invention.
본 발명의 또 다른 실시양태는 세모고랭이 추출물 또는 이의 분획물을 포함하는 폐암의 예방 또는 개선용 사료 조성물을 제공한다.Another embodiment of the present invention provides a feed composition for preventing or improving lung cancer comprising a triangulum extract or a fraction thereof.
이때, 상기 용어 "세모고랭이", "추출물", "분획물", "예방" 및 "개선"의 정의는 상기에서 서술한 바와 같다.At this time, the definitions of the terms "trigonose", "extract", "fraction", "prevention" and "improvement" are as described above.
본 발명에 따른 세모고랭이 추출물은 우수한 폐암 치료 효과를 나타내므로, 폐암의 예방 또는 개선을 목적으로 사료 조성물에 포함될 수 있으며, 상기 사료 조성물은 동물이 일상적으로 섭취하는 것이 가능하기 때문에 폐암의 예방 또는 개선에 대하여 높은 효과를 기대할 수 있다.Since the trigonium extract according to the present invention exhibits an excellent lung cancer treatment effect, it may be included in a feed composition for the purpose of preventing or improving lung cancer, and the feed composition can be consumed by animals on a daily basis, so that the prevention of lung cancer or High effects can be expected for improvement.
본 발명의 용어, "사료"는 동물이 먹고, 섭취하며, 소화시키기 위한 또는 이에 적당한 임의의 천연 또는 인공 규정식, 한끼식 등 또는 상기 한끼식의 성분을 의미한다.The term "feed" of the present invention means any natural or artificial diet, one meal meal, etc., or a component of the one meal meal, for animals to eat, ingest, and digest.
상기 사료의 종류는 특별히 제한되지 아니하며, 당해 기술 분야에서 통상적으로 사용되는 사료를 사용할 수 있다. 상기 사료의 비제한적인 예로는, 곡물류, 근과류, 식품 가공 부산물류, 조류, 섬유질류, 제약 부산물류, 유지류, 전분류, 박류 또는 곡물 부산물류 등과 같은 식물성 사료; 단백질류, 무기물류, 유지류, 광물성류, 유지류, 단세포 단백질류, 동물성 플랑크톤류 또는 음식물 등과 같은 동물성 사료를 들 수 있다. 이들은 단독으로 사용되거나 2종 이상을 혼합하여 사용될 수 있다.The kind of feed is not particularly limited, and feed commonly used in the art may be used. Non-limiting examples of the feed include vegetable feeds such as grains, root fruits, food processing by-products, algae, fiber, pharmaceutical by-products, oils and fats, starches, meals or grain by-products; Animal feeds such as proteins, inorganic logistics, oils and fats, minerals, oils and fats, single-cell proteins, zooplanktons or foods. These may be used alone or in combination of two or more.
본 발명의 세모고랭이 추출물은 안전하면서도 효과적으로 폐암의 예방 또는 치료효과를 나타냄을 확인하였으므로, 본 발명의 세모고랭이 추출물은 폐암의 예방 또는 치료에 널리 활용될 수 있을 것이다.Since it was confirmed that the trigonolite extract of the present invention exhibits a safe and effective preventive or therapeutic effect on lung cancer, the trigonolite extract of the present invention may be widely used in the prevention or treatment of lung cancer.
도 1은 세모고랭이 추출물(TAR)의 처리농도에 따른 폐암세포의 생존율 변화를 나타내는 그래프이다.
도 2는 세모고랭이 추출물(TAR)의 처리농도에 따른 폐암세포의 증식능 변화를 나타내는 그래프이다.
도 3은 세모고랭이 추출물(TAR)의 처리농도에 따른 폐암세포의 세포침투능 변화를 나타내는 그래프이다.
도 4는 세모고랭이 추출물(TAR)의 처리농도에 따른 폐암세포의 세포이주능 변화를 나타내는 현미경 사진(좌측) 및 그래프(우측)이다.
도 5는 세모고랭이 추출물(TAR)의 처리농도에 따른 카스파제-3 및 PARP의 변화를 나타내는 웨스턴블럿 사진이다.
도 6은 세모고랭이 추출물(TAR)의 처리농도에 따른 Survivin, IAP-1, Cyclin D1, COX-2 및 MMP-9의 단백질 수준의 변화를 나타내는 웨스턴블럿 사진이다.
도 7은 세모고랭이 추출물(TAR)의 처리시간에 따른 STAT3 패밀리 단백질의 수준변화를 나타내는 웨스턴블럿 사진이다.
도 8은 세모고랭이 추출물(TAR)의 처리농도 및 처리시간에 따른 STAT3의 DNA 결합활성의 변화를 나타내는 EMSA 분석결과를 나타내는 사진이다.
도 9는 세모고랭이 추출물(TAR)의 처리여부에 따른 STAT3 단백질의 핵으로의 전이여부를 확인한 결과를 나타내는 면역형광염색분석(Immunocytochemistry) 결과를 나타내는 형광현미경 사진이다.
도 10은 세모고랭이 추출물(TAR)의 처리시간에 따른 STAT3을 인산화시키는 효소의 단백질 수준의 변화를 나타내는 웨스턴블럿 사진이다.1 is a graph showing the change in the survival rate of lung cancer cells according to the treatment concentration of triangulum extract (TAR).
