KR101771897B1 - Pharmaceutical composition for the treatment of cancers or inhibition of metastasis containing extract of chlorella sp. - Google Patents
Pharmaceutical composition for the treatment of cancers or inhibition of metastasis containing extract of chlorella sp. Download PDFInfo
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- KR101771897B1 KR101771897B1 KR1020150116160A KR20150116160A KR101771897B1 KR 101771897 B1 KR101771897 B1 KR 101771897B1 KR 1020150116160 A KR1020150116160 A KR 1020150116160A KR 20150116160 A KR20150116160 A KR 20150116160A KR 101771897 B1 KR101771897 B1 KR 101771897B1
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- chlorella
- cancer
- extract
- cell
- microalgae
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Abstract
본 발명은 클로렐라 속(chlorella sp.) 미세조류의 추출물을 유효성분으로 함유하는 암 예방, 치료 또는 전이 억제용 약학적 조성물에 관한 것이다. 본 발명은 또한 클로렐라 속(chlorella sp.) 미세조류의 추출물을 유효성분으로 함유하는 암 예방 및 개선용 식품 조성물에 관한 것이다. The present invention relates to cancer prevention, treatment or pharmaceutical composition for the inhibition of metastasis comprising an extract of microalgae Chlorella genus (chlorella sp.) As an active ingredient. The invention further relates to cancer prevention and improved food composition containing an extract of microalgae Chlorella genus (chlorella sp.) As an active ingredient.
Description
본 발명은 클로렐라(chlorella sp.) 속 미세조류의 추출물을 유효성분으로 함유하는 암 예방, 치료 또는 전이 억제용 조성물에 관한 것이다.The present invention relates to cancer prevention, treatment, or inhibition of metastasis composition containing the extract of the genus Chlorella microalgae (chlorella sp.) As an active ingredient.
암이란 주로 통제되지 않는 세포의 증식에서 시작되어 주위의 정상조직 또는 기관으로 침윤하여 파괴시키고 새로운 성장 장소를 만들 수 있어 개체의 생명을 빼앗아 갈 수 있는 질환 군을 총칭한다.Cancer is a group of diseases that can start from the growth of uncontrolled cells, infiltrate into the surrounding normal tissues or organs, destroy them, create new growth places, and take away the life of the individual.
지난 10여 년 동안 암을 정복하기 위해 세포주기나 세포사멸(apoptosis)의 조절과 발암유전자나 암 억제 유전자들을 포함한 새로운 표적을 모색함에 있어서 눈에 띄는 발전을 거듭해 왔음에도 불구하고 암의 발생률은 문명이 발달함에 따라 증가되고 있다. 현재, 암환자의 치료법은 외과적 수술, 방사선 치료 및 40여 종의 강한 세포독성을 보이는 항암물질 투여에 의한 화학요법에 의존하고 있는 상태인데, 이들 치료법도 대부분 조기 암환자나 특정 암에만 국한되어 암으로 인한 사망은 계속 증가하고 있는 추세이다. 한편, 암이 생명에 위협이 되는 가장 큰 원인은 암세포의 전이성에 있으며, 암으로 인한 사망의 대부분은 암 전이로 설명된다. 현재 임상적으로 입증된 보편적인 암 치료 방법이 외과 수술이지만, 원인이 되는 암이 제거되더라도 다른 조직으로 전이된 암세포에 의해 환자의 치료가 어렵게 된다. 따라서 암 정복은 실질적으로는 암 전이와의 싸움이라 볼 수 있다. Despite having made remarkable progress in the search for new targets, including the regulation of cell lineage or apoptosis, and the development of oncogenes or cancer-suppressing genes to conquer cancer over the last decade, It is increasing with development. Currently, the treatment of cancer patients depends on chemotherapy by surgical treatment, radiation therapy, and 40 kinds of strong cytotoxic chemotherapy. Most of these treatments are limited to early cancer patients or specific cancer, Of deaths are continuing to increase. On the other hand, the most common cause of life-threatening cancer is cancer metastasis, and most of cancer deaths are explained by cancer metastasis. Although the current clinically proven method of treating cancer is surgery, it is difficult to treat patients with cancer cells that have metastasized to other tissues even if the underlying cancer is removed. Therefore, cancer conquest is actually a fight against cancer metastasis.
암 전이에 있어서 세포의 이동은 여러 단계에 관여하는데, 암세포가 초기의 원발암 위치에서 세포간질(extracellular matrix(ECM))을 지나 혈관으로 이동할 때, 제 2의 전이 조직에서 혈관 밖으로 이동할 때 및 신생혈관에서 혈관 내피세포(vascular endothelial cell)가 이동할 때에 관여하는 등 그 과정이 매우 복잡하고 다양한 기능을 갖고 있다. In cancer metastasis, cell migration is involved in several stages: when the cancer cells migrate from the original primary carcinoma location through the extracellular matrix (ECM) to the blood vessels, from the second metastatic tissue outside the vessel, And the vascular endothelial cell (vascular endothelial cell) is involved in the movement of the process is very complex and has a variety of functions.
이동하는 세포는 세포이동 유도물질에 의해 활성화된 신호수용체에 의해 극성(polarity)이 유도된다. 세포 앞쪽의 끝부분은 엑틴(actin)의 중합에 의해 세포막이 앞으로 확장되며 인테그린(integrin)을 통해 세포간질에 부착한다. 이때, 엑틴 폴리머에 결합된 마이오신(myosin)에 의해 엑틴 폴리머들 사이에 강한 수축력이 형성되며 세포 전체에 강한 수축력이 부여된다. 따라서 세포의 앞부분 및 뒷부분의 부착력의 차이에 의해 세포이동의 방향이 결정된다. 만약 새로 형성된 앞부분의 부착력이 뒷부분의 부착력 보다 클 경우 세포의 뒷부분이 세포간질로부터 떨어져 세포는 앞으로 이동하게 되며, 그 반대의 경우 세포는 원래의 위치에 머물게 된다. 세포이동 신호수용체에 의해 활성화된 신호전달 분자에 따라 구조 형태학적으로 다른 세포돌출부가(lamellipoda, Filapoda) 형성된다. 이런 서로 다른 돌출부는 모두 실모양의 액틴(actin)을 포함할 뿐만 아니라 다양한 구조적, 신호적 단백질 세트를 포함하고 ECM과 역동적인 상호관계를 이끈다(Peter Friedl, et al., Nature Cancer Review, 2003, 3: 362).The migrating cells are polarized by signaling receptors activated by cell migration inducers. The anterior end of the cell is expanded by the polymerization of actin, and the cell membrane is attached to the cell epilepsy via the integrin. At this time, strong contraction force is formed between the actin polymers by myosin bound to the actin polymer, and strong contractile force is given to the entire cell. Therefore, the direction of cell movement is determined by the difference in the adhesion between the anterior and posterior cells. If the adhesion of the newly formed anterior portion is greater than that of the posterior portion of the cell, the cell will move away from the cell epilepsy and move forward, and vice versa. Depending on the signaling molecules activated by the cell migration signal receptor, other cell protrusions (lamellipoda, Filapoda) are formed morphologically. These different protrusions not only contain thread-like actin, but also contain a diverse set of structural and signaling proteins and lead to dynamic interactions with the ECM (Peter Friedl, et al., Nature Cancer Review , 2003, 3: 362).
암세포 이동을 표적으로 하는 항암제는 암 전이 억제를 목표로 하고 있다. 세포이동 억제제가 최상의 표적은 아니나, 우리가 추구하는 암 환자의 생명을 연장할 수 있는 현실적인 접근 방법이라고 할 수 있다. 실제로 암은 어떤 부위에 발생하든지 생성 부위만 찾으면 외과적 수술에 의해 간단하게 제거될 수 있는데, 이러한 외과적 수술의 한계는 암세포가 원발암 부위 이외의 여러 다른 곳으로 퍼져나가기 때문에 초기 시기에만 수술을 통한 완치를 기대할 수 있다. 그러나 초기에 암을 진단하지 못하였을 경우에는 이미 암세포가 혈관을 경유하여 온몸에 퍼져있고 제2, 또는 제3의 위치에서 매우 작은 콜로니(colony)를 형성한 경우에는 외과적 수술에 의해서는 암 치료를 성공적으로 치료할 수 없다. 실제로 많은 경우 암세포가 전이되어 외과적 치료를 포기하는 경우가 많은데, 이러한 경우에는 더 이상의 전이가 확산되지 않도록 암세포 이동을 억제한 상태에서 항암제를 투여하여 암세포의 사멸을 유도함으로써, 환자의 생명을 연장시키는데 도움을 줄 수 있을 것이다. 따라서, 암세포의 이동 억제제의 개발은 새로운 개념의 신약 항암제로 개발될 수 있으며, 확인된 저해제는 세포의 이동에 관한 학문적 연구에 중요한 재료로 사용될 수 있다.Anticancer drugs targeting cancer cell migration are aimed at inhibiting cancer metastasis. Cell migration inhibitors are not the best targets, but they are a realistic approach to prolong the life of cancer patients we seek. In fact, cancer can be removed simply by surgical operation if it finds any part of the body that occurs in any part of the body. The limitation of such surgical operation is that the cancer cells spread to various places other than the primary cancer site, Can be expected to cure through. However, if cancer is not diagnosed at an early stage, if cancer cells already spread through the blood vessels and form a very small colony at the second or third position, Can not be successfully treated. In many cases, in many cases, cancer cells are transferred to abandon surgical treatment. In such a case, the cancer cells are killed by inhibiting the cancer cell migration so as to prevent further metastasis, You can help. Therefore, the development of cancer cell migration inhibitors can be developed as a new concept of new drug chemotherapeutic agents, and the identified inhibitors can be used as an important material for academic research on cell migration.
