KR102269844B1 - Composition for preventing, treating, or improving cancer comprising erybraedin A - Google Patents
Composition for preventing, treating, or improving cancer comprising erybraedin A Download PDFInfo
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- KR102269844B1 KR102269844B1 KR1020180088056A KR20180088056A KR102269844B1 KR 102269844 B1 KR102269844 B1 KR 102269844B1 KR 1020180088056 A KR1020180088056 A KR 1020180088056A KR 20180088056 A KR20180088056 A KR 20180088056A KR 102269844 B1 KR102269844 B1 KR 102269844B1
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- erybraedin
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Abstract
본 발명은 에리브라에딘 A(erybraedin A)를 유효성분으로 포함하는 암의 예방, 치료, 또는 개선용 조성물에 관한 것으로, 본 발명에 따른 에리브라에딘 A(erybraedin A)는 Src 단백질과의 상호작용을 통한 Src 활성화 억제 작용을 통하여 암세포의 성장 및 전이를 억제하고 세포자멸(apoptosis)을 유도하며, 암세포가 세포외 기질인 피브로넥틴(fibronectin)에 접착하는 것을 억제하는 효과가 있다. 또한, 상기 에리브라에딘 A(erybraedin A)는 천연물 유래 화합물로, 독성이 없고 안정성이 높아 암의 예방, 치료, 또는 개선을 위한 약학적 조성물 또는 식품 조성물 등으로 유용하게 이용될 것으로 기대된다.The present invention relates to a composition for preventing, treating, or improving cancer comprising erybraedin A as an active ingredient, wherein erybraedin A according to the present invention is associated with Src protein It has the effect of inhibiting the growth and metastasis of cancer cells, inducing apoptosis, and inhibiting the adhesion of cancer cells to the extracellular matrix, fibronectin, by inhibiting Src activation through interaction. In addition, the erybraedin A (erybraedin A) is a compound derived from a natural product, has no toxicity and has high stability, so it is expected to be usefully used as a pharmaceutical composition or a food composition for the prevention, treatment, or improvement of cancer.
Description
본 발명은 에리브라에딘 A(erybraedin A)를 유효성분으로 포함하는 암의 예방, 치료, 또는 개선용 조성물 등에 관한 것이다.The present invention relates to a composition for preventing, treating, or improving cancer comprising erybraedin A as an active ingredient.
암은 국민건강에 가장 큰 위협요인으로 대두되고 있으며, 고령화를 비롯하여 다양한 환경의 변화로 인해 암으로 인한 건강의 위협 및 사망은 더욱 증가될 것으로 보인다. 특히, 폐암은 5년 생존율이 20%에 불과한 난치암으로 사망률 1위의 질환이다. 폐암의 높은 사망률은 다수의 환자가 전이암이 발생된 3기 이상에서 발견되어, 수술이 제한적이고 항암 치료에 대한 내성으로 인한 재발이 흔하기 때문이다. Cancer is emerging as the biggest threat to public health, and the threat to health and death due to cancer is expected to increase further due to aging and other changes in the environment. In particular, lung cancer is the most incurable cancer with a 5-year survival rate of only 20%, and is the leading cause of death. The high mortality rate of lung cancer is because many patients are found at
현재 화학항암제, 표적항암제, 면역항암요법이 폐암 치료에 사용되고 있는데 이들은 치료 효과가 미약하거나 초기에 우수한 치료 효과를 나타낸 경우에도 내성으로 인한 치료 효과 저하 및 암 재발이 유도되므로, 이를 극복할 수 있는 효과적인 치료법 및 효능 물질 개발이 필요하다.Currently, chemotherapy, targeted chemotherapy, and immunotherapy are being used to treat lung cancer. Even when the therapeutic effect is weak or shows an excellent therapeutic effect at an early stage, the therapeutic effect decreases due to resistance and cancer recurrence is induced. There is a need to develop therapeutics and effective substances.
한편, 티로신 키나아제(Tyrosine kinase; TK)는 ATP로부터 하나의 인산기를 티로신의 하이드록시페닐(hydroxyphenyl)기에 전달하는 효소의 일종이다. 티로신 키나아제들은 정상세포의 성장에 중요한 역할을 하며 이는 직접적으로 세포의 신호 전달과정에 참여한다.On the other hand, tyrosine kinase (Tyrosine kinase; TK) is a kind of enzyme that transfers one phosphate group from ATP to the hydroxyphenyl group of tyrosine. Tyrosine kinases play an important role in the growth of normal cells, and they participate directly in cellular signal transduction.
일반적으로, 외부의 자극을 세포가 인지하는 방법 중의 하나로서 세포막에 있는 수용체인 티로신 키나아제(tyrosine kinase)류를 통한 인지가 알려져 있다. 수용체 티로신 키나아제(RTK)는 세포 밖에 노출된 세포 외 부분, 세포 내 사이토졸에 노출된 세포 내 부분 및 그 중간에 위치하는 원형질막을 통과하는 막 통과 부분으로 구성되어 있다. 수용체의 세포 외 부분은 특정 리간드가 결합하는 부분이며, 세포 내 부분은 리간드에 의하여 활성화된 수용체의 활성 신호를 세포 내로 전달하는 기능을 수행한다.In general, as one of the methods for cells to recognize external stimuli, recognition through tyrosine kinases, which are receptors on cell membranes, is known. Receptor tyrosine kinase (RTK) consists of an extracellular portion exposed to the outside of the cell, an intracellular portion exposed to the intracellular cytosol, and a transmembrane portion that passes through the plasma membrane located in the middle. The extracellular part of the receptor is a part to which a specific ligand binds, and the intracellular part performs a function of transmitting the activation signal of the receptor activated by the ligand into the cell.