Figure 2 is a graph showing the change in the proliferative ability of lung cancer cells according to the treatment concentration of triangulum extract (TAR).
Figure 3 is a graph showing the change in cell penetrating ability of lung cancer cells according to the treatment concentration of triangulum extract (TAR).
4 is a photomicrograph (left) and a graph (right) showing the change in cell migration ability of lung cancer cells according to the treatment concentration of triangulum extract (TAR).
Figure 5 is a Western blot photograph showing the change of caspase-3 and PARP according to the treatment concentration of triangulum extract (TAR).
6 is a Western blot photograph showing changes in the protein levels of Survivin, IAP-1, Cyclin D1, COX-2, and MMP-9 according to the treatment concentration of triangulum extract (TAR).
7 is a Western blot photograph showing the change in the level of STAT3 family proteins according to the treatment time of the triangulum extract (TAR).
Figure 8 is a photograph showing the result of EMSA analysis showing the change in the DNA binding activity of STAT3 according to the treatment concentration and treatment time of the triangulum extract (TAR).
FIG. 9 is a fluorescence micrograph showing the result of immunofluorescence staining analysis (Immunocytochemistry) showing the result of confirming the transfer of STAT3 protein to the nucleus according to treatment with trigonolite extract (TAR).
10 is a Western blot photograph showing the change in the protein level of an enzyme that phosphorylates STAT3 according to the treatment time of the triangulum extract (TAR).
이하 본 발명을 실시예를 통하여 보다 상세하게 설명한다. 그러나 이들 실시예는 본 발명을 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail through examples. However, these examples are for illustrative purposes only, and the scope of the present invention is not limited to these examples.
실시예 1: 세모고랭이 추출물(TAR)의 폐암세포 사멸 효과Example 1: Lung cancer cell killing effect of triangulum extract (TAR)
먼저, 세모고랭이에 95%(v/v) 에탄올을 가하여 추출하고, 이를 여과하여 액상성분을 수득한 다음, 용매성분을 제거하여 세모고랭이 추출물(TAR)을 수득하였다.First, 95% (v/v) ethanol was added to the triangulum for extraction, followed by filtration to obtain a liquid component, and then the solvent component was removed to obtain a triangulum extract (TAR).
한편, American Type Culture Collection (Manassas, VA, USA)에서 구입한 인간 폐암 세포주 A549와 인간 정상 폐 세포주 HEL 299를 각각 항생제(100 units/㎖ 페니실린 A 및 100 ㎍/㎖ 스트렙토마이신) 및 10% FBS(Gibco-BRL)가 첨가된 DMEM low glucose 배지에서 37℃ 및 5% CO2 조건으로 배양하였다.Meanwhile, the human lung cancer cell line A549 and the human normal lung
상기 배양된 A549 및 HEL 299를 96 웰(well) 플레이트에 웰당 5 X 103 세포수로 분주하고, 37℃에서 배양한 다음, 이에 상기 수득한 TAR을 다양한 농도(0, 1, 2.5 또는 5 ㎍/㎖)로 처리하고 24시간 동안 배양하였다.The cultured A549 and
상기 배양된 A549 및 HEL 299의 세포 생존율을 측정하기 위하여 MTT 분석을 수행하였다: 대략적으로, 상기 배양된 A549 및 HEL 299에 MTT 용액(2 mg/㎖, Sigma Aldrich, USA) 30 ㎕를 첨가하고 37℃에서 2시간 동안 반응시킨 다음, MTT 용해버퍼를 추가로 처리하고 37℃에서 하룻밤 동안 반응시켰다. 반응이 종료된 후, ELISA를 이용하여 570 nm 파장에서 흡광도를 측정하였다(도 1). MTT analysis was performed to measure the cell viability of the cultured A549 and HEL 299: Approximately, 30 μl of MTT solution (2 mg/ml, Sigma Aldrich, USA) was added to the cultured A549 and
도 1은 세모고랭이 추출물(TAR)의 처리농도에 따른 폐암세포의 생존율 변화를 나타내는 그래프이다.1 is a graph showing the change in the survival rate of lung cancer cells according to the treatment concentration of triangulum extract (TAR).
도 1에서 보듯이, 정상 세포(HEL 299)는 TAR을 과량으로 처리하여도 약 10%의 세포생존율이 감소되는 반면, 폐암 세포(A549)는 1 ㎍/㎖의 TAR을 처리하여도 TAR을 과량으로 처리한 정상 세포 보다도 낮은 세포생존율을 나타내었고, 상기 TAR의 처리농도에 따라 급격히 세포생존율이 감소됨을 확인하였다.As shown in Fig. 1, the cell viability of normal cells (HEL 299) is reduced by about 10% even when TAR is treated in excess, whereas lung cancer cells (A549) are excessively TAR even when treated with 1 µg/ml TAR. The cell viability was lower than that of the normal cells treated with and it was confirmed that the cell viability was rapidly decreased according to the treatment concentration of the TAR.
상기 결과로부터, TAR은 정상세포에 대하여는 세포독성을 나타내지 않으면서도, 폐암세포를 사멸하는 효과를 나타냄을 알 수 있었다.From the above results, it can be seen that TAR does not show cytotoxicity to normal cells, but has an effect of killing lung cancer cells.