한편, 클로렐라는 녹조류로 담수 중에 증식하는 단세포 식물로, 분류학상 클로로파이세아(chlorophycea) 강, 클로로코쿰(chlorococcum) 목, 클로렐라 속에 속한다. 이들은 보통 연못이나 호수 등 담수에서 생육하며, 직경 2 내지 10 ㎛의 구형 단세포 조류로 하나의 세포는 현미경으로만 볼 수 있는 정도이다. 생식은 무성생식으로 증식하고 물, 공기, 질소와 인산 등의 식물 성장요소가 있으면 빛과 이산화탄소를 이용한 독립 영양적 성장 증식을 한다는 점이 생물학적으로 가장 큰 특징으로, 이는 산업적 대량 배양 공정에서 가장 중요하게 고려되는 사항이다. 클로렐라는 필수 아미노산 조성이 좋은 고 단백질 식품으로 총 아미노산 함량은 쇠고기에 비하여 월등히 높으며 단백질, 지질, 식이섬유, 비타민류와 무기질에 관하여 다른 식품과 비교할 수 없을 만큼 영양학적으로도 균형잡힌 식품이다. 클로렐라는 현재 사료와 식품의 1, 2차적 목적으로 사용되어 영양학적으로 우수성이 확인되었고, 항암 활성외에 3차적 식품으로서 기능성의 탐색이 활발히 진행중에 있다. 특히 최근 연구에 의하면 클로렐라에 카로티노이드와 클로로필이 다량 존재하고 있으며 카로티노이드 성분 중 눈 건강 기능성에 도움을 줄 수 있는 루테인의 함량이 특별히 많음이 밝혀진 바 있다. 그러나 현재까지 클로렐라 속 미세조류의 추출물을 이용한 암 예방, 치료 또는 전이 억제 효과에 대해서는 알려진 바가 없다. On the other hand, chlorella is a single-celled plant that grows in fresh water as green algae and belongs to the genus chlorophycea river, chlorococcum tree, chlorella. They usually grow in fresh water, such as ponds and lakes, and are spherical, single-celled algae with a diameter of 2 to 10 ㎛, so that one cell can only be seen under a microscope. Reproduction is proliferated by asexual reproduction, and the presence of plant growth factors such as water, air, nitrogen, and phosphorus is the biologically most important feature of independent growth of nutrition using light and carbon dioxide. This is the most important feature in industrial mass culture This is something to consider. Chlorella is a high protein food with good essential amino acid composition. The total amino acid content is much higher than beef. It is a nutritionally balanced food with respect to protein, lipid, dietary fiber, vitamins and minerals. Chlorella is currently used for primary and secondary purposes in feed and food, and its nutritional excellence has been confirmed. In addition to its anticancer activity, exploration of its functionality as a tertiary food is underway. In particular, recent studies have shown that chlorothiophene and chlorophyll are abundant in chlorella, and that the content of lutein, which can contribute to eye health function, is particularly high among carotenoids. However, the inhibitory effect of chlorella microalgae extract on cancer prevention, treatment or metastasis has not been known.
이에, 본 발명자들은 클로렐라 속 신규 미세조류가 항암 활성, 암세포 사멸 효과, 암세포 전이 억제 효과, 암세포 침윤 억제 효과, 암세포 부착 억제 효과가 있음을 확인함으로써 본 발명을 완성하기에 이르렀다.Accordingly, the present inventors have completed the present invention by confirming that the microalgae of the genus Chlorella have anticancer activity, cancer cell killing effect, cancer cell metastasis inhibiting effect, cancer cell infiltration inhibiting effect, and cancer cell adhesion inhibiting effect.
본 발명의 목적은 클로렐라 속(chlorella sp.) 미세조류의 추출물을 유효성분으로 함유하는 암 예방, 치료 또는 전이 억제용 약학적 조성물을 제공하는 것이다.An object of the present invention is to provide a pharmaceutical composition for cancer prevention, treatment, or inhibition of metastasis comprising an extract of microalgae Chlorella genus (chlorella sp.) As an active ingredient.
본 발명의 다른 목적은 클로렐라 속(chlorella sp.) 미세조류의 추출물을 유효성분으로 함유하는 암 예방 및 개선용 식품 조성물을 제공하는 것이다.It is another object of the invention to provide a cancer prevention and improved food composition containing an extract of microalgae Chlorella genus (chlorella sp.) As an active ingredient.
상기 목적을 달성하기 위하여, 본 발명은 클로렐라 속(chlorella sp.) 미세조류의 추출물을 유효성분으로 함유하는 암 예방, 치료 또는 전이 억제용 약학적 조성물을 제공한다. In order to achieve the above object, the present invention provides a cancer prevention, treatment or pharmaceutical composition for the inhibition of metastasis comprising an extract of microalgae Chlorella genus (chlorella sp.) As an active ingredient.
본 발명의 용어, "항암"은 암세포의 형성 또는 증식을 억제하거나, 암세포의 사멸시키는 작용을 억제 또는 차단하는 작용을 의미하는 것으로, 암의 예방 및 치료를 의미한다. The term "anti-cancer" of the present invention means the action of inhibiting or blocking the action of inhibiting the formation or proliferation of cancer cells or killing cancer cells, and means the prevention and treatment of cancer.
본 발명의 용어, "예방"은 본 발명의 조성물의 투여로 암 형성을 억제시키거나 발병을 지연시키는 모든 행위를 의미한다. The term "prophylactic" of the present invention means any action that inhibits cancer formation or delays onset by administration of the composition of the present invention.
본 발명의 용어, "치료" 및 "개선"은 본 발명의 조성물의 투여로 상기 질환의 증세가 호전 또는 이롭게 변경되는 모든 행위를 의미한다. The terms "treatment" and "improvement" of the present invention refer to any action in which administration of the composition of the present invention improves or alleviates the symptoms of the disease.
상기 클로렐라 속 미세조류는 이에 제한되는 것은 아니나 Chlorella sp. JD002일 수 있다. The chlorella microalgae include, but are not limited to, Chlorella sp. JD002.
본 발명의 상기 클로렐라 추출물은 이에 제한되는 것은 아니나 C1 - C4의 저급 알코올, 헥산, 에틸아세테이트, 물 또는 이들의 혼합물을 용매로 사용하여 추출된 것일 수 있으며, 상기 저급 알코올은 바람직하게 메탄올 또는 에탄올일 수 있으며, 가장 바람직하게 에탄올일 수 있다. The chlorella extract of the present invention may be extracted with a C1-C4 lower alcohol, hexane, ethyl acetate, water or a mixture thereof, but not limited thereto, and the lower alcohol preferably is methanol or ethanol And most preferably ethanol.
상기 클로렐라 추출물의 추출 방법으로는 여과법, 열수추출, 침지추출, 환류냉각추출 및 초음파추출 등 당업계의 통상적인 방법을 이용할 수 있으며, 열수추출 방법으로 1회 내지 5회 추출하는 것일 수 있고, 보다 구체적으로 3회 반복 추출하는 것일 수 있으나 이에 한정하지 않는다. 상기 추출용매는 파쇄한 클로렐라에 0.1 내지 10배로 첨가할 수 있으며, 0.3 내지 5배 첨가하는 것이 바람직하다. 추출온도는 20℃ 내지 80℃인 것일 수 있으나 이에 한정하지 않는다. 또한, 추출시간은 12 내지 72 시간인 것일 수 있으나 이에 한정하지 않는다.The chlorella extract may be extracted by a conventional method such as filtration, hot water extraction, immersion extraction, reflux cooling extraction, and ultrasonic extraction, and may be one to five times by hot water extraction. Specifically, it may be repeated three times, but is not limited thereto. The extraction solvent may be added to the crushed chlorella in an amount of 0.1 to 10 times, preferably 0.3 to 5 times. The extraction temperature may be 20 占 폚 to 80 占 폚, but is not limited thereto. In addition, the extraction time may be 12 to 72 hours, but is not limited thereto.
상기 방법에 있어서, 상기 감압농축은 진공감압농축기 또는 진공회전증발기를 이용하는 것일 수 있으나 이에 한정하지 않는다. 또한, 건조는 감압건조, 진공건조, 비등건조, 분무건조 또는 동결건조하는 것일 수 있으나 이에 한정하지 않는다.In the above method, the vacuum concentration may be performed using a vacuum decompression concentrator or a vacuum rotary evaporator, but is not limited thereto. The drying may be, but not limited to, vacuum drying, vacuum drying, boiling, spray drying or lyophilization.