Src는 비수용체 티로신 키나아제(non-receptor tyrosine kinase)로서 여러 receptor tyrosine kinase 및 세포 또는 세포 외 기질 접착에 의해 활성화되는 인자이며, 세포주기, 세포흡착과 세포이동, 증식 및 분화에 작용할 뿐만 아니라, 림포카인(lymphokine)을 매개로 하는 세포생존과 VEGF가 유도하는 혈관신생에도 관여하고, 정상세포의 형질전환 및 암세포 성장, 전이, 부착, 침윤을 촉진하여 표적 항암제 개발의 주요 타깃이 되고 있다. Src 활성은 대부분의 인체 암: 유방암, 위암, 결장암, 모발상세포 백혈병 및 B-세포 림프종의 아족, 하급 사람 방광암종, 신경모세포종, 난소암, 비-소세포암종 등에서 급격하게 증가한다. Src is a non-receptor tyrosine kinase that is activated by several receptor tyrosine kinases and cell or extracellular matrix adhesion. It is also involved in lymphokine-mediated cell survival and VEGF-induced angiogenesis, and is a major target in the development of targeted anticancer drugs by promoting transformation of normal cells and growth, metastasis, adhesion, and invasion of cancer cells. Src activity is sharply increased in most human cancers: breast cancer, gastric cancer, colon cancer, hairy cell leukemia and subfamily of B-cell lymphoma, lower human bladder carcinoma, neuroblastoma, ovarian cancer, non-small cell carcinoma, etc.
현재 Src를 억제하는 표적 항암제가 임상 사용 중이나 다른 kinase에 대한 선택성 저하 및 조혈기계 독성 등의 부작용이 문제가 되고 있어, 이를 극복할 수 있는 Src 억제제 개발이 필요한 실정이다. Currently, targeted anticancer drugs that inhibit Src are in clinical use, but side effects such as reduced selectivity to other kinases and hematopoietic toxicity are a problem, so it is necessary to develop an Src inhibitor that can overcome them.
본 발명자들은 상기와 같은 종래의 항암제에 대한 문제점을 해결할 수 있는 방법을 개발하기 위해 연구한 결과, 천연물 유래 화합물인 에리브라에딘 A(erybraedin A)가 Src를 억제함으로써 암세포의 성장 및 전이를 억제하고 세포자멸(apoptosis)을 유도하며, 암세포가 피브로넥틴에 접착하는 것을 억제하는 효과를 나타냄을 확인하였다.The present inventors have studied to develop a method to solve the problems of conventional anticancer drugs as described above. As a result, erybraedin A, a compound derived from a natural product, inhibits Src, thereby inhibiting the growth and metastasis of cancer cells. It was confirmed that it induces apoptosis and inhibits the adhesion of cancer cells to fibronectin.
이에, 본 발명의 목적은 에리브라에딘 A(erybraedin A)를 유효성분으로 포함하는 암의 예방, 치료, 또는 개선용 조성물을 제공하는 것이다.Accordingly, an object of the present invention is to provide a composition for preventing, treating, or improving cancer comprising erybraedin A as an active ingredient.
그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당해 기술분야의 통상의 기술자에게 명확하게 이해될 수 있을 것이다.However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problems, and other problems not mentioned will be clearly understood by those skilled in the art from the following description.
상기와 같은 목적을 달성하기 위하여, 본 발명은 에리브라에딘 A(erybraedin A)를 유효성분으로 포함하는 암의 예방 또는 치료용 약학적 조성물을 제공한다.In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating cancer comprising erybraedin A as an active ingredient.
또한, 본 발명은 에리브라에딘 A(erybraedin A)를 유효성분으로 포함하는 암의 예방 또는 개선용 식품 조성물을 제공한다.In addition, the present invention provides a food composition for preventing or improving cancer comprising erybraedin A (erybraedin A) as an active ingredient.
본 발명의 일구현예로, 상기 암은 갑상선암, 자궁경부암, 뇌암, 폐암, 난소암, 간암, 췌장암, 전립선암, 피부암, 혀암, 유방암, 자궁암, 위암, 직장암, 대장암, 혈액암, 및 결장암으로 이루어지는 군으로부터 선택되는 하나 이상일 수 있다.In one embodiment of the present invention, the cancer is thyroid cancer, cervical cancer, brain cancer, lung cancer, ovarian cancer, liver cancer, pancreatic cancer, prostate cancer, skin cancer, tongue cancer, breast cancer, uterine cancer, stomach cancer, rectal cancer, colorectal cancer, blood cancer, and colon cancer It may be one or more selected from the group consisting of.
본 발명의 다른 구현예로, 상기 식품 조성물은 건강기능식품 조성물일 수 있다.In another embodiment of the present invention, the food composition may be a health functional food composition.
본 발명의 또 다른 구현예로, 상기 조성물은 비수용체 티로신 키나아제인 Src를 억제할 수 있다.In another embodiment of the present invention, the composition may inhibit Src, which is a non-receptor tyrosine kinase.
본 발명의 또 다른 구현예로, 상기 조성물은 Src와 인테그린β1 또는 인테그린β3와의 상호작용을 억제할 수 있다.In another embodiment of the present invention, the composition may inhibit the interaction of Src with integrin β1 or integrin β3.
본 발명의 또 다른 구현예로, 상기 조성물은 Src의 ATP-결합 포켓 및 알로스테릭 조절 부위와 상호작용할 수 있다.In another embodiment of the present invention, the composition is capable of interacting with the ATP-binding pocket and allosteric regulatory site of Src.
본 발명의 또 다른 구현예로, 상기 조성물은 암세포 성장 억제, 콜로니 생성 억제, 또는 세포 자멸(apoptosis) 유도 작용을 할 수 있다.In another embodiment of the present invention, the composition may inhibit cancer cell growth, inhibit colony production, or induce apoptosis.
본 발명의 또 다른 구현예로, 상기 조성물은 암세포의 세포외 기질에의 접착을 억제할 수 있다.In another embodiment of the present invention, the composition may inhibit the adhesion of cancer cells to the extracellular matrix.
본 발명의 또 다른 구현예로, 상기 세포외 기질은 피브로넥틴(fibronectin)일 수 있다.In another embodiment of the present invention, the extracellular matrix may be fibronectin.
또한, 본 발명은 상기 약학적 조성물을 개체에 투여하는 단계를 포함하는 암의 예방 또는 치료 방법을 제공한다.In addition, the present invention provides a method for preventing or treating cancer comprising administering the pharmaceutical composition to a subject.