실시예 2: 세모고랭이 추출물(TAR)의 폐암세포 증식능 억제 효과Example 2: Inhibitory effect of trigonolite extract (TAR) on proliferation of lung cancer cells
상기 실시예 1에서 수득한, 0, 1 또는 5 ㎍/㎖의 TAR을 처리하여 배양한 각각의 A549를 원심분리 방법으로 수집하고, 수집된 각각의 세포를 16-well E-plates에 웰당 5 × 103 세포수로 분주하고 72시간 동안 배양하였다. 배양을 진행하면서, Roche xCELLigence Real-Time Cell Analyzer (RTCA) DP instrument (Roche Diagnostics GmbH, Germany)를 이용하여, 15분 마다 저항 값을 측정함으로써, 세포증식능의 변화를 측정하였다(도 2).Each A549 obtained in Example 1 and cultured by treating 0, 1 or 5 μg/ml of TAR was collected by centrifugation, and each of the collected cells was placed in 16-well E-plates at 5 × Divided into 10 3 cells and incubated for 72 hours. While the cultivation was in progress, the change in cell proliferation ability was measured by measuring the resistance value every 15 minutes using a Roche xCELLigence Real-Time Cell Analyzer (RTCA) DP instrument (Roche Diagnostics GmbH, Germany) (FIG. 2).
도 2는 세모고랭이 추출물(TAR)의 처리농도에 따른 폐암세포의 증식능 변화를 나타내는 그래프이다.Figure 2 is a graph showing the change in the proliferative ability of lung cancer cells according to the treatment concentration of triangulum extract (TAR).
도 2에서 보듯이, TAR의 처리농도가 증가할 수록, A549의 세포증식능이 감소됨을 확인하였다.As shown in FIG. 2, it was confirmed that as the treatment concentration of TAR increased, the cell proliferative ability of A549 decreased.
실시예 3: 폐암세포의 세포침투능 억제 효과Example 3: Inhibitory effect of cell penetrating ability of lung cancer cells
상기 실시예 1에서 수득한, 0 또는 1 ㎍/㎖의 TAR을 처리하여 배양한 각각의 A549를 원심분리 방법으로 수집하고, 수집된 각각의 세포를 CIM (cellular invasion/migration)-plate 16에 분주한 다음 48시간 동안 배양하면서, Roche xCELLigence Real-Time Cell Analyzer (RTCA) DP instrument (Roche Diagnostics GmbH, Germany)를 이용하여 cell index를 비교하여, 폐암세포의 세포침투능의 변화를 측정하였다(도 3). 이때, 대조군으로는 SFM(serum free media)를 처리한 것을 사용하였다.Each A549 obtained in Example 1, cultured by treating 0 or 1 µg/ml of TAR, was collected by a centrifugation method, and each of the collected cells was dispensed into CIM (cellular invasion/migration)-
도 3은 세모고랭이 추출물(TAR)의 처리농도에 따른 폐암세포의 세포침투능 변화를 나타내는 그래프이다.Figure 3 is a graph showing the change in cell penetrating ability of lung cancer cells according to the treatment concentration of triangulum extract (TAR).
도 3에서 보듯이, TAR을 처리하지 않은 A549의 cell index에 비하여, TAR을 처리한 A549의 cell index가 상대적으로 낮은 값을 나타내어, TAR의 처리에 의해 cell index가 감소됨을 확인하였다.As shown in FIG. 3, the cell index of A549 treated with TAR showed a relatively low value compared to the cell index of A549 that was not treated with TAR, and thus it was confirmed that the cell index was decreased by the treatment of TAR.
상기 결과로부터, TAR이 암세포의 침투능력을 억제함을 알 수 있었다.From the above results, it was found that TAR inhibits the penetration ability of cancer cells.
실시예 4: 폐암세포의 세포이주능 억제 효과Example 4: Effect of inhibiting cell migration ability of lung cancer cells
배양접시에 A549가 80-90%의 포화도를 나타내도록 분주하고, 배양접시의 중간에 십자가 형태의 스크래치를 유발하였다. 이어, 상기 배양접시에 TAR을 다양한 농도(0, 1, 2.5 또는 5 ㎍/㎖)로 처리하고 24시간 동안 배양한 다음, 스크래피 부위의 면적 변화를 관찰하고, 상기 변화를 정량화하기 위하여, TAR을 처리하지 않은 배양접시를 기준으로, 스크래치의 간격(distance)을 측정하여, A549의 이주 거리(migration distance)를 백분율(percentage)로 환산하였다(도 4).The culture dish was dispensed so that A549 had a saturation of 80-90%, and a cross-shaped scratch was induced in the middle of the culture dish. Subsequently, in the culture dish, TAR was treated at various concentrations (0, 1, 2.5 or 5 μg/ml) and incubated for 24 hours, and then the change in the area of the scrapie site was observed, and in order to quantify the change, TAR was used. Based on the untreated culture dish, the distance of the scratch was measured, and the migration distance of A549 was converted into a percentage (FIG. 4).
도 4는 세모고랭이 추출물(TAR)의 처리농도에 따른 폐암세포의 세포이주능 변화를 나타내는 현미경 사진(좌측) 및 그래프(우측)이다.4 is a photomicrograph (left) and a graph (right) showing the change in cell migration ability of lung cancer cells according to the treatment concentration of triangulum extract (TAR).