본 발명의 상기 암은 유방암, 자궁암, 결장암, 간암, 악성흑색종, 난소암, 뇌종양 및 폐암으로 구성된 군으로부터 선택되는 것일 수 있으나 이에 제한되는 것은 아니다. The cancer of the present invention may be selected from the group consisting of breast cancer, cervical cancer, colon cancer, liver cancer, malignant melanoma, ovarian cancer, brain tumor and lung cancer, but is not limited thereto.
본 발명의 약학적 조성물은, 투여를 위해서 상기 기재한 유효성분 이외에 추가로 약제학적으로 허용 가능한 담체를 1종 이상 포함하여 제조할 수 있다. 약제학적으로 허용 가능한 담체는 식염수, 멸균수, 링거액, 완충 식염수, 덱스트로즈 용액, 말토 덱스트린 용액, 글리세롤, 에탄올, 리포좀 및 이들 성분 중 1 성분 이상을 혼합하여 사용할 수 있으며, 필요에 따라 항산화제, 완충액, 정균제 등 다른 통상의 첨가제를 첨가할 수 있다. 또한 희석제, 분산제, 계면활성제, 결합제 및 윤활제를 부가적으로 첨가하여 수용액, 현탁액, 유탁액 등과 같은 주사용 제형, 환약, 캡슐, 과립 또는 정제로 제제화할 수 있으며, 표적 기관에 특이적으로 작용할 수 있도록 표적 기관 특이적 항체 또는 기타 리간드를 상기 담체와 결합시켜 사용할 수 있다. 더 나아가 당해 기술분야의 적정한 방법으로 또는 레밍턴의 문헌(Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA)에 개시되어 있는 방법을 이용하여 각 질환에 따라 또는 성분에 따라 바람직하게 제제화할 수 있다.The pharmaceutical composition of the present invention may further comprise at least one pharmaceutically acceptable carrier in addition to the above-described effective ingredient for administration. The pharmaceutically acceptable carrier may be a mixture of saline, sterilized water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, liposome and one or more of these components. , A buffer solution, a bacteriostatic agent, and the like may be added. In addition, it can be formulated into injection formulations, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like by additionally adding diluents, dispersants, surfactants, binders and lubricants, Specific antibody or other ligand can be used in combination with the carrier. Can be formulated according to each disease or component, using methods well known in the art or as disclosed in Remington ' s Pharmaceutical Science, Mack Publishing Company, Easton PA.
본 발명의 용어, "투여"는 임의의 적절한 방법으로 환자에게 소정의 본 발명의 조성물을 제공하는 것을 의미한다. The term "administering" of the present invention means providing the desired composition of the invention to the patient in any suitable manner.
본 발명의 용어, "환자"는 본 발명의 조성물을 투여하여 증상이 호전될 수 있는 질환을 가진 인간, 원숭이, 개, 염소, 돼지 또는 쥐 등 모든 동물을 의미한다. The term "patient" of the present invention means any animal such as a human, a monkey, a dog, a goat, a pig or a mouse having a disease whose symptoms can be alleviated by administration of the composition of the present invention.
본 발명의 용어, "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜 또는 위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 이는 환자의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출비율, 치료기간, 동시에 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다.The term "pharmaceutically effective amount" of the present invention means an amount sufficient to treat a disease at a reasonable benefit or risk rate applicable to medical treatment, including the type of disease, severity, activity of the drug, The drug's sensitivity, the time of administration, the route of administration and the rate of release, the duration of the treatment, factors including simultaneously used drugs, and other factors well known in the medical arts.
본 발명의 약학적 조성물은 경구, 국소, 비경구, 비 내, 정맥 내, 근육 내, 피하, 안 내, 경피 등의 투여를 목적으로 제조될 수 있다.The pharmaceutical composition of the present invention can be manufactured for oral, topical, parenteral, intranasal, intravenous, intramuscular, subcutaneous, intraocular, transdermal, and the like administration.
바람직하게는, 본 발명의 약학적 조성물이 주사가능한 형태로 사용된다. 이에 따라서 특히 처리될 영역으로는 직접적인 주입을 위하여 주사 가능한 조성물을 위한 임의의 약학적으로 허용되는 매개체와 혼합될 수 있다. 본 발명의 약학적 조성물은 특히 등장 멸균 용액 또는 건조 특히 멸균수 또는 적절한 생리 식염수의 첨가에 따라 주사 가능한 용액의 조성을 가능케 하는 동결건조 조성물을 포함할 수 있다. 환자의 종양으로의 핵산의 직접적인 주입은 치료 효율을 감염된 조직에 집중시키도록 하므로 유리하다. 사용되는 투여량은 다양한 파라미터, 특히 사용되는 투여 방식, 문제시되는 질병 또는 대안적으로 요구되는 치료기간에 의해 조절될 수 있다. 또한, 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설율 및 질환의 중증도 등에 따라 그 범위가 다양하다. 일일 투여량은 약 0.0001 내지 100 ㎎/㎏이고, 바람직하게는 0.001 내지 10 ㎎/㎏이며, 하루 1회 내지 수회 나누어 투여하는 것이 바람직하다.Preferably, the pharmaceutical composition of the present invention is used in an injectable form. And accordingly can be mixed with any pharmaceutically acceptable vehicle for the injectable composition for direct injection into the area to be treated accordingly. The pharmaceutical compositions of the present invention may comprise a freeze-dried composition which allows for the composition of an injectable solution, in particular by addition of an isotonic sterile solution or dry, in particular sterile water, or an appropriate physiological saline. Direct injection of the nucleic acid into the patient's tumor is advantageous because it allows the therapeutic efficiency to be concentrated in the infected tissue. The dosage used can be controlled by various parameters, in particular the mode of administration employed, the disease in question, or alternatively the desired duration of treatment. Also, the range varies depending on the patient's body weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and severity of disease. The daily dose is about 0.0001 to 100 mg / kg, preferably 0.001 to 10 mg / kg, and is preferably administered once to several times a day.
또한, 본 발명은 약학적으로 유효한 양의 상기 약학적 조성물을 암에 걸린 개체에 투여하는 단계를 포함하는 암의 치료 방법 또는 암전이 억제 방법을 제공한다.The present invention also provides a method for treating cancer or a method for inhibiting cancer metastasis, which comprises administering a pharmaceutically effective amount of the above pharmaceutical composition to a subject suffering from cancer.
상기 약학적으로 유효한 양이란 0.0001 내지 100 ㎎/㎏이고, 바람직하게는 0.001 내지 10 ㎎/㎏이며, 이에 한정되는 것은 아니다. 투여량은 특정 환자의 체중, 연령, 성별, 건강상태, 식이, 투여기간, 투여방법, 제거율, 질환의 중증도 등에 따라 변화될 수 있다.The pharmacologically effective amount is 0.0001 to 100 mg / kg, preferably 0.001 to 10 mg / kg, but is not limited thereto. The dose may vary depending on the weight, age, sex, health condition, diet, administration period, method of administration, rate of elimination, severity of disease, and the like of a particular patient.
상기 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 있다.The pharmaceutical composition may be administered orally or parenterally at the time of clinical administration and may be administered orally or parenterally in the case of parenteral administration by intraperitoneal injection, rectal injection, subcutaneous injection, intravenous injection, intramuscular injection, intrauterine injection, And can be used in the form of a general pharmaceutical preparation.
본 발명은 또한, 클로렐라 속(chlorella sp.) 미세조류의 추출물을 유효성분으로 함유하는 암 예방 및 개선용 식품 조성물을 제공한다. The present invention also provides a cancer prevention and improved food composition containing an extract of microalgae Chlorella genus (chlorella sp.) As an active ingredient.
상기 클로렐라 속 미세조류는 바람직하게 Chlorella sp. JD002일 수 있으나 이에 제한되는 것은 아니다. The chlorella microalgae are preferably selected from the group consisting of Chlorella sp. JD002, but is not limited thereto.
본 발명의 상기 암은 유방암, 자궁암, 결장암, 간암, 악성흑색종, 난소암, 뇌종양 및 폐암으로 구성된 군으로부터 선택되는 것일 수 있으나 이에 제한되는 것은 아니다. The cancer of the present invention may be selected from the group consisting of breast cancer, cervical cancer, colon cancer, liver cancer, malignant melanoma, ovarian cancer, brain tumor and lung cancer, but is not limited thereto.
상기 식품 조성물은 바람직하게 건강기능성 식품일 수 있으며, 식품 첨가제일 수 있다. 상기 건강기능성 식품 또는 식품 첨가제는 분말, 과립, 정제, 캡슐 또는 음료인 것이 바람직하나, 이에 한정되지 않는다.The food composition may preferably be a health functional food, and may be a food additive. The health functional food or food additive is preferably powder, granule, tablet, capsule or beverage, but is not limited thereto.