또한, 본 발명은 상기 약학적 조성물의 암 예방 또는 치료 용도를 제공한다.In addition, the present invention provides the use of the pharmaceutical composition for preventing or treating cancer.
본 발명에 따른 에리브라에딘 A(erybraedin A)는 Src 단백질과의 상호작용을 통한 Src 활성화 억제 작용을 통하여 암세포의 성장 및 전이를 억제하고 세포자멸(apoptosis)을 유도하며, 암세포가 세포외 기질인 피브로넥틴(fibronectin)에 접착하는 것을 억제하는 효과가 있다. 또한, 상기 에리브라에딘 A(erybraedin A)는 천연물 유래 화합물로, 독성이 없고 안정성이 높아 암의 예방, 치료, 또는 개선을 위한 약학적 조성물 또는 식품 조성물 등으로 유용하게 이용될 것으로 기대된다.According to the present invention, erybraedin A (erybraedin A) inhibits the growth and metastasis of cancer cells and induces apoptosis through Src activation inhibition through interaction with Src protein, It has the effect of inhibiting adhesion to fibronectin. In addition, the erybraedin A (erybraedin A) is a compound derived from a natural product, has no toxicity and has high stability, so it is expected to be usefully used as a pharmaceutical composition or a food composition for the prevention, treatment, or improvement of cancer.
도 1은 본 발명의 일구현예에 따른 erybraedin A의 구조를 나타낸 도면이다.
도 2는 본 발명의 일구현예에 따른 폐암세포의 피브로넥틴에의 접착에 대한 erybraedin A의 억제 효과를 나타낸 도면이다.
도 3은 본 발명의 일구현예에 따른 폐암세포의 피브로넥틴에의 접착에 대한 erybraedin A의 농도 의존적인 억제 효과를 나타낸 도면이다.
도 4는 도 3과 동일한 실험 조건에서 본 발명의 일구현예에 따른 폐암세포의 viability에 대한 erybraedin A의 영향을 나타낸 도면이다.
도 5는 본 발명의 일구현예에 따른 erybraedin A의 Src 및 하위 신호전달의 인산화 억제 효과를 나타낸 도면이다.
도 6은 본 발명의 일구현예에 따른 Src와 integrin β1 또는 integrin β3와의 상호작용에 대한 erybraedin A의 억제 효과를 나타낸 도면이다.
도 7은 본 발명의 일구현예에 따른 erybraedin A가 Src의 ATP-결합 포켓 및 알로스테릭 조절 부위에 결합할 수 있음을 예측하는 분자모델링을 나타낸 도면이다.
도 8은 본 발명의 일구현예에 따른 폐암세포의 viability에 대한 erybraedin A의 농도 의존적인 억제 효과를 나타낸 도면이다.
도 9는 본 발명의 일구현예에 따른 폐암세포의 anchorage 의존적/비의존적 배양 조건에서의 colony 형성에 대한 erybraedin A의 농도 의존적인 억제 효과를 나타낸 도면이다.
도 10은 본 발명의 일구현예에 따른 erybraedin A의 폐암세포 사멸 유도 효과를 나타낸 도면이다.
도 11은 본 발명의 일구현예에 따른 erybraedin A에 의한 PARP cleavage 증가를 확인한 결과를 나타낸 도면이다.1 is a view showing the structure of erybraedin A according to an embodiment of the present invention.
2 is a diagram showing the inhibitory effect of erybraedin A on the adhesion of lung cancer cells to fibronectin according to an embodiment of the present invention.
3 is a diagram showing the concentration-dependent inhibitory effect of erybraedin A on the adhesion of lung cancer cells to fibronectin according to an embodiment of the present invention.
4 is a diagram showing the effect of erybraedin A on the viability of lung cancer cells according to an embodiment of the present invention under the same experimental conditions as FIG. 3 .
5 is a diagram showing the phosphorylation inhibitory effect of Src and sub-signaling of erybraedin A according to an embodiment of the present invention.
6 is a diagram showing the inhibitory effect of erybraedin A on the interaction between Src and integrin β1 or integrin β3 according to an embodiment of the present invention.
7 is a view showing molecular modeling predicting that erybraedin A can bind to the ATP-binding pocket and allosteric regulatory region of Src according to an embodiment of the present invention.
8 is a diagram showing the concentration-dependent inhibitory effect of erybraedin A on the viability of lung cancer cells according to an embodiment of the present invention.
9 is a diagram showing the concentration-dependent inhibitory effect of erybraedin A on colony formation in anchorage-dependent/independent culture conditions of lung cancer cells according to an embodiment of the present invention.
10 is a view showing the lung cancer cell death inducing effect of erybraedin A according to an embodiment of the present invention.
11 is a view showing the results of confirming the increase in PARP cleavage by erybraedin A according to an embodiment of the present invention.
본 발명은 다양한 변환을 가할 수 있고 여러 가지 실시예를 가질 수 있는 바, 특정 실시예들을 도면에 예시하고 상세한 설명에 상세하게 설명하고자 한다. 그러나, 이는 본 발명을 특정한 실시 형태에 대해 한정하려는 것이 아니며, 본 발명의 사상 및 기술 범위에 포함되는 모든 변환, 균등물 내지 대체물을 포함하는 것으로 이해되어야 한다. 본 발명을 설명함에 있어서 관련된 공지 기술에 대한 구체적인 설명이 본 발명의 요지를 흐릴 수 있다고 판단되는 경우 그 상세한 설명을 생략한다.Since the present invention can apply various transformations and can have various embodiments, specific embodiments are illustrated in the drawings and described in detail in the detailed description. However, this is not intended to limit the present invention to specific embodiments, and it should be understood to include all modifications, equivalents and substitutes included in the spirit and scope of the present invention. In describing the present invention, if it is determined that a detailed description of a related known technology may obscure the gist of the present invention, the detailed description thereof will be omitted.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 에리브라에딘 A(erybraedin A)를 유효성분으로 포함하는 암의 예방 또는 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating cancer comprising erybraedin A as an active ingredient.