도 4에서 보듯이, TAR의 처리농도가 증가할 수록, A549의 세포 이주 거리가 감소됨을 확인하였다.As shown in FIG. 4, it was confirmed that as the treatment concentration of TAR increased, the cell migration distance of A549 decreased.
상기 결과로부터, TAR이 암세포의 이주 능력을 억제함을 알 수 있었다.From the above results, it was found that TAR inhibits the ability of cancer cells to migrate.
실시예 5: 세모고랭이 추출물(TAR)의 카스파아제 활성화 효과Example 5: Caspase Activation Effect of Triangulum Extract (TAR)
상기 실시예 1에서 수득한, 다양한 농도의 TAR을 처리하여 배양한 각각의 A549를 원심분리 방법으로 수집하고, 수집된 각각의 A549를 PBS로 2회 세척하고 단백질 분해효소 억제제(Roche Molecular Biochemicals, Mannheim, Germany)를 추가적으로 포함하는 추출 용해 버퍼(50 mM Tris-HCl(pH 7.5), 150 mM NaCl, 1 mM EDTA, 20 mM NaF, 0.5% NP-40, 1% Triton X-100)로 부유시켰다. 단백질 정량 후 단백질을 10% 소디움 도데실 설페이트-폴리아크릴아마이드 겔의 각 웰에 주입하여 전기영동하였다. 전기영동이 끝난 소디움 도데실 설페이트-폴리아크릴아마이드 겔은 니트로셀룰로오스 멤브레인(Bio0RAD)에 블로팅(blotting)하고 이 멤브레인에 5% 스킴 밀크를 포함한 TBST(Tris-buffered saline with 0.1% Tween 20) 용액에서 1시간 동안 가하여 블로킹시켰다. 반응이 끝나면 1X TBST액으로 세척한 후 TBST에 1/3000으로 희석된 1차 항체(항-카스파제-3 항체; 항-절단된 카스파제-3 항체; 항-PARP 항체; 항-절단된 PARP 항체)에 담가 4℃에서 하룻밤동안 반응시켰다. 반응이 끝나면 세척 후 TBST에 1/5000으로 희석된 HRP-결합 항-마우스 IgG 또는 항-토끼 IgG 항체에 1시간 동안 반응시켰다. 반응이 완료되면 세척 후 멤브레인에 화학발광 기질 용액(ECL, Amersham Biosciences, UK)을 첨가하여 발색시켰다. 이때, 내부대조군으로는 β-액틴을 사용하였다(도 5).Each A549 obtained in Example 1 and cultured by treating various concentrations of TAR was collected by centrifugation, and each of the collected A549s was washed twice with PBS and a protease inhibitor (Roche Molecular Biochemicals, Mannheim , Germany) was suspended in an extraction lysis buffer (50 mM Tris-HCl (pH 7.5), 150 mM NaCl, 1 mM EDTA, 20 mM NaF, 0.5% NP-40, 1% Triton X-100). After protein quantification, the protein was injected into each well of a 10% sodium dodecyl sulfate-polyacrylamide gel, followed by electrophoresis. The electrophoretic sodium dodecyl sulfate-polyacrylamide gel was blotted onto a nitrocellulose membrane (Bio0RAD), and in a solution of TBST (Tris-buffered saline with 0.1% Tween 20) containing 5% skim milk on this membrane. Blocked by adding for 1 hour. After the reaction is finished, the primary antibody (anti-caspase-3 antibody; anti-cleaved caspase-3 antibody; anti-PARP antibody; anti-cleaved PARP antibody) diluted 1/3000 in TBST after washing with 1X TBST solution Antibody) and reacted overnight at 4°C. At the end of the reaction, after washing, HRP-binding anti-mouse IgG or anti-rabbit IgG antibody diluted 1/5000 in TBST was reacted for 1 hour. When the reaction was complete, a chemiluminescent substrate solution (ECL, Amersham Biosciences, UK) was added to the membrane after washing to develop color. At this time, β-actin was used as an internal control group (Fig. 5).
도 5는 세모고랭이 추출물(TAR)의 처리농도에 따른 카스파제-3 및 PARP의 변화를 나타내는 웨스턴블럿 사진이다.Figure 5 is a Western blot photograph showing the change of caspase-3 and PARP according to the treatment concentration of triangulum extract (TAR).
도 5에서 보듯이, TAR의 처리농도가 증가할 수록 카스파제-3의 활성이 증가하여, 116kDa PARP 단백질이 87kDa의 단편으로 절단됨을 확인하였다.As shown in FIG. 5, as the treatment concentration of TAR increased, caspase-3 activity increased, and it was confirmed that the 116kDa PARP protein was cleaved into 87kDa fragments.
상기 결과로부터, TAR은 카스파아제-3 의존적 세포사멸을 유도함을 알 수 있었다.From the above results, it was found that TAR induces caspase-3 dependent apoptosis.
실시예 6: 세포사멸 단백질의 발현에 미치는 영향Example 6: Effect on the expression of apoptosis protein
1차 항체로서 암세포의 사멸을 억제하고, 증식을 촉진하는 단백질(Survivin, IAP-1, Cyclin D1, COX-2, MMP-9)에 대한 1차 항체를 사용하는 것을 제외하고는, 실시예 5의 방법을 수행하여, 폐암세포에 미치는 TAR의 효과를 검증하였다(도 6).Example 5, except for the use of a primary antibody against a protein (Survivin, IAP-1, Cyclin D1, COX-2, MMP-9) that inhibits cancer cell death and promotes proliferation as the primary antibody. By performing the method of, the effect of TAR on lung cancer cells was verified (FIG. 6).