본 발명의 식품은 본 발명에 따른 클로렐라 추출물을 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다.The food of the present invention can be used as it is or directly with other food or food ingredients according to the present invention, and can be suitably used according to conventional methods.
상기 식품의 종류에는 특별한 제한은 없다. 본 발명에 따른 클로렐라 추출물을 첨가할 수 있는 식품의 예로는 육류, 소시지, 빵, 초콜릿, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알코올음료 및 비타민 복합제 등이 있으며, 통상적인 의미에서의 식품을 모두 포함한다.There is no particular limitation on the kind of the food. Examples of the food to which the chlorella extract according to the present invention can be added include meat products, sausages, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, Tea, a drink, an alcoholic beverage, and a vitamin complex, and includes foods in a conventional sense.
본 발명의 식품 조성물은 바람직하게 음료 조성물을 포함할 수 있다. 상기음료 조성물은 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물은 포도당, 과당과 같은 모노사카라이드, 말토스, 슈크로스와 같은 디사카라이드, 및 덱스트린, 사이클로덱스트린과 같은 폴리사카라이드, 자일리톨, 소르비톨, 에리트리톨 등의 당알코올이다. 감미제로서는 타우마틴, 스테비아 추출물과 같은 천연 감미제나, 사카린, 아스파르탐과 같은 합성 감미제 등을 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 ㎖당 일반적으로 약 0.01 ~ 0.04 g, 바람직하게는 약 0.02 ~ 0.03 g 이다.The food composition of the present invention may preferably comprise a beverage composition. The beverage composition may contain various flavors or natural carbohydrates as an additional ingredient such as ordinary beverages. The above-mentioned natural carbohydrates are sugar alcohols such as monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and xylitol, sorbitol and erythritol. Examples of sweeteners include natural sweeteners such as tau martin and stevia extract, synthetic sweeteners such as saccharin and aspartame, and the like. The ratio of the natural carbohydrate is generally about 0.01 to 0.04 g, preferably about 0.02 to 0.03 g per 100 ml of the composition of the present invention.
본 발명의 식품 조성물에서 포함할 수 있는 필수 성분으로서 상기 본 발명에 따른 클로렐라 추출물은 본 발명에 따른 클로렐라 추출물상의 식품과 같이 여러 가지 생약 추출물, 식품 보조 첨가제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 또한, 식품보조첨가제를 추가로 첨가할 수도 있는바 식품보조첨가제는 당업계에 통상적인 식품보조첨가제, 예를 들어 향미제, 풍미제, 착색제, 충진제, 안정화제 등을 포함한다. 상기 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스 등; 및 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연 향미제 (타우마틴, 스테비아 추출물 (예를 들어 레바우디오시드 Ａ, 글리시르히진등) 및 합성 향미제 (사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 상기 외에 본 발명의 식품 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제 (치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다. 그 밖에 천연 과일 주스 및 과일 주스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 크게 중요하진 않지만 본 발명의 조성물 100 중량부 당 0.01 ~ 0.1 중량부의 범위에서 선택되는 것이 일반적이다.The chlorella extract according to the present invention as an essential ingredient which can be contained in the food composition of the present invention may contain various herbal medicine extracts, food supplementary additives or natural carbohydrates as an additional ingredient such as food on the chlorella extract according to the present invention have. In addition, the food-aid additive may further include food-aid additives. Examples of the food-aid additive include food-aid additives customary in the art, for example, flavoring agents, flavoring agents, coloring agents, fillers, stabilizers and the like. Examples of such natural carbohydrates include monosaccharides such as glucose, fructose, and the like; Disaccharides such as maltose, sucrose and the like; And polysaccharides, for example, conventional sugars such as dextrin, cyclodextrin and the like, and sugar alcohols such as xylitol, sorbitol and erythritol. Natural flavors (tau martin, stevia extracts (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavors (saccharin, aspartame, etc.) can be advantageously used as flavors other than those described above . In addition to the above, the food composition of the present invention may contain flavoring agents such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, coloring agents and thickening agents (cheese, chocolate etc.), pectic acid and its salts, And salts thereof, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated beverages, etc. Besides natural fruit juices and fruit juice drinks and vegetable drinks These additives may be used independently or in combination. Although the ratio of such additives is not critical, 100 parts by weight of the composition of the present invention It is generally selected from the range of 0.01 to 0.1 wt.
본 발명의 구체적인 실시예에서, 청정수계지역에서 신규한 미세조류인 Chlorella sp. JD002를 분리 및 동정하였다. 또한 EtOAc를 이용한 Chlorella sp. JD002 추출물을 암세포에 농도별로 처리한 결과, 모든 암 종에서 항암효과를 나타내었으며, 농도의존적으로 세포사멸이 증가된 것을 확인하였다. 또한 본 발명의 구체예에서, Chlorella sp. JD002 추출물을 전이모델세포주인 MDA-MB-231에 농도별로 처리한 결과 농도의존적으로 전이가 억제되고, 암세포 침윤이 억제되는 것을 확인하였다. 또한 본 발명의 구체예에서, Chlorella sp. JD002 추출물을 전이모델세포주인 MDA-MB-231에 농도별로 처리한 결과, 농도의존적으로 전이관련 유전자(VEGF, uPA, ICAM, Integrin-α2, MMP-9)의 mRNA발현이 억제되는 것을 확인하였다. In a specific embodiment of the present invention, the novel microalgae Chlorella sp. JD002 was isolated and identified. Chlorella using EtOAc sp. As a result of treating JD002 extract with concentration in cancer cells, it showed anticancer effect in all cancer species, and it was confirmed that cell death was increased in a concentration dependent manner. Also in embodiments of the present invention, Chlorella sp. MDA-MB-231, a transgenic model cell line, was found to inhibit metastasis and inhibit cancer cell infiltration in a concentration-dependent manner. Also in embodiments of the present invention, Chlorella sp. MDA-MB-231, a transgenic model cell line, was found to inhibit mRNA expression of transcription-related genes (VEGF, uPA, ICAM, Integrin-α2 and MMP-9) in a concentration-dependent manner.
본 발명의 청정지역수계에서 분리 및 동정하여 얻은 Chlorella sp. JD002 의 추출물은 항암활성, 암세포 사멸효과, 암세포 전이 억제 효과, 암세포 침윤 억제 효과 그리고 암세포 부착 억제효과가 있다. 따라서, 항암용 약학적 조성물 또는 식품으로 용이하게 활용할 수 있다. Chlorella sp. ≪ / RTI > obtained by isolation and identification in the clean water system of the present invention. The extract of JD002 has anticancer activity, cancer cell killing effect, cancer cell metastasis inhibiting effect, cancer cell infiltration inhibition effect and cancer cell adhesion inhibition effect. Therefore, it can be easily utilized as a pharmaceutical composition or food for anti-cancer.
도 1은 본 발명의 Chlorella sp. JD002의 크기 및 형태를 나타낸 현미경 사진이다.
도 2는 본 발명의 Chlorella sp. JD002의 성장 곡선을 나타낸다.
도 3은 본 발명의 Chlorella sp. JD002의 배양 완료 후 광처리 반응 결과를 나타낸다. A) 배양 환경; B)High light 상태
도 4는 Chlorella sp. JD002 용매별 추출물을 이용해 다양한 암세포주에 대한 항암활성을 나타낸 결과이다. (MDA-MB-231: 유방암세포주; HeLa: 자궁암세포주; HT-29: 결장암세포주; SKHEP-1: 간암세포주; SK-MEL-28: 악성흑색종세포주; SK-OV-3: 난소암세포주; U87MG: 뇌종양세포주; Cisplatin: 대조군)
도 5는 EtOAc를 이용한 Chlorella sp. JD002 추출물을 각각의 암세포주에 농도별로 처리한 항암 활성 결과이다.
도 6은 EtOAc를 이용한 Chlorella sp. JD002 추출물을 암세포에 농도별로 처리한 후, 세포 사멸 효과를 확인한 결과이다.
도 7은 EtOAc를 이용한 Chlorella sp. JD002 추출물을 전이모델세포주인 MDA-MB-231에 농도별로 처리한 결과이다.
도 8은 EtOAc를 이용한 Chlorella sp. JD002 추출물을 전이모델세포주인 MDA-MB-231에 농도별로 처리한 결과이다.
도 9는 EtOAc를 이용한 Chlorella sp. JD002 추출물을 전이모델세포주인 MDA-MB-231에 농도별로 처리하고 암세포 부착 억제 효과를 확인한 결과이다.
도 10은 EtOAc를 이용한 Chlorella sp. JD002 추출물을 전이모델세포주인 MDA-MB-231에 농도별로 처리한 후의 VEGF, uPA, ICAM, Integrin-α2, MMP-9의 mRNA발현 결과를 타나탠다. Figure 1 of the present invention Chlorella sp. A microscope photograph showing the size and shape of JD002.