본 발명에서 상기 에리브라에딘 A(erybraedin A) [4,10-bis(3-methylbut-2-enyl)-6a,11a-dihydro-6H-[1]benzofuro[3,2-c]chromene-3,9-diol]의 구조는 도 1에 나타낸 바와 같다. In the present invention, the erybraedin A [4,10-bis(3-methylbut-2-enyl)-6a,11a-dihydro-6H-[1]benzofuro[3,2-c]chromene- 3,9-diol] is as shown in FIG. 1 .
본 발명에서 사용되는 용어 "암"은 세포가 정상적인 성장 한계를 무시하고 분열 및 성장하는 공격적(aggressive) 특성, 주위 조직에 침투하는 침투적(invasive) 특성, 및 체내의 다른 부위로 퍼지는 전이적(metastatic) 특성을 갖는 세포에 의한 질병을 총칭하는 의미이다.As used herein, the term “cancer” refers to an aggressive characteristic in which cells divide and grow ignoring the normal growth limit, an invasive characteristic that penetrates into surrounding tissues, and a metastatic (cancerous) characteristic that spreads to other parts of the body. Metastatic) refers to diseases caused by cells with characteristics.
본 발명에 있어서, 상기 암의 종류에는 제한이 없으며, 갑상선암, 자궁경부암, 뇌암, 폐암, 난소암, 간암, 췌장암, 전립선암, 피부암, 혀암, 유방암, 자궁암, 위암, 직장암, 대장암, 혈액암, 및 결장암으로 이루어지는 군으로부터 선택되는 하나 이상일 수 있고, 본 발명의 일 실시예에 따르면 상기 암은 폐암일 수 있으나, 이에 제한되지 않는다. In the present invention, the type of cancer is not limited, and thyroid cancer, cervical cancer, brain cancer, lung cancer, ovarian cancer, liver cancer, pancreatic cancer, prostate cancer, skin cancer, tongue cancer, breast cancer, uterine cancer, stomach cancer, rectal cancer, colon cancer, blood cancer , and may be at least one selected from the group consisting of colon cancer, and according to an embodiment of the present invention, the cancer may be lung cancer, but is not limited thereto.
본 발명에서 사용되는 용어 "폐암"은 폐에 생긴 악성 종양을 말하며, 전 세계적으로 암으로 인한 사망 원인의 20~30%를 차지하고 있어 암으로 인한 사망의 주요 원인 중의 하나이다. 폐암은 암세포의 크기와 형태 등 병리조직학적 기준에 따라 소세포폐암과 비소세포폐암으로 나뉘는데, 이 중 전체 폐암의 80% 이상이 비소세포폐암(non-small cell lung cancer, NSCLC)이며, 비소세포암에는 편평상피세포암, 선암, 대세포암, 선(腺)편평세포암, 육종양암, 카르시노이드 종양, 침샘형암, 미분류암 등이 있다.As used herein, the term “lung cancer” refers to a malignant tumor in the lungs, and accounts for 20 to 30% of cancer-related deaths worldwide, and is one of the main causes of cancer-related deaths. Lung cancer is divided into small cell lung cancer and non-small cell lung cancer according to histopathological criteria such as the size and shape of cancer cells. Of these, more than 80% of all lung cancers are non-small cell lung cancer (NSCLC), and non-small cell lung cancer is These include squamous cell carcinoma, adenocarcinoma, large cell carcinoma, adeno squamous cell carcinoma, sarcoma, carcinoid tumor, salivary gland carcinoma, and unclassified carcinoma.
본 발명에서 사용되는 용어 "예방"은 본 발명에 따른 약학적 조성물의 투여에 의해 암을 억제시키거나 발병을 지연시키는 모든 행위를 의미한다.As used herein, the term “prevention” refers to any action of inhibiting or delaying the onset of cancer by administering the pharmaceutical composition according to the present invention.
본 발명에서 사용되는 용어 "치료"는 본 발명에 따른 약학적 조성물의 투여에 의해 암에 대한 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다.As used herein, the term “treatment” refers to any action in which symptoms for cancer are improved or beneficially changed by administration of the pharmaceutical composition according to the present invention.
본 발명에서 사용되는 용어 "약학적 조성물"은 암의 예방 또는 치료를 목적으로 제조된 것을 의미하며, 각각 통상의 방법에 따라 다양한 형태로 제형화하여 사용될 수 있다. 예컨대, 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽 등의 경구형 제형으로 제형화할 수 있고, 크림, 젤, 패취, 분무제, 연고제, 경고제, 로션제, 리니멘트제, 파스타제 또는 카타플라스마제 등의 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용할 수 있다.The term "pharmaceutical composition" used in the present invention means one prepared for the purpose of preventing or treating cancer, and may be formulated in various forms according to a conventional method, respectively. For example, it can be formulated in oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, creams, gels, patches, sprays, ointments, warnings, lotions, liniments, pastas, or It can be formulated and used in the form of external preparations such as cataplasma, suppositories, and sterile injection solutions.
본 발명에 따른 약학적 조성물은 약학적 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제 및 희석제를 더 포함할 수 있다. 이 때, 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 올리고당, 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. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 추출물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스티레이트 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜 (propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈 (tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.The pharmaceutical composition according to the present invention may further include suitable carriers, excipients and diluents commonly used in the preparation of pharmaceutical compositions. In this case, carriers, excipients and diluents that may be included in the composition include lactose, dextrose, sucrose, oligosaccharides, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In the case of formulation, it is prepared using diluents or excipients, such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient in the extract, for example, starch, calcium carbonate, sucrose ) or lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate talc are also used. Liquid formulations for oral use include suspensions, solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients, for example, wetting agents, sweeteners, fragrances, preservatives, etc. may be included. . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As a base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like can be used.
본 발명의 약학적 조성물은 목적하는 방법에 따라 경구 투여하거나 비경구투여(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.The pharmaceutical composition of the present invention may be administered orally or parenterally (eg, intravenously, subcutaneously, intraperitoneally or topically) according to a desired method, and the dosage may vary depending on the condition and weight of the patient, and the disease. Although it varies depending on the degree, drug form, administration route and time, it may be appropriately selected by those skilled in the art.