도 6은 세모고랭이 추출물(TAR)의 처리농도에 따른 Survivin, IAP-1, Cyclin D1, COX-2 및 MMP-9의 단백질 수준의 변화를 나타내는 웨스턴블럿 사진이다.6 is a Western blot photograph showing changes in the protein levels of Survivin, IAP-1, Cyclin D1, COX-2, and MMP-9 according to the treatment concentration of triangulum extract (TAR).
도 6에서 보듯이, TAR의 처리농도가 증가할 수록 Survivin, IAP-1, Cyclin D1, COX-2 및 MMP-9의 단백질 수준이 감소됨을 확인하였다.As shown in FIG. 6, it was confirmed that as the treatment concentration of TAR increased, the protein levels of Survivin, IAP-1, Cyclin D1, COX-2, and MMP-9 decreased.
상기 결과로부터, TAR은 암세포의 사멸을 억제하고, 증식을 촉진하는 단백질의 수준을 감소시켜서 폐암세포의 사멸을 촉진함을 알 수 있었다.From the above results, it was found that TAR promotes the death of lung cancer cells by inhibiting the death of cancer cells and reducing the level of proteins that promote proliferation.
실시예 7: STAT3 활성화 억제 효과Example 7: Inhibitory effect of STAT3 activation
A549세포에 5 ㎍/㎖의 TAR을 처리하고 0 내지 12시간 동안 배양하였다. 배양이 종료된 후, 상기 배양된 세포와 STAT3 패밀리 단백질에 대한 1차 항체(항-STAT3 항체; 항-p-STAT3(Tyr705) 항체; 항-p-STAT3(Ser727) 항체)를 사용하는 것을 제외하고는, 실시예 5의 방법을 수행하여, 폐암세포의 STAT3에 미치는 TAR의 효과를 검증하였다(도 7).A549 cells were treated with 5 μg/ml of TAR and cultured for 0 to 12 hours. After the cultivation was completed, except for the use of the primary antibody (anti-STAT3 antibody; anti-p-STAT3 (Tyr705) antibody; anti-p-STAT3 (Ser727) antibody) against the cultured cells and STAT3 family proteins. Then, by performing the method of Example 5, the effect of TAR on STAT3 of lung cancer cells was verified (FIG. 7).
도 7은 세모고랭이 추출물(TAR)의 처리시간에 따른 STAT3 패밀리 단백질의 수준변화를 나타내는 웨스턴블럿 사진이다.7 is a Western blot photograph showing the change in the level of STAT3 family proteins according to the treatment time of the triangulum extract (TAR).
도 7에서 보듯이, TAR의 처리시간이 증가하여도 STAT3 단백질의 발현수준은 변화되지 않았으나, TAR의 처리시간이 증가함에 따라 STAT3의 인산화가 억제됨을 확인하였다.As shown in FIG. 7, the expression level of STAT3 protein did not change even when the treatment time of TAR increased, but it was confirmed that phosphorylation of STAT3 was suppressed as the treatment time of TAR increased.
상기 결과로부터, TAR이 STAT3의 인산화를 억제함을 알 수 있었다.From the above results, it was found that TAR inhibits phosphorylation of STAT3.
실시예 8: STAT3 결합활성 억제 효과Example 8: STAT3 binding activity inhibitory effect
상기 실시예 7의 결과로부터 TAR이 STAT3의 인산화를 억제함을 확인하였으므로, TAR이 DNA에 대한 STAT3의 결합 활성에도 영향을 미치는지 확인하고자 하였다.Since it was confirmed from the results of Example 7 that TAR inhibits the phosphorylation of STAT3, it was attempted to confirm whether TAR also affects the binding activity of STAT3 to DNA.
이를 위하여, EMSA(Electrophoretic mobility shift assay)를 수행하였다. To this end, EMSA (Electrophoretic mobility shift assay) was performed.
먼저, 0, 1, 2.5 또는 5 ㎍/㎖의 TAR을 처리하여 배양한 A549 및 5 ㎍/㎖의 TAR을 처리하고 0 내지 8시간 동안 배양한 A549로부터 각각의 핵 추출물을 수득하였다. First, A549 cultured with 0, 1, 2.5 or 5 µg/ml of TAR and 5 µg/ml of TAR were treated, and each nuclear extract was obtained from A549 cultured for 0 to 8 hours.