Fig. 2 is a graph showing the effect of the chlorella sp. The growth curve of JD002 is shown.
Fig. 3 is a graph showing the activity of the Chlorella sp. The result of light treatment reaction after completion of incubation of JD002 is shown. A) culture environment; B) High light condition
FIG. The results of the anti-cancer activity of various cancer cell lines using JD002 solvent extract are shown. SK-MEL-28: malignant melanoma cell line; SK-OV-3: ovarian cancer cell line; MDA-MB-231: breast cancer cell line: HeLa: cervical cancer cell line; HT-29: colon cancer cell line; SKHEP-1: liver cancer cell line; U87MG: brain tumor cell line; Cisplatin: control group)
FIG. 5 is a graph showing the effect of Chlorella sp. The results of the anticancer activity of JD002 extract treated with each concentration of cancer cells.
FIG. 6 is a graph showing the change in the concentration of chlorella sp. The results of confirming the cell death effect after treating the extract of JD002 with the cancer cells at different concentrations.
Figure 7 shows the < RTI ID = 0.0 > Chlorella sp. MDA-MB-231, a transgenic model cell line.
FIG. 8 is a graph showing the change of the concentration of Chlorella sp. MDA-MB-231, a transgenic model cell line.
FIG. 9 is a graph showing the activity of Chlorella sp. MDA-MB-231, a metastatic model cell line, and the effect of inhibiting cancer cell adhesion was examined.
FIG. 10 is a graph showing the activity of Chlorella sp. Expression of mRNA of VEGF, uPA, ICAM, Integrin-α2, and MMP-9 after treatment of JD002 extract with MDA-MB-231, a transgenic model cell line, was shown.
이하, 본 발명의 이해를 돕기 위하여 실시예를 들어 상세하게 설명하기로 한다. 다만 하기의 실시예는 본 발명의 내용을 예시하는 것일 뿐 본 발명의 범위가 하기 실시예에 한정되는 것은 아니다. 본 발명의 실시예는 이 기술분야에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다.BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are intended to illustrate the contents of the present invention, but the scope of the present invention is not limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.
<< 실시예Example 1> 1> 청정 담수로부터 미세조류 분리 및 동정Isolation and identification of microalgae from clean fresh water
<1-1> 미세조류의 분리<1-1> Isolation of microalgae
청정지역 수계인 금강 유역 전라도 정읍에서 담수 시료를 채취한 뒤 담수 시료는 1L 채수병에 채취하여 즉시 아이스박스를 이용하여 저온보관을 유지하였고, 실험실에서 시료를 Combi 514R(Hanil, 한국)를 이용하여 농축하였다. 농축한 담수시료를 마이크로피펫팅(micropipetting)을 통해 각각의 미세조류로 분리하였으며, 분리된 미세조류들을 BG11 media (표 1)가 들은 96 well plate에서 100μmol/m2/s의 광원 하에서 배양하였다. 분리된 미세조류는 광학현미경(Nicon ECLIPSE 80i, nikon, 일본) 및 형광현미경(Nicon ECLIPSE 80i, nikon, 일본)으로 관찰하였다. Fresh water samples were collected from the Jeongeup Jeonbuk (Jeongeup), a clean water area, in Jeongeup, Jeolla province, and fresh water samples were collected in 1L bottles and immediately kept at low temperature using an ice box. The samples were collected in a laboratory using Combi 514R Lt; / RTI > The concentrated freshwater samples were separated into microalgae by micropipetting and the separated microalgae were cultured on a 96 well plate with BG11 media (Table 1) under a light source of 100 μmol / m 2 / s. The isolated microalgae were observed under an optical microscope (Nicon ECLIPSE 80i, nikon, Japan) and a fluorescence microscope (Nicon ECLIPSE 80i, nikon, Japan).
그 결과, 형태적으로 chlorella sp . 와 유사함을 알 수 있었다 (도 1). As a result, the morphologically chlorella sp . (Fig. 1).
<1-2> 분리 미생물의 동정<1-2> Identification of isolated microorganisms
상기 실시예 <1-1>에서 분리한 미세조류를 동정하기 위해 유전학적 방법이 사용되었다. 구체적으로, 하기 표 2에 기재된 ch165F와 ch1200R 프라이머 쌍을 이용하여 하기 표 3와 같은 구성으로 PCR을 위한 혼합물을 혼합한 뒤 표 4의 PCR 조건으로 GeneAmp PCR system 2700(ABI, 미국)을 이용하여 분리된 미세조류 JD002의 18S rRNA을 동정하였다. A genetic method was used to identify the microalgae isolated in Example <1-1>. Specifically, using the pair of ch165F and ch1200R primers shown in Table 2 below, the mixture for PCR was synthesized as shown in Table 3 below, and then subjected to GeneAmp PCR system 2700 (ABI, USA) under the PCR conditions shown in Table 4 The 18S rRNA of the microalgae JD002 was identified.
동정한 JD002의 18S rRNA 서열을 ncbi의 blast 프로그램을 이용하여 확인한 결과, chlorella sp. 와 99% 유사한 것으로 동정되었다. 따라서, 본 발명에서 분리한 미세조류를 chlorella sp. JD002으로 정하였다. The 18S rRNA sequence of the identified JD002 was confirmed by ncbi blast program, and chlorella sp. And 99%, respectively. Therefore, the microalgae isolated in the present invention are chlorella sp. JD002.
<< 실시예Example 2> 미세조류 배양 및 수확 2> Cultivating and harvesting microalgae
분리 및 동정된 미세조류 chlorella sp. JD002미세조류의 cell biomass를 얻기 위해 2L culture bottle를 멸균상태로 준비하고 1 L의 BG11 배지를 넣고 미세조류를 접종하였다. 배양 조건은 온도 25℃, 교반속도 100 rpm, 광조사 70~100 μmol/m2/s에서 건조중량 1 g/L 수준으로 배양하였다. 균체농도 1 g/L 수준으로 배양된 미세조류 배양액은 High light condition(PAR 1,200 μmol/m2/s)로 12시간 동안 반응하였다(도 2 및 도 3).Isolated and identified microalga chlorella sp. JD002 A 2 L culture bottle was prepared in sterile condition to obtain microalgae cell biomass, and microalgae were inoculated with 1 L of BG11 medium. The culture conditions were as follows: a temperature of 25 ° C, a stirring speed of 100 rpm, a light irradiation of 70 to 100 μmol / m 2 / s, and a dry weight of 1 g / L. The microalgae cultured at a cell concentration of 1 g / L was reacted for 12 hours under high light condition (PAR 1,200 μmol / m 2 / s) (FIGS. 2 and 3).
미세조류 배양 및 반응이 끝난 Chlorella sp. JD002시료는 50 ml tube로 옮겨 4000 rpm(3,800 x g)에서 20~40분 원심분리하여 cell biomass를 얻었다. 획득한 미세조류 cell biomass는 -70℃에서 동결 후, 동결건조기를 이용하여 수분을 제거하였다. 동결건조는 수분을 완전히 제거하기 위하여 over night으로 진행하였다.Cultivation of microalgae and reaction of Chlorella sp. The JD002 sample was transferred to a 50 ml tube and centrifuged at 4000 rpm (3,800 xg) for 20 to 40 minutes to obtain cell biomass. The obtained microalgae cell biomass was frozen at -70 ℃, and water was removed by using a freeze dryer. Freeze-drying was carried out over night to completely remove moisture.
<< 실시예Example 3> 시료의 제조 3> Preparation of sample
Chlorella sp. JD002 추출물을 얻기 위해 당업계에서 통상적으로 이용되는 추출법을 사용하였다. 먼저 파쇄한 Chlorella sp. JD002를 멸균수, 핵산, 에탄올 그리고 에틸아세테이트 각각에 혼합하였다. 상기 혼합된 원료를 60℃의 온도에서 48 시간 교반하여 추출하였다. 상기 Chlorella sp. JD002 추출물을 250 메쉬와 0.5 ㎛ 필터페이퍼로 여과하여 액상추출물을 수득하였다. 상기 여과된 액상추출물을 회전감압농축기를 이용하여 감압 농축하여 본 발명의 조성물의 농축물을 획득하였다. Chlorella sp. Extraction methods commonly used in the art were used to obtain the JD002 extract. First, the crushed Chlorella sp. JD002 was mixed with sterile water, nucleic acid, ethanol and ethyl acetate respectively. The mixed raw materials were extracted by stirring at a temperature of 60 캜 for 48 hours. The Chlorella sp. The JD002 extract was filtered through 250 mesh and 0.5 mu m filter paper to obtain a liquid extract. The filtered liquid extract was concentrated under reduced pressure using a rotary vacuum concentrator to obtain a concentrate of the composition of the present invention.