본 발명의 약학적 조성물은 약학적으로 유효한 양으로 투여한다. 본 발명에 있어서 "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효용량 수준은 환자의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명에 따른 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is determined by the type, severity of the patient's disease, the activity of the drug, Sensitivity to the drug, administration time, administration route and excretion rate, treatment period, factors including concurrent drugs and other factors well known in the medical field may be determined. The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered single or multiple. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, which can be easily determined by those skilled in the art. Administration may be administered once a day, or may be administered in several divided doses.
본 발명에서 상기 조성물은 비수용체 티로신 키나아제인 Src를 억제할 수 있다.In the present invention, the composition may inhibit Src, which is a non-receptor tyrosine kinase.
본 발명에 있어서 상기 "Src"는 세포막과 결합된 단백질 티로신 키나아제(PTK)로서, 신호 전달과 성장 조절 경로에 관여하며, ATP의 감마 인산염을 기질 단백질에서 티로신 잔기의 측쇄에 전달함으로써 세포 신호를 전파한다. Src 단백질 티로신 키나아제 계통군의 구성원으로는 Src, Yes, Fyn, Fgr, Blk, Lck, Lyn, Hck 등이 있다. In the present invention, the "Src" is a cell membrane-bound protein tyrosine kinase (PTK), which is involved in signal transduction and growth regulation pathways, and propagates cell signals by transferring gamma phosphate of ATP to the side chain of tyrosine residues in the substrate protein. do. Members of the Src protein tyrosine kinase family include Src, Yes, Fyn, Fgr, Blk, Lck, Lyn, and Hck.
본 발명에서 상기 조성물은 Src와 인테그린(integrin)β1 또는 인테그린(integrin)β3와의 상호작용을 억제할 수 있다.In the present invention, the composition may inhibit the interaction between Src and integrin β1 or integrin β3.
본 발명에서 사용되는 용어 "인테그린(integrin)"은 세포막 수용체에서 세포 외 기질 단백질과 결합하는 수용체로, αβ 형태의 heterodimer로 구성된 세포막 단백으로서 세포 외 기질단백 또는 다른 세포막 단백을 인식하는 수용체로 작용한다. 인테그린은 24 종류의 αβ 서브유닛의 조합에 의해 α5β1, αIIbβ3, αVβ3, αVβ5 등 다 양한 종류의 서브유닛이 존재하며 기질 외 단백과의 결합 이후 세포 내 신호전달 경로를 통해 세포 부착 및 이동, 증식 또는 분화를 유도하고 혈관 생성과 종양 전이에 참여한다.As used herein, the term "integrin" is a receptor that binds to an extracellular matrix protein at a cell membrane receptor, a cell membrane protein composed of an αβ heterodimer, and acts as a receptor for recognizing extracellular matrix protein or other cell membrane proteins . Various types of subunits such as α5β1, αIIbβ3, αVβ3, and αVβ5 exist due to the combination of 24 types of αβ subunits. After binding to extracellular proteins, integrins can be attached to cells, migrated, proliferated, or transformed through intracellular signaling pathways. It induces differentiation and participates in angiogenesis and tumor metastasis.
본 발명에서 상기 조성물은 Src의 ATP-결합 포켓 및 알로스테릭 조절 부위와 상호작용할 수 있다.In the present invention, the composition can interact with the ATP-binding pocket and allosteric regulatory region of Src.
본 발명에서 상기 조성물은 암세포 성장 억제, 콜로니 생성 억제, 또는 세포 자멸(apoptosis) 유도 작용을 할 수 있다.In the present invention, the composition may inhibit cancer cell growth, inhibit colony production, or induce apoptosis.
본 발명에서 사용되는 용어 "세포자멸(apoptosis)"은 생리적 조건하에서 세포 스스로가 적극적으로 일으키는 세포사이며, 환경악화에 의한 세포사(괴사: necrosis)와 명확하게 구별되고 있다. 이 세포자멸은 세포핵의 염색체응집, 세포핵의 단편화, 세포 표층 미융모(microvillus)의 소실, 세포질의 응집 등을 형태학적인 특징으로 하고있다. 세포자멸이 일어나는 세포는 위축(atrophy)되고, 세포 내용물은 외부에 방출되지 않고 마크로파아지 또는 주위의 세포에 신속하게 합입되기 때문에, 염증이 일어나지 않고 주위의 세포에 영향을 주지 않는다. 따라서, 그 존재가 숙주생물에 있어서 유해한 세포(예를 들어, 암세포 등)에 세포자멸을 유도하여 질환을 치료하는 시도가 많아지고 있다.The term "apoptosis" used in the present invention is a cell death that is actively caused by cells themselves under physiological conditions, and is clearly distinguished from cell death (necrosis) caused by environmental deterioration. This apoptosis is characterized by morphological features such as chromosome aggregation of the cell nucleus, fragmentation of the cell nucleus, loss of the cell surface microvillus, and aggregation of the cytoplasm. Cells in which apoptosis occurs are atrophy (atrophy), and since the cell contents are not released to the outside and are quickly incorporated into macrophages or surrounding cells, inflammation does not occur and the surrounding cells are not affected. Therefore, there are many attempts to treat diseases by inducing apoptosis in cells (eg, cancer cells) whose presence is harmful in the host organism.
본 발명에서 상기 조성물은 암세포의 세포 외 기질에의 접착을 억제할 수 있다.In the present invention, the composition can inhibit the adhesion of cancer cells to the extracellular matrix.
이 때, 상기 세포외 기질은 피브로넥틴(fibronectin)일 수 있으나, 이에 제한되지 않는다.In this case, the extracellular matrix may be fibronectin, but is not limited thereto.
본 발명에서 사용되는 용어 "세포외 기질(extracellular matrix, ECM)"은 세포를 둘러싼 공간에서 네트워크를 형성해 조직의 형태를 유지하고 지탱하여, 세포와 조직의 구조 및 기능에 있어 중요한 역할을 한다. 또한, 세포외 기질은 신호전달과 세포활성을 제한하는 성장인자를 방출하므로 세포는 각기 다른 세포외 기질에 반응한다. 세포외 기질은 콜라겐(collagen), 피브로넥틴(fibronectin), 라미닌(laminin), 섬유질 및 당단백질로 구성되어 있다. As used herein, the term "extracellular matrix (ECM)" forms a network in the space surrounding the cells to maintain and support the shape of the tissue, and plays an important role in the structure and function of cells and tissues. In addition, cells respond to different extracellular matrices because the extracellular matrix releases growth factors that limit signal transduction and cellular activity. The extracellular matrix is composed of collagen, fibronectin, laminin, fibers and glycoproteins.