그런 다음, 다음과 같은 프로브를 이용하여 STAT3 단백질의 DNA 결합 활성을 측정하였다; 대략적으로, 5’-biotinylated STAT3 oligonucleotide (5’-GATCCTTCTGGGAATTCCTAGATC-3’ and 5’-GATCTAGGAATTCCCAGAAGGATC-3’;BIONEER, Daejeon, Korea)는 핵 단백질과 복합체를 이루고 Oct-1 (5’-TTCTAGTGATTTGCATTCGACA-3’ and 5’-TGTCGAATGCAAATCACTAGAA-3’;BIONEER, Daejeon, Korea)는 로딩 대조군으로 이용되었다. Protein-oligonucleotide complex 는 폴리아크릴아마이그 겔 에 로딩되었고, 나일론 멤브레인에 transfer된 뒤 540nm UV에 의해 cross-link된다. 마지막으로 LightShift® Chemiluminescent EMSA kit를 이용해 결과를 확인하였다(도 8).Then, the following probe was used to measure the DNA binding activity of the STAT3 protein; Roughly, 5'-biotinylated STAT3 oligonucleotide (5'-GATCCTTCTGGGAATTCCTAGATC-3' and 5'-GATCTAGGAATTCCCAGAAGGATC-3';BIONEER, Daejeon, Korea) forms a complex with nuclear protein and Oct-1 (5'-TTCTAGTGATTTGCATTCGACA-3' and 5'-TGTCGAATGCAAATCACTAGAA-3';BIONEER, Daejeon, Korea) was used as a loading control. The protein-oligonucleotide complex was loaded on a polyacrylamide gel, transferred to a nylon membrane, and cross-linked by UV at 540 nm. Finally, the results were confirmed using LightShift® Chemiluminescent EMSA kit (FIG. 8).
도 8은 세모고랭이 추출물(TAR)의 처리농도 및 처리시간에 따른 STAT3의 DNA 결합활성의 변화를 나타내는 EMSA 분석결과를 나타내는 사진이다.Figure 8 is a photograph showing the result of EMSA analysis showing the change in the DNA binding activity of STAT3 according to the treatment concentration and treatment time of the triangulum extract (TAR).
도 8에서 보듯이, TAR의 처리농도 및 처리시간이 증가할 수록, STAT3의 DNA 결합활성이 감소됨을 확인하였다.As shown in FIG. 8, it was confirmed that as the treatment concentration and treatment time of TAR increased, the DNA-binding activity of STAT3 decreased.
실시예 9: STAT3 전이 억제 효과Example 9: STAT3 metastasis inhibitory effect
상기 실시예 8의 결과로부터 TAR이 DNA에 대한 STAT3의 결합 활성을 억제함을 확인하였으므로, TAR이 STAT3의 전이 활성에도 영향을 미치는지 확인하고자 하였다.Since it was confirmed from the results of Example 8 that TAR inhibits the binding activity of STAT3 to DNA, it was attempted to confirm whether TAR also affects the metastatic activity of STAT3.
이를 위하여, A549를 8-well glasss chamber 슬라이드에 분주하고, 5 ㎍/㎖의 TAR 을 처리한 다음, 8시간 동안 배양하였다. 배양이 종료된 후, 배양된 A549에 4% paraformaldehyde(PFA)를 처리하고 20분간 반응시켜 A549를 고정하고, 1×PBS로 3회 세척한 후, 0.2% Triton-X-100를 처리하여 세포막을 천공하였다. 그런 다음, 5% BSA를 1시간 동안 처리하고, 블로킹하고, 항-STAT3 항체 또는 항-p-STAT3 항체를 처리한 후, 하룻밤 동안 반응시켰다. 반응이 종료된 후, 1×PBS로 3회 세척하고, 2차 항체인 Alexa Fluor® 488 donkey anti-mouse IgG (H+L) 항체와 Alexa Fluor® 594 donkey anti-rabbit IgG (H+L) 항체를 1시간 반응시킨 뒤, 3분간 DAPI 염색 후 Olympus FluoView FV1000 confocal microscope을 이용하여 형광발광을 확인하였다(도 9).To this end, A549 was dispensed into an 8-well glasss chamber slide, treated with 5 μg/ml of TAR, and incubated for 8 hours. After the culture was completed, the cultured A549 was treated with 4% paraformaldehyde (PFA) and reacted for 20 minutes to fix A549, washed three times with 1×PBS, and then treated with 0.2% Triton-X-100 to repair the cell membrane. Perforated. Then, 5% BSA was treated for 1 hour, blocked, treated with anti-STAT3 antibody or anti-p-STAT3 antibody, and reacted overnight. After completion of the reaction, wash 3 times with 1×PBS, and secondary antibodies Alexa Fluor® 488 donkey anti-mouse IgG (H+L) antibody and Alexa Fluor® 594 donkey anti-rabbit IgG (H+L) antibody After reacting for 1 hour, after DAPI staining for 3 minutes, fluorescence was confirmed using an Olympus FluoView FV1000 confocal microscope (FIG. 9).
도 9는 세모고랭이 추출물(TAR)의 처리여부에 따른 STAT3 단백질의 핵으로의 전이여부를 확인한 결과를 나타내는 면역형광염색분석(Immunocytochemistry) 결과를 나타내는 형광현미경 사진이다.FIG. 9 is a fluorescence micrograph showing the result of immunofluorescence staining analysis (Immunocytochemistry) showing the result of confirming the transfer of STAT3 protein to the nucleus according to treatment with trigonolite extract (TAR).
도 9에서 보듯이, TAR을 처리하지 않은 경우에는 STAT3가 핵으로 이동하였으나, TAR을 처리한 경우에는 STAT3의 핵으로의 이동이 억제됨을 확인하였다.As shown in FIG. 9, it was confirmed that when the TAR was not treated, STAT3 migrated to the nucleus, but when TAR was treated, the migration of STAT3 to the nucleus was inhibited.