<< 실시예Example 4> 활성 측정 4> Measurement of activity
암세포 배양 및 Cancer cell culture and ChlorellaChlorella spsp . JD002 추출물의 처리. Treatment of JD002 extract
실시예 3에 따른 Chlorella sp. JD002 추출물 각각을 인간고형암주에 대한 항암활성 검정용 시료로 사용하였다. 인간고형암주는 유방암세포주(MDA-MB-231; ATCC CRM-HTB-26D, DMEM), 자궁암세포주(HeLa; ATCC CCL-2; MEM), 결장암세포주(HT-29; ATCC HTV-38; McCoy s 5A), 간암세포주(SKHEP-1; ATCC HTB-52; MEM), 악성흑색종세포주(SK-MEL-28; ATCC HTB-72; MEM), 난소암세포주(SK-OV-3; ATCC HTB-77; McCoy s 5A), 뇌종양세포주(U87MG; ATCC HTB-14; DMEM) 7종은 ATCC(American Type Culture Collection)로부터 분양받아 사용하였다. 각 인간고형암주에 적합배지에 항생제(gentamycin) 50 ㎍/㎖를 첨가하여 0.22 ㎛ 여과지로 여과한 후, 배양 전에 태아송아지혈청(fetal bovine serum, FBS)을 56℃에서 20분 동안 가열, 활성화하여 최종농도가 10% 되도록 첨가하여 세포를 배양하였다. According to Example 3 Chlorella sp. Each of the extracts of JD002 was used as a test sample for anticancer activity against human solid cancer cells. (ATCC CRM-HTB-26D, DMEM), a cervical cancer cell line (HeLa; ATCC CCL-2; MEM), a colon cancer cell line (HT-29; ATCC HTV-38; McCoy s 5A SK-OV-3, ATCC HTB-72, MEM), liver cancer cell line SKHEP-1 (ATCC HTB-52; MEM), malignant melanoma cell line SK- ; McCoy s 5A) and brain tumor cell line (U87MG; ATCC HTB-14; DMEM) were purchased from ATCC (American Type Culture Collection). Fetal bovine serum (FBS) was heated and activated at 56 ° C for 20 minutes before the incubation. After the culture, The cells were cultured by adding 10% final concentration.
각 시료는 소량의 DMSO (dimethyl sulfoxide)에 용해시킨 후 실험용 배지에 일정농도로 희석하여 사용하였으며, 최종 DMSO의 농도가 0.5 % 이하가 되도록 하였다. DMSO는 0.5 % 이하의 농도에서 7종의 세포주에 대해 어떠한 부작용도 나타내지 않는다.Each sample was dissolved in a small amount of dimethyl sulfoxide (DMSO), diluted to a certain concentration in the experimental medium, and the final concentration of DMSO was adjusted to 0.5% or less. DMSO does not show any side effects for 7 cell lines at concentrations of 0.5% or less.
1) One) ChlorellaChlorella spsp . JD002. JD002 추출물의 항암활성Anticancer activity of extract
MTT 분석법을 위하여, 배양한 각 세포주를 3 x 105 세포/㎖의 농도로 조정하고, 96-웰 마이크로플레이트(Falcon, USA)에 웰 당 100 ㎕씩 넣었다. 실시예 3에 따른 Chlorella sp. JD002 추출물을 DMSO에 용해한 후 100 ㎕씩 각기 다른 웰(well)에 넣고, 최종 농도 50 ㎍/㎖에서부터 PBS(phosphate buffer saline)로 1/3씩 단계적으로 희석하여 0.01 ㎍/㎖ 농도까지 희석하였다. 이때 각 희석액의 최종부피는 200 ㎕로 조정하였다. 각 농도별 희석액을 각각의 세포주에 첨가하여 37℃, 5% CO2 배양기에서 48시간 동안 배양하였다. 이후 MTT 시약을 5 mg/㎖로 포함하는 PBS를 20 ㎕씩 처리하여 세포주들을 4시간 배양하였고, 상층액 100 ㎕를 제거한 다음 DMSO로 MTT formazan을 녹였다. 이후 자동 엘라이자 리더(automatic ELIZA reader)를 이용하여 495 nm에서 흡광도를 측정하였으며, 대조군으로 상용 항암제인 시스플라틴(cisplatin)을 동일한 방법으로 실험하여 비교하였다.For MTT assay, each cell line cultured was adjusted to a concentration of 3 x 10 5 cells / ml, and 100 μl per well was added to a 96-well microplate (Falcon, USA). According to Example 3 Chlorella sp. The JD002 extract was dissolved in DMSO, and 100 μl of the extract was added to each well. The diluted solution was diluted stepwise with 1/3 of PBS (phosphate buffer saline) at a final concentration of 50 μg / ml to a concentration of 0.01 μg / ml. At this time, the final volume of each dilution was adjusted to 200 mu l. Dilutions of each concentration were added to each cell line and cultured in a 5% CO 2 incubator at 37 ° C for 48 hours. After that, 20 ㎕ of PBS containing 5 mg / ml of MTT reagent was treated for 4 hours, and 100 ㎕ of the supernatant was removed and MTT formazan was dissolved with DMSO. The absorbance was measured at 495 nm using an automatic ELISA reader. Cisplatin, a commercial anticancer drug, was also tested and compared in the same manner.
분석 결과, 도 4, 도 5, 표 5 및 표 6에서 나타낸 것과 같이 양성대조군인 cisplatin보다 암세포의 성장을 억제하였고, 이중 특히 가장효과가 좋았던 EtOAc를 이용한 미세조류 추출물을 농도별로 처리한 결과, 모든 암종에서 농도의존적으로 세포성장이 억제되는 것을 확인하였다.As shown in FIG. 4, FIG. 5, Table 5 and Table 6, the growth of cancer cells was inhibited more than the positive control group, cisplatin. Especially, treatment of microalgae extract using EtOAc, which was the most effective, And cell growth was inhibited in a dose dependent manner in the carcinoma.
2) 2) ChlorellaChlorella spsp . JD002의 추출물에 의한 암세포의 세포사멸 효과. Effect of JD002 Extract on the Cell Death of Cancer Cells
Chlorella sp. JD002 추출물의 아팝토시스(apoptosis) 억제 효과를 알아보기 위해, 각각의 암세포주에 실시예 3에 따른 Chlorella sp. JD002 추출물을 처리하여 flow cytometer로 apoptotic cell을 나타내는 sub-G1기의 세포수를 측정하였다. 먼저 암세포주를 60 mm dish에 1×106 cell/dish로 세포를 분주하여 24시간 동안 배양한 후, Chlorella sp. JD002 추출물을 처리하였다. 이후, 세포를 24시간 동안 배양시키고, 부유 세포 및 트립신(trypsin)을 처리한 세포들을 모아서 4℃에서 2,000 rpm으로 5분간 원심분리 하였다. 원심분리 완료 후, 에탄올 1 ml을 넣고, 4℃에서 세포를 고정시켰다. 다시 4℃에서 2,000 rpm으로 2분간 원심분리하고, PBS 용액으로 수세한 후, propidium iodide/RNase staining buffer(BD pharmingen TM)를 500 μg/ml 첨가하고, 빛을 차단한 상태로 상온에서 30분간 염색(staining)시킨 후, flow cytometry caliber(BD)를 이용하여 세포주기를 분석하였다. 또한 대조군으로 상용 항암제인 시스플라틴(cisplatin)을 동일한 방법으로 실험하여 비교하였다. Chlorella sp. In order to examine the effect of the JD002 extract on apoptosis inhibition, Chlorella sp. The JD002 extract was treated with a flow cytometer to measure the number of sub-G1 cells expressing apoptotic cells. First, then divides the cells with 1 × 10 6 cell / dish a cancer cell in 60 mm dish for 24 hours, Chlorella sp. The JD002 extract was processed. Then, the cells were cultured for 24 hours, and the suspended cells and trypsin-treated cells were collected and centrifuged at 4 ° C at 2,000 rpm for 5 minutes. After completion of the centrifugation, 1 ml of ethanol was added and the cells were fixed at 4 ° C. After centrifugation at 2,000 rpm for 2 minutes at 4 ° C and washing with PBS, 500 μg / ml of propidium iodide / RNase staining buffer (BD pharmingen ™) was added and stained for 30 minutes at room temperature After staining, cell cycle was analyzed using flow cytometry caliber (BD). As a control group, cisplatin, a commercial anticancer drug, was also tested by the same method.
EtOAc를 이용한 Chlorella sp. JD002 추출물을 암세포에 농도별로 처리한 결과, 모든 암종에서 농도의존적으로 세포사멸이 증가된 것을 확인하였다(표 7 및 도 6). Chlorella using EtOAc sp. As a result of treating the extract of JD002 with various concentrations of cancer cells, it was confirmed that cell death was increased in a dose-dependent manner in all the carcinomas (Table 7 and FIG. 6).