본 발명에서 사용되는 용어 "피브로넥틴(fibronectin)"은 다른 세포외 기질 단백질뿐만 아니라 인테그린에 결합하는 세포외 기질의 고분자량(약 440kDa)의 당단백질로, 세포의 부착, 이동 및 분화에 결정적인 역할을 하며 특히 RGD (Arg-Gly-Asp)가 세포부착기능을 하는 것으로 알려져 있다.As used herein, the term "fibronectin" is a high molecular weight (about 440 kDa) glycoprotein of the extracellular matrix that binds to integrin as well as other extracellular matrix proteins, and plays a decisive role in cell adhesion, migration and differentiation. In particular, RGD (Arg-Gly-Asp) is known to have a cell adhesion function.
본 발명에서 사용되는 용어 "세포 접착"은 "세포 부착"이라고도 하며 세포가 세포끼리 또는 다른 물질에 달라붙는 현상을 말한다. 다세포동물에서는 그 기본적 속성으로, 세포와 세포가 세포막을 사이에 두고 서로 달라붙어 있고(세포간부착), 특별한 실험적 처리를 하지 않는 한 개개의 세포는 해리되지 않는다. 따라서 단순히 부착이라고도 하며, 세포-세포간부착(cell-cell adhesion) 및 세포-세포외 기질부착(cell-substrate adhesion)을 말한다. 세포접착현상은 세포정보전달, 암, 면역, 신경, 발생, 세포증식, 세포분화, 세포인식 등의 여러 가지 생명현상에 관여하고 있고 염증, 암전이등과 같은 질병과 관련이 있는 것으로 밝혀져 있다. 암환자의 주된 사망요인은 초기 종양에 의한 것이 아니라 암세포의 다른 조직으로의 전이에 의한 것이다. 따라서 암세포의 전이 기작에 관한 연구가 많이 진행되어 접착, 침윤, 혈관형성 등의 삼단계설이 확립되어 있으며 이 중 어느 하나를 차단하는 것에 의하여 암세포의 전이를 억제하는 것이 가능하다.As used herein, the term "cell adhesion" is also referred to as "cell adhesion" and refers to a phenomenon in which cells adhere to each other or to other substances. In multicellular animals, the basic property is that cells and cells adhere to each other with a cell membrane interposed between them (intercellular adhesion), and individual cells do not dissociate unless special experimental treatment is performed. Therefore, it is simply referred to as adhesion, and refers to cell-cell adhesion and cell-substrate adhesion. Cell adhesion phenomenon is involved in various life phenomena such as cell information transmission, cancer, immunity, nerve, development, cell proliferation, cell differentiation, and cell recognition, and it has been found to be related to diseases such as inflammation and cancer metastasis. The main cause of death in cancer patients is not the initial tumor, but the metastasis of cancer cells to other tissues. Therefore, many studies on the metastasis mechanism of cancer cells have been conducted, and the three-step theory of adhesion, invasion, and angiogenesis has been established, and it is possible to inhibit cancer cell metastasis by blocking any one of them.
또한, 본 발명은 에리브라에딘 A(erybraedin A)를 유효성분으로 포함하는 암의 예방 또는 개선용 식품 조성물을 제공한다.In addition, the present invention provides a food composition for preventing or improving cancer comprising erybraedin A (erybraedin A) as an active ingredient.
이 때, 상기 식품 조성물은 건강기능식품 조성물일 수 있으나, 이에 제한되지 않는다.At this time, the food composition may be a health functional food composition, but is not limited thereto.
본 발명에서 사용되는 용어 “개선”은 치료되는 상태와 관련된 파라미터, 예를 들면 증상의 정도를 적어도 감소시키는 모든 행위를 의미한다.As used herein, the term “improvement” refers to any action that at least reduces a parameter related to the condition being treated, for example, the severity of symptoms.
본 발명에서 사용되는 용어 "식품 조성물"은, 담체, 희석제, 부형제 및 첨가제 중 하나 이상을 포함하여 정제, 환제, 산제, 과립제, 분말제, 캡슐제 및 액제 제형으로 이루어진 군에서 선택된 하나로 제형된 것을 특징으로 한다. The term "food composition" used in the present invention is one selected from the group consisting of tablets, pills, powders, granules, powders, capsules and liquid formulations, including one or more of carriers, diluents, excipients and additives. characterized.
본 발명의 에리브라에딘 A(erybraedin A)에 첨가할 수 있는 식품으로는, 각종 식품류, 분말, 과립, 정제, 캡슐, 시럽제, 음료, 껌, 차, 비타민 복합제, 건강 기능성 식품류 등이 있다. 상기 본 발명에 더 포함될 수 있는 첨가제로는, 천연 탄수화물, 향미제, 영양제, 비타민, 광물(전해질), 풍미제(합성 풍미제, 천연 풍미제 등), 착색제, 충진제, 팩트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH조절제, 안정화제, 방부제, 산화 방지제, 글리세린, 알코올, 탄산화제, 및 과육으로 이루어진 군으로부터 선택된 1종 이상의 성분을 사용할 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토오스, 수크로오스 등; 및 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리트리톨 등의 당알코올이다. 상기 향미제로서 천연 향미제(타우마틴, 스테비아추출물(예를 들어 레바우디오시드 A, 글리시르히진 등) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. Foods that can be added to erybraedin A of the present invention include various foods, powders, granules, tablets, capsules, syrups, beverages, gums, tea, vitamin complexes, health functional foods, and the like. Additives that may be further included in the present invention include natural carbohydrates, flavoring agents, nutrients, vitamins, minerals (electrolytes), flavoring agents (synthetic flavoring agents, natural flavoring agents, etc.), coloring agents, fillers, lactic acid and salts thereof, At least one component selected from the group consisting of alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, antioxidants, glycerin, alcohols, carbonation agents, and pulp may be used. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; disaccharides such as maltose, sucrose and the like; and polysaccharides such as conventional sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As the flavoring agent, natural flavoring agents (taumatin, stevia extract (eg, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used.