실시예 10: STAT3 인산화 억제 효과Example 10: STAT3 phosphorylation inhibitory effect
상기 실시예 7의 결과로부터 TAR이 STAT3의 인산화를 억제함을 확인하였으므로, TAR이 STAT3을 인산화시키는 효소의 활성에도 영향을 미치는지 확인하고자 하였다.Since it was confirmed from the results of Example 7 that TAR inhibits phosphorylation of STAT3, it was attempted to confirm whether TAR also affects the activity of an enzyme that phosphorylates STAT3.
이를 위하여, A549세포에 5 ㎍/㎖의 TAR을 처리하고 8시간 동안 배양하였다. 배양이 종료된 후, 상기 배양된 세포와 STAT3을 인산화시키는 효소에 대한 1차 항체(항-p-JAK1(Tyr1022/1023) 항체; 항-JAK1 항체; 항-p-JAK2(Tyr1007/1008) 항체; 항-JAK2 항체; 항-p-Src(Tyr416) 항체; 항-Src 항체)를 사용하는 것을 제외하고는, 실시예 5의 방법을 수행하여, 폐암세포의 STAT3을 인산화시키는 효소에 미치는 TAR의 효과를 검증하였다(도 10).To this end, A549 cells were treated with 5 μg/ml of TAR and cultured for 8 hours. After the cultivation was completed, the primary antibody (anti-p-JAK1(Tyr1022/1023) antibody; anti-JAK1 antibody; anti-p-JAK2(Tyr1007/1008) antibody) against the enzyme that phosphorylates the cultured cells and STAT3 ; Anti-JAK2 antibody; anti-p-Src (Tyr416) antibody; anti-Src antibody), except for the use of the method of Example 5, by performing the method of TAR on the enzyme that phosphorylates STAT3 of lung cancer cells The effect was verified (FIG. 10).
도 10은 세모고랭이 추출물(TAR)의 처리시간에 따른 STAT3을 인산화시키는 효소의 단백질 수준의 변화를 나타내는 웨스턴블럿 사진이다.10 is a Western blot photograph showing the change in the protein level of an enzyme that phosphorylates STAT3 according to the treatment time of the triangulum extract (TAR).
도 10에서 보듯이, TAR의 처리시간이 증가하여도 STAT3을 인산화시키는 효소(JAK1, JAK, Src)의 단백질 수준은 변화되지 않았으나, TAR의 처리시간이 증가함에 따라 STAT3을 인산화시키는 효소(JAK1, JAK, Src)의 인산화가 억제됨을 확인하였다.As shown in FIG. 10, the protein level of the enzymes (JAK1, JAK, Src) phosphorylating STAT3 did not change even when the treatment time of TAR increased, but as the treatment time of TAR increased, enzymes that phosphorylated STAT3 (JAK1, It was confirmed that phosphorylation of JAK, Src) was inhibited.
상기 결과로부터, TAR이 STAT3의 인산화 억제효과는 STAT3을 인산화시키는 효소의 활성화를 억제함에 의하여 나타남을 알 수 있었다.From the above results, it can be seen that the inhibitory effect of TAR on phosphorylation of STAT3 is exhibited by inhibiting the activation of an enzyme that phosphorylates STAT3.
결국, 상기 실시예의 결과를 종합하면, 본 발명에서 제공하는 세모고랭이 추출물 또는 이의 분획물은 정상세포에는 독성을 나타내지 않으면서도 폐암세포를 사멸시키고, 폐암세포의 증식능, 침투능 및 이주능을 억제하는 효과를 나타내는데, 이는 카스파제-3의 활성촉진, 폐암세포의 사멸을 억제하고 증식을 촉진하는 단백질의 수준을 감소, 폐암의 발병에 관여하는 것으로 알려진 STAT3 단백질의 인산화, DNA 결합활성 및 전이활성을 억제함에 의한 것임을 알 수 있었다.In conclusion, when the results of the above examples are summarized, the triangulum extract or a fraction thereof provided in the present invention is effective in killing lung cancer cells without showing toxicity to normal cells, and inhibiting the proliferation, penetration and migration ability of lung cancer cells. It promotes caspase-3 activity, inhibits the death of lung cancer cells, reduces the level of protein that promotes proliferation, and inhibits phosphorylation of STAT3 protein, which is known to be involved in the onset of lung cancer, DNA binding activity and metastasis activity. It can be seen that it was due to the ham.
따라서, 본 발명에서 제공하는 세모고랭이 추출물 또는 이의 분획물은 안전하면서도 효과적인 폐암 치료제의 유효성분으로 사용될 수 있다.Therefore, the triangulum extract or a fraction thereof provided by the present invention can be used as an active ingredient in a safe and effective lung cancer therapeutic agent.
이상의 설명으로부터, 본 발명이 속하는 기술분야의 당업자는 본 발명이 그 기술적 사상이나 필수적 특징을 변경하지 않고서 다른 구체적인 형태로 실시될 수 있다는 것을 이해할 수 있을 것이다. 이와 관련하여, 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적인 것이 아닌 것으로 이해해야만 한다. 본 발명의 범위는 상기 상세한 설명보다는 후술하는 특허 청구범위의 의미 및 범위 그리고 그 등가 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.From the above description, those skilled in the art to which the present invention pertains will be able to understand that the present invention can be implemented in other specific forms without changing the technical spirit or essential features thereof. In this regard, it should be understood that the embodiments described above are illustrative in all respects and not limiting. The scope of the present invention should be construed that all changes or modifications derived from the meaning and scope of the claims to be described later rather than the above detailed description, and equivalent concepts thereof, are included in the scope of the present invention.