3) 3) ChlorellaChlorella spsp . JD002. JD002 추출물의 암세포 전이(migration) 억제효과Effect of extract on cancer cell migration
Chlorella sp. JD002 추출물의 암세포 전이 억제효과를 확인하기 위하여, 전이가 활발하게 일어나는 배양한 유방암세포주(MDA-MB-231)을 이용하였다. 암세포 전이 억제효과는 Transwell cell culture chamber에서 MDA-MB-231 세포의 이동을 조사하는 방법으로 수행하였다. 보다 상세하게는, Transwell membrane의 아래쪽을 0.1% type A gelatin(15 μL)으로 코팅한 후, Transwell cell culture chamber의 아랫부분에 BSA를 첨가하고 Transwell membrane의 윗부분에는 MDA-MB-231와 Chlorella sp. JD002 추출물을 첨가하고, 37℃에서 4시간 동안 배양하였다. 4시간 배양 후, Transwell membrane 윗부분의 이동하지 않은 세포를 면봉으로 제거하고, polycarbonate filter를 통해 이동한 세포를 hematoxylin-eosin staining 방법으로 염색하였다. 이동된 세포의 수는 현미경(× 100)을 이용하여 정량하고 이를 비교하여 암세포 전이 억제효과를 측정하였다. 또한 대조군으로 상용 항암제인 시스플라틴(cisplatin)을 동일한 방법으로 실험하여 비교하였다. Chlorella sp. In order to confirm the inhibitory effect of the JD002 extract on cancer cell metastasis, a cultured breast cancer cell line (MDA-MB-231) in which metastasis occurred actively was used. The inhibitory effect of MDA-MB-231 cells in the transwell cell culture chamber was investigated. More specifically, BSA was added to the lower part of the Transwell cell culture chamber after coating the lower part of the Transwell membrane with 0.1% type A gelatin (15 μL). MDA-MB-231 and Chlorella sp. The JD002 extract was added and incubated at 37 [deg.] C for 4 hours. After 4 hours of incubation, the non-migrated cells on the upper part of the Transwell membrane were removed with a cotton swab, and cells moved through a polycarbonate filter were stained with hematoxylin-eosin staining method. The number of transferred cells was quantitated using a microscope (× 100), and the inhibitory effect of cancer cell metastasis was measured. As a control group, cisplatin, a commercial anticancer drug, was also tested by the same method.
분석결과, EtOAc를 이용한 Chlorella sp. JD002 추출물을 전이모델세포주인 MDA-MB-231에 농도별로 처리결과 농도의존적으로 전이가 억제되었다. 또한 양성대조군인 cisplatin과 비교하였을 때 유사한 전이 억제능을 가졌다(표 8 및 도 7). As a result, Chlorella sp. MDA-MB-231, a transgenic model cell line, resulted in a dose-dependent inhibition of the transfer of JD002 extract. And had similar inhibitory effects when compared to the positive control group cisplatin (Table 8 and Figure 7).
4) 4) ChlorellaChlorella spsp . JD002. JD002 추출물의 암세포 침윤(invasion) 억제효과Inhibitory effect of extract on invasion of cancer cells
Chlorella sp. JD002 추출물의 암세포 침윤 억제효과를 확인하기 위하여, 침윤이 활발하게 일어나는 유방암세포주(MDA-MB-231)을 이용하였다. 암세포 침윤 억제효과는 matrigel이 미리 코팅된 BD Matrigel Invasion Chamber를 사용하여 암세포 전이실험 방법에 준하는 방법으로 조사하였다. 상기 이동된 세포의 수는 현미경 (× 100)을 이용하여 정량하고 이를 비교하여 암세포 침윤 억제효과를 측정하였다. 또한 대조군으로 상용 항암제인 시스플라틴(cisplatin)을 동일한 방법으로 실험하여 비교하였다. Chlorella sp. To confirm the inhibitory effect of JD002 extract on cancer cell infiltration, a breast cancer cell line (MDA-MB-231) in which infiltration was active was used. The inhibition effect of cancer cell infiltration was investigated by a method similar to the method of cancer cell metastasis using BD Matrigel Invasion Chamber in which matrigel was precoated. The number of transferred cells was quantitated using a microscope (× 100), and the inhibitory effect against cancer cell infiltration was measured. As a control group, cisplatin, a commercial anticancer drug, was also tested by the same method.
분석결과, EtOAc를 이용한 Chlorella sp. JD002 추출물을 전이모델세포주인 MDA-MB-231에 농도별로 처리결과 농도의존적으로 침윤이 억제되었다. 또한 양성대조군인 cisplatin과 비교하였을 때 유사한 침윤 억제능을 가졌다(표 9 및 도 8). As a result of analysis, Chlorella sp. Treatment of MDA-MB-231 with the JD002 extract as a metastatic model cell line inhibited concentration-dependent infiltration. And had similar inhibition of infiltration when compared to the positive control, cisplatin (Table 9 and Figure 8).
5) 5) ChlorellaChlorella spsp . JD002 추출물의 암세포 부착(adhesion) 억제효과. Effect of JD002 extract on inhibition of cancer cell adhesion
Chlorella sp. JD002 추출물의 암세포 부착 억제효과를 확인하기 위하여, 암세포 부착이 활발하게 일어나는 유방암세포주(MDA-MB-231)을 이용하였다. 암세포 부착 억제효과는 human collagen type I이 미리 코팅된 CytoMatrixTM Cell Adhesion Strips(Chemicon)를 사용하여 측정하였으며, 측정은 제조회사에서 제시하는 방법에 따라 수행하였다. 보다 구체적으로, 플레이트(plate)를 PBS에 첨가하여 상온에서 15분간 재수화한 후, 재수화한 플레이트에서 PBS를 제거하고 배양한 세포를 분리한다. 분리된 세포를 다양한 농도의 (미세조류) 추출물이 첨가된 배양액에 1 × 105 cells/100 ㎕의 밀도로 첨가하여 플레이트에 분주하였다. 분주된 세포를 CO2 incubator에서 45분간 배양한 후, Ca2 +/Mg2 +를 포함한 PBS로 플레이트를 씻어내고(wash), 0.2% crystal violet solution으로 상온에서 5분간 염색하였다. 염색 후, PBS로 여러 번 씻어낸 후, solubilization buffer(0.1 mol/L NaH2PO4(pH 4.5): 50% EtOH(50:50))로 cell-bound stain을 완전히 용해시켰다. Cell-bound stain을 용해시킨 플레이트에 대해 570 nm에서 흡광도를 측정함으로써 세포의 부착능에 대한 (미세조류) 추출물의 저해효과를 확인하였다. 또한 대조군으로 상용 항암제인 시스플라틴(cisplatin)을 동일한 방법으로 실험하여 비교하였다. Chlorella sp. To confirm the inhibitory effect of JD002 extract on cancer cell adhesion, a breast cancer cell line (MDA-MB-231) in which cancer cell adhesion was active was used. The inhibitory effect on cancer cell adhesion was measured using CytoMatrix (TM) Cell Adhesion Strips (Chemicon) precoated with human collagen type I, and the measurement was carried out according to the method proposed by the manufacturer. More specifically, the plate is added to PBS, rehydrated at room temperature for 15 minutes, the PBS is removed from the rehydrated plate, and the cultured cells are separated. Separated cells were added to the culture medium to which various concentrations of (microalgae) extract had been added at a density of 1 x 10 5 cells / 100 μl and dispensed on a plate. By a frequency divider cell culture for 45 minutes at CO 2 incubator and then, Ca 2 + / Mg, wash the plates with PBS containing 2 + (wash), and stained for 5 minutes at room temperature with 0.2% crystal violet solution. After staining, the cell-bound stain was completely dissolved in a solubilization buffer (0.1 mol / L NaH2PO4 (pH 4.5): 50% EtOH (50:50)) several times with PBS. The inhibition of the cell adhesion activity (microalgae) extract was confirmed by measuring the absorbance at 570 nm on the plate in which the cell-bound stain was dissolved. As a control group, cisplatin, a commercial anticancer drug, was also tested by the same method.
분석결과, EtOAc를 이용한 Chlorella sp. JD002 추출물을 전이모델세포주인 MDA-MB-231에 농도별로 처리한 결과, 농도의존적으로 암세포 부착이 억제되는 것을 확인하였다. 또한 양성대조군인 cisplatin과 비교하였을 때, 유사한 암세포 부착 억제능을 가짐을 확인하였다(표 10 및 도 9). As a result, Chlorella sp. The JD002 extract was treated with MDA-MB-231, a metastatic model cell line, in a concentration-dependent manner. In addition, when compared with the positive control group, cisplatin, it was confirmed that they have a similar ability to inhibit cancer cell adhesion (Table 10 and Fig. 9).