상기 외에 본 발명에 따른 조성물은 여러 가지 영양제, 비타민, 광물 (전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제, 팩트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다. In addition to the above, the composition according to the present invention includes various nutrients, vitamins, minerals (electrolytes), synthetic flavoring agents and flavoring agents such as natural flavoring agents, coloring agents and thickening agents, facic acid and salts thereof, alginic acid and salts thereof, organic acids, protection It may contain a sexual colloid thickener, a pH adjuster, a stabilizer, a preservative, glycerin, alcohol, a carbonation agent used in carbonated beverages, and the like.
그밖에 본 발명에 따른 조성물은 천연 과일 주스 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. In addition, the composition according to the present invention may contain pulp for the production of natural fruit juices and vegetable beverages. These components may be used independently or in combination.
상기 담체, 부형제, 희석제 및 첨가제의 구체적인 예로는 이에 한정하는 것은 아니나, 락토오스, 덱스트로즈, 수크로오스, 솔비톨, 만니톨, 에리스리톨, 전분, 아카시아 고무, 인산칼슘, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 미세결정성 셀룰로오스, 폴리비닐키롤리돈, 셀룰로오스, 폴리비닐피로리돈, 메틸셀룰로오스, 물, 설탕시럽, 메틸 하이드록시 벤조에이트, 프로필하이드록시 벤조에이트, 활석, 스테아르산 마그네슘, 및 미네랄 오일로 이루어진 그룹으로부터 선택된 1종 이상이 사용되는 것이 바람직하다.Specific examples of the carrier, excipient, diluent and additive include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, erythritol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium phosphate, calcium silicate, The group consisting of microcrystalline cellulose, polyvinylkirolidone, cellulose, polyvinylpyrrolidone, methylcellulose, water, sugar syrup, methyl hydroxy benzoate, propyl hydroxy benzoate, talc, magnesium stearate, and mineral oil. It is preferable to use at least one selected from
또한, 본 발명은 상기 약학적 조성물을 개체에 투여하는 단계를 포함하는 암의 예방 또는 치료 방법을 제공한다.In addition, the present invention provides a method for preventing or treating cancer comprising administering the pharmaceutical composition to a subject.
또한, 본 발명은 상기 약학적 조성물의 암 예방 또는 치료 용도를 제공한다.In addition, the present invention provides the use of the pharmaceutical composition for preventing or treating cancer.
본 발명에서 사용되는 용어 "투여"는 임의의 적절한 방법으로 개체에게 소정의 본 발명의 조성물을 제공하는 것을 의미한다.As used herein, the term “administration” means providing a given composition of the present invention to a subject by any suitable method.
본 발명에서 사용되는 용어 "개체"란 암의 치료를 필요로 하는 대상을 의미하고, 보다 구체적으로는, 인간 또는 비-인간인 영장류, 생쥐(mouse), 개, 고양이, 말, 및 소 등의 포유류를 의미한다.As used herein, the term "individual" refers to a subject in need of treatment for cancer, and more specifically, human or non-human primates, mice, dogs, cats, horses, and cattle. means mammals.
본 발명의 일실시예에서는 에리브라에딘 A(erybraedin A, EBA)를 동정하고 폐암세포의 피브로넥틴에의 접착에 대한 상기 EBA의 억제 효과를 확인하였다(실시예 1 참조).In one embodiment of the present invention, erybraedin A (EBA) was identified and the inhibitory effect of EBA on adhesion of lung cancer cells to fibronectin was confirmed (see Example 1).
본 발명의 다른 실시예에서는 EBA의 Src 및 하위 신호전달 억제 효과 및 Src와 integrin β1 또는 integrin β3와의 상호작용 억제 효과를 확인함으로써 EBA의 Src 활성화 억제 효과를 확인하였다(실시예 2 참조).In another embodiment of the present invention, the inhibitory effect of EBA on Src activation was confirmed by confirming the inhibitory effect of EBA on Src and sub-signaling and the inhibitory effect on the interaction between Src and integrin β1 or integrin β3 (see Example 2).
본 발명의 또 다른 실시예에서는 EBA의 apoptosis 유도를 통한 폐암세포 viability 및 콜로니 형성 억제 효과를 확인하였다(실시예 3 참조).In another embodiment of the present invention, the effect of inhibiting lung cancer cell viability and colony formation through the induction of apoptosis of EBA was confirmed (see Example 3).
이하, 본 발명의 바람직한 실시예를 첨부도면을 참조하여 상세히 설명하기로 한다. 다만, 이들 실시예는 오로지 본 발명을 예시하기 위한 것으로서, 본 발명의 범위가 이들 실시예에 의해 제한되는 것으로 해석되지는 않는다 할 것이다.Hereinafter, preferred embodiments of the present invention will be described in detail with reference to the accompanying drawings. However, these examples are only for illustrating the present invention, and the scope of the present invention is not to be construed as being limited by these examples.
실시예Example 1. One. 에리브라에딘Eribraedin A( A( EBAEBA )의 동정 및 폐암세포의 ) and identification of lung cancer cells 피브로넥틴에의to fibronectin 접착에 대한 for adhesion 에리브라에딘Eribraedin A의 억제 효과 확인 Confirmation of inhibitory effect of A
다양한 구조의 화합물로 구성된 화합물 라이브러리를 이용하여 세포외 기질인 피브로넥틴(fibronectin)에의 암세포 접착을 억제하는 효능 물질을 adhesion assay를 이용하여 검색하였다. Efficacy substances that inhibit the adhesion of cancer cells to the extracellular matrix, fibronectin, were searched for using an adhesion assay using a compound library composed of compounds of various structures.