Claims (9)
상기 폐암의 예방 또는 치료는 카스파제-3의 활성촉진; Survivin, IAP-1, COX-2, MMP-9로 이루어진 군에서 선택되는 어느 하나 이상의 단백질의 수준 감소; 또는 STAT3 단백질의 인산화, DNA 결합활성 및 전이활성을 억제함에 따라 달성되는 것인, 약학 조성물.
As a pharmaceutical composition for the prevention or treatment of lung cancer, comprising a triangulum extract or a fraction thereof,
The prevention or treatment of lung cancer may include promoting caspase-3 activity; Reducing the level of any one or more proteins selected from the group consisting of Survivin, IAP-1, COX-2, and MMP-9; Or it will be achieved by inhibiting the phosphorylation, DNA binding activity and transfer activity of the STAT3 protein, the pharmaceutical composition.
상기 세모고랭이 추출물은 폐암세포의 사멸을 유도하고, 폐암세포의 증식, 세포침투 및 세포이주를 억제하는 것인, 폐암의 예방 또는 치료용 약학 조성물.
The method of claim 1,
The trigonolite extract induces the death of lung cancer cells, and inhibits proliferation, cell penetration and cell migration of lung cancer cells, a pharmaceutical composition for preventing or treating lung cancer.
상기 폐암세포는 A549 세포인 것인, 폐암의 예방 또는 치료용 약학 조성물.
The method of claim 2,
The lung cancer cells will be A549 cells, a pharmaceutical composition for the prevention or treatment of lung cancer.
상기 추출물은 세모고랭이를 물, 탄소수 1 내지 4의 알코올 및 이들의 혼합 용매로 이루어진 군에서 선택된 1종 이상의 용매로 추출하여 수득한 것인, 폐암의 예방 또는 치료용 약학 조성물.
The method of claim 1,
The extract is obtained by extracting the trigonolite with one or more solvents selected from the group consisting of water, an alcohol having 1 to 4 carbon atoms, and a mixed solvent thereof, and a pharmaceutical composition for preventing or treating lung cancer.
상기 분획물은 세모고랭이 추출물을 물, 탄소수 1 내지 4의 알코올, 헥산(Hexane), 에틸 아세테이트(Ethyl acetate), 클로로포름(Chloroform), 디클로로메탄(Dichloromethane) 및 이들의 혼합용매로 구성되는 군으로부터 선택되는 용매로 분획하여 수득한 것인, 폐암의 예방 또는 치료용 약학 조성물.
The method of claim 1,
The fraction is selected from the group consisting of water, alcohol having 1 to 4 carbon atoms, hexane (Hexane), ethyl acetate (Ethyl acetate), chloroform (Chloroform), dichloromethane (Dichloromethane) and a mixed solvent thereof The pharmaceutical composition for preventing or treating lung cancer, which is obtained by fractionation with a solvent.
상기 조성물은 약학적으로 허용되는 담체, 부형제 또는 희석제를 추가로 포함하는 것인, 폐암의 예방 또는 치료용 약학 조성물.
The method of claim 1,
The composition further comprises a pharmaceutically acceptable carrier, excipient or diluent, a pharmaceutical composition for preventing or treating lung cancer.
A method of treating lung cancer, comprising administering the pharmaceutical composition of any one of claims 1 to 6 to a suspected lung cancer subject excluding humans.
상기 폐암의 예방 또는 개선은 카스파제-3의 활성촉진; Survivin, IAP-1, COX-2, MMP-9로 이루어진 군에서 선택되는 어느 하나 이상의 단백질의 수준 감소; 또는 STAT3 단백질의 인산화, DNA 결합활성 및 전이활성을 억제함에 따라 달성되는 것인, 식품 조성물.
As a food composition for preventing or improving lung cancer, comprising a triangulum extract or a fraction thereof,
The prevention or improvement of lung cancer may include promoting caspase-3 activity; Reducing the level of any one or more proteins selected from the group consisting of Survivin, IAP-1, COX-2, and MMP-9; Or it will be achieved by inhibiting the phosphorylation, DNA binding activity and transfer activity of STAT3 protein, food composition.
상기 폐암의 예방 또는 개선은 카스파제-3의 활성촉진; Survivin, IAP-1, COX-2, MMP-9로 이루어진 군에서 선택되는 어느 하나 이상의 단백질의 수준 감소; 또는 STAT3 단백질의 인산화, DNA 결합활성 및 전이활성을 억제함에 따라 달성되는 것인, 사료 조성물.As a feed composition for preventing or improving lung cancer, comprising a triangulum extract or a fraction thereof,
The prevention or improvement of lung cancer may include promoting caspase-3 activity; Reducing the level of any one or more proteins selected from the group consisting of Survivin, IAP-1, COX-2, and MMP-9; Or it will be achieved by inhibiting the phosphorylation, DNA binding activity and metastasis activity of STAT3 protein, feed composition.
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