6) 6) ChlorellaChlorella spsp . JD002. JD002 추출물의 전이효과 관련 Related to the transfer effect of extract mRNAmRNA 발현 저해효과 Expression inhibition effect
암세포의 이동, 침윤 및 부착과 관련된 단백질인 TIMP-2, VEGF, uPA, ICAM 및 Integrin-α2에 대한 발현억제효과를 다시 확인하기 위하여, 암세포의 이동, 침윤 및 부착과 관련된 단백질인 TIMP-2, VEGF, uPA, ICAM 및 Integrin-α2의 발현에 영향을 미치는 각 단백질의 mRNA 전사정도 즉, mRNA 함량의 변화를 GADPH 및 β-actin의 mRNA 함량과 대히한 수치를 대조군과 비교하는 방법으로 확인하였다. MDA-MB-231 세포를 serum starvation medium으로 24시간 동안 배양하였다. Serum starvation 후, 다양한 농도의 실시예 3에서 제조된 (미세조류) 추출물을 첨가한 후, 실시예 2의 방법으로 12시간 배양한 뒤, 상기 배양된 세포로부터 Qiagen RNase mini kit(Qiagen, Germany)를 사용하여 RNA를 분리(RNA isolation)하였다. 상기 RNA 분리는 상기 kit에서 제공되는 방법(protocol)으로 수행하였다. 상기 방법으로 분리된 RNA 3 μg에 Superscript II reverse transcriptase(Invitrogen, USA)를 첨가하고 42℃에서 1시간 45분 동안 incubation한 후, 70℃에서 15분 동안 incubation하여, cDNA를 수득하였다. 상기 수득한 cDNA는 real-time PCR(BioER, China)로 정량 하였다. 상기 real-time PCR을 수행하기 위한 Primer의 서열과 실험조건은 하기 표 11에 기재하였다. Real-time PCR 결과는 β-actin 대비 mRNA 량으로 환산한 후, 대조군 대비 함량으로 표시하여 나타내었다. 또한 대조군으로 상용 항암제인 시스플라틴(cisplatin)을 동일한 방법으로 실험하여 비교하였다.2, TIMP-2, VEGF, uPA, ICAM and Integrin-α2, which are proteins involved in the migration, invasion and adhesion of cancer cells, The level of mRNA transcription, that is, the mRNA level of each protein, which affects the expression of VEGF, uPA, ICAM and Integrin-α2, was compared with the level of mRNA of GADPH and β-actin compared with the control group. MDA-MB-231 cells were cultured in serum starvation medium for 24 hours. After serum starvation, various concentrations of the extract prepared in Example 3 (microalgae) were added and cultured for 12 hours in the same manner as in Example 2. Then, Qiagen RNase mini kit (Qiagen, Germany) The RNA was isolated using the RNA isolation method. The RNA isolation was performed by the protocol provided in the kit. Superscript II reverse transcriptase (Invitrogen, USA) was added to 3 μg of RNA isolated by the above method, incubated at 42 ° C for 1 hour and 45 minutes, and incubated at 70 ° C for 15 minutes to obtain cDNA. The obtained cDNA was quantified by real-time PCR (BioER, China). The sequences of the primers for performing the real-time PCR and the experimental conditions are shown in Table 11 below. Real-time PCR results were expressed as the amount of mRNA versus β-actin and then expressed as the content of the control. As a control group, cisplatin, a commercial anticancer drug, was also tested by the same method.
분석결과, EtOAc를 이용한 Chlorella sp. JD002 추출물을 전이모델세포주인 MDA-MB-231에 농도별로 처리한 결과, 농도의존적으로 전이관련 유전자(VEGF, uPA, ICAM, Integrin-α2, MMP-9)의 mRNA발현이 억제되는 것을 확인하였다. 또한 양성대조군인 cisplatin과 비교하였을 때 유사한 VEGF, uPA, ICAM, Integrin-α2, MMP-9의 mRNA 발현 억제능을 가짐을 확인하였다(표 12 및 도 10). As a result, Chlorella sp. MDA-MB-231, a transgenic model cell line, was found to inhibit mRNA expression of transcription-related genes (VEGF, uPA, ICAM, Integrin-α2 and MMP-9) in a concentration-dependent manner. In addition, it was confirmed that mRNA expression of VEGF, uPA, ICAM, Integrin-α2 and MMP-9 was inhibited when compared with the positive control group, cisplatin (Table 12 and FIG. 10).
<110> Korea Research Institute of Bioscience and Biotechnology Konkuk University Industrial Cooperation Corp <120> PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF CANCERS OR INHIBITION OF METASTASIS CONTAINING EXTRACT OF CHLORELLA SP. <130> P15R16D0022 <160> 20 <170> KopatentIn 2.0 <210> 1 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Green Algae_ch165F <400> 1 cgacttctgg aagggacgta 20 <210> 2 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Green Algae_ch1200R <400> 2 gagtcaaatt aagccgcagg 20 <210> 3 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Green Algae_ch1155F <400> 3 cctgcggctt aatttgactc 20 <210> 4 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Green Algae_ch1780R <400> 4 ctaggtggga gggtttaatg 20 <210> 5 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> Cyanobacteria_27F <400> 5 gagtttgatc ctggctcag 19 <210> 6 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Cyanobacteria_1542R <400> 6 agaaaggagg tgatccagcg 20 <210> 7 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Diatom_D514F <400> 7 attccagctc caatagcg 18 <210> 8 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Diatom_D987R <400> 8 gactacgatg gtatctaatc 20 <210> 9 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> VEGF_sense <400> 9 atgccaagtg gtcccaggct 20 <210> 10 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> VEGF_anti-sense <400> 10 cagggtctcg attggatggc 20 <210> 11 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> uPA_sense <400> 11 gccatctaca caggaggcac cg 22 <210> 12 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> uPA_anti-sense <400> 12 gggtaatcaa tgaagcagtg tg 22 <210> 13 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> ICAM_sense <400> 13 gccggccagc ttatacacaa 20 <210> 14 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> ICAM_anti-sense <400> 14 caatccctct gtccagtcg 19 <210> 15 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> Intergrin-alpha2_sense <400> 15 gcacagcaat gtgggaatc 19 <210> 16 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> Intergrin-alpha2_anti-sense <400> 16 ggctgagttg caggtgaga 19 <210> 17 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> MMP9_sense <400> 17 gctcttccct ggagacctg 19 <210> 18 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> MMP9_anti-sense <400> 18 tttcgactct ccacgcatc 19 <210> 19 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> beta-actin_sense <400> 19 gagccgtgtt tccttccat 19 <210> 20 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> beta-actin_anti-sense <400> 20 gtcccagttg gtgacgatg 19 <110> Korea Research Institute of Bioscience and Biotechnology Konkuk University Industrial Cooperation Corp <120> PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF CANCERS OR INHIBITION OF METASTASIS CONTAINING EXTRACT OF CHLORELLA SP. <130> P15R16D0022 <160> 20 <170> Kopatentin 2.0 <210> 1 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Green Algae_ch165F <400> 1 cgacttctgg aagggacgta 20 <210> 2 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Green Algae_ch1200R <400> 2 gagtcaaatt aagccgcagg 20 <210> 3 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Green Algae_ch1155F <400> 3 cctgcggctt aatttgactc 20 <210> 4 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Green Algae_ch1780R <400> 4 ctaggtggga gggtttaatg 20 <210> 5 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> Cyanobacteria_27F <400> 5 gagtttgatc ctggctcag 19 <210> 6 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Cyanobacteria 1542R <400> 6 agaaaggagg tgatccagcg 20 <210> 7 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Diatom_D514F <400> 7 attccagctc caatagcg 18 <210> 8 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Diatom_D987R <400> 8 gactacgatg gtatctaatc 20 <210> 9 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> VEGF_sense <400> 9 atgccaagtg gtcccaggct 20 <210> 10 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> VEGF_anti-sense <400> 10 cagggtctcg attggatggc 20 <210> 11 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> uPA_sense <400> 11 gccatctaca caggaggcac cg 22 <210> 12 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> uPA_anti-sense <400> 12 gggtaatcaa tgaagcagtg tg 22 <210> 13 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> ICAM_sense <400> 13 gccggccagc ttatacacaa 20 <210> 14 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> ICAM_anti-sense <400> 14 caatccctct gtccagtcg 19 <210> 15 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> Intergrin-alpha2_sense <400> 15 gcacagcaat gtgggaatc 19 <210> 16 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> Intergrin-alpha2_anti-sense <400> 16 ggctgagttg caggtgaga 19 <210> 17 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> MMP9_sense <400> 17 gctcttccct ggagacctg 19 <210> 18 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> MMP9_anti-sense <400> 18 tttcgactct ccacgcatc 19 <210> 19 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> beta-actin_sense <400> 19 gagccgtgtt tccttccat 19 <210> 20 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> beta-actin_anti-sense <400> 20 gtcccagttg gtgacgatg 19
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As Chlorella genus (chlorella sp.) Cancer prevention, treatment, or inhibition of metastasis pharmaceutical composition containing the ethyl acetate extract of microalgae JD002 (KCTC18352P) as an active ingredient, wherein the cancer is selected from the group consisting of malignant melanoma, and brain tumors Or a pharmaceutically acceptable salt thereof.
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| KR101428486B1 (en) | 2012-12-18 | 2014-08-12 | 대구가톨릭대학교산학협력단 | Method for producing chlorella extract with improved functionality using supercritical fluid extraction technique |
Non-Patent Citations (1)
| Title |
|---|
| Journal of Functional Foods, 2012, 제4권, 페이지 302-310* |
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| KR20170021959A (en) | 2017-03-02 |
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