그 결과, 도 2에 나타낸 바와 같이 compound 24인 에리브라에딘 A(erybraedin A, EBA)가 가장 우수한 효능을 나타냄을 확인하였으며, 상기 에리브라에딘 A의 구조는 도 1에 나타내었다.As a result, as shown in FIG. 2 , it was confirmed that
폐암세포의 피브로넥틴에의 접착에 대한 상기 EBA의 억제 효과를 확인하기 위해, 폐암세포 H1299, H226B, 및 A549에서 상기 EBA의 농도별 처리에 따른 효과를 확인한 결과, 도 3에 나타낸 바와 같이, EBA의 농도가 높을수록 상기 폐암세포 H1299, H226B, 및 A549의 피브로넥틴에의 접착이 억제되는 것을 확인하였다.In order to confirm the inhibitory effect of EBA on the adhesion of lung cancer cells to fibronectin, the effect of each concentration of EBA treatment in lung cancer cells H1299, H226B, and A549 was confirmed. It was confirmed that the higher the concentration, the more inhibited the adhesion of lung cancer cells H1299, H226B, and A549 to fibronectin.
또한, 상기 도 3과 동일한 실험 조건에서 EBA가 폐암세포의 viability에 영향을 미치는지 확인한 결과, 도 4에 나타낸 바와 같이, EBA는 폐암세포의 viability에는 영향을 미치지 않아, EBA의 세포 접착 억제 효과는 세포독성에 의한 것이 아님을 확인할 수 있었다.In addition, as a result of confirming whether EBA affects the viability of lung cancer cells under the same experimental conditions as in FIG. 3 , as shown in FIG. 4 , EBA does not affect the viability of lung cancer cells, and the cell adhesion inhibitory effect of EBA is It was confirmed that it was not caused by toxicity.
실시예Example 2. 2. EBA의EBA's SrcSrc 활성화 억제 효과 확인 Check the activation inhibitory effect
EBA의 Src 및 하위 신호전달 억제 효과를 확인하기 위해 폐암세포 H1299 및 A549에서 상기 EBA의 처리에 따른 효과를 확인한 결과, 도 5에 나타낸 바와 같이, EBA의 처리 시간이 증가함에 따라 Src 및 FAK, Akt의 인산화가 억제되는 것을 확인하였으며, EBA의 Src와 integrin β1 또는 integrin β3와의 상호작용 억제 효과를 확인하기 위해 폐암세포 H1299에서 상기 EBA의 처리에 따른 효과를 확인한 결과, 도 6에 나타낸 바와 같이, EBA 처리에 의해 Src와 integrin β1 또는 integrin β3와의 상호작용이 억제되는 것을 확인하였다.As a result of confirming the effect of the EBA treatment in lung cancer cells H1299 and A549 to confirm the Src and sub-signaling inhibitory effect of EBA, as shown in FIG. 5 , as the treatment time of EBA increased, Src, FAK, Akt It was confirmed that phosphorylation of EBA was inhibited, and the effect of EBA treatment in lung cancer cells H1299 was confirmed to confirm the effect of inhibiting the interaction of EBA with Src and integrin β1 or integrin β3 As a result, as shown in FIG. 6 , EBA It was confirmed that the interaction between Src and integrin β1 or integrin β3 was inhibited by the treatment.
또한, 분자모델링을 통해 EBA가 Src의 ATP 결합 포켓(binding pocket) 및 알로스테릭 조절 부위(allosteric regulatory site)에 작용할 수 있음을 확인하였으며, 이를 도 7에 나타내었다.In addition, it was confirmed through molecular modeling that EBA can act on the ATP binding pocket of Src and the allosteric regulatory site, which is shown in FIG. 7 .
상기 결과로부터, EBA는 Src 활성화를 억제시키는 효과가 있음을 알 수 있었다.From the above results, it can be seen that EBA has an effect of inhibiting Src activation.
실시예Example 3. 3. EBA의EBA's apoptosisapoptosis 유도를 통한 폐암세포 viability 및 Lung cancer cell viability and 콜로니colony 형성 억제 효과 formation inhibitory effect
폐암세포 H1299, H226B, 및 A549에서 cell viability를 측정한 결과, 도 8에 나타낸 바와 같이, EBA가 상기 폐암세포 H1299, H226B, 및 A549의 viability를 농도 의존적으로 억제하는 효과를 나타내는 것을 확인하였으며, 폐암세포의 콜로니 형성을 측정한 결과, 도 9에 나타낸 바와 같이, EBA가 anchorage 의존/비의존적 배양 조건에서 모두 상기 폐암세포 H1299, H226B, 및 A549의 콜로니 형성을 농도 의존적으로 억제하는 효과를 나타내는 것을 확인하였다.As a result of measuring cell viability in lung cancer cells H1299, H226B, and A549, as shown in FIG. 8, it was confirmed that EBA exerts an effect of inhibiting the viability of the lung cancer cells H1299, H226B, and A549 in a concentration-dependent manner, and lung cancer As a result of measuring the colony formation of cells, as shown in FIG. 9 , it was confirmed that EBA exhibits an effect of concentration-dependently inhibiting colony formation of the lung cancer cells H1299, H226B, and A549 in both anchorage-dependent/independent culture conditions. did.
또한, EBA의 apoptosis 유도 효과를 확인하기 위해 폐암세포 H1299, H226B, 및 A549에서 상기 EBA의 처리에 따른 효과를 확인한 결과, 도 10에 나타낸 바와 같이, 상기 EBA가 폐암세포의 세포 사멸을 유도함을 확인하였으며, 도 11에 나타낸 바와 같이, 폐암세포 H1299, H226B, 및 A549에서 EBA에 의한 PARP cleavage의 증가를 확인함으로써 상기 세포 사멸 유도 작용이 apoptosis 유도와 관련됨을 확인하였다.In addition, in order to confirm the apoptosis-inducing effect of EBA, the effect of the treatment of EBA in lung cancer cells H1299, H226B, and A549 was confirmed, and as shown in FIG. 10 , it was confirmed that the EBA induces apoptosis of lung cancer cells. As shown in FIG. 11, by confirming the increase in PARP cleavage by EBA in lung cancer cells H1299, H226B, and A549, it was confirmed that the apoptosis-inducing action is related to apoptosis induction.
따라서, 상기 결과로부터 EBA는 apoptosis 유도를 통해 폐암세포의 생존 및 콜로니 형성을 억제하는 효과가 있음을 알 수 있었다. Therefore, it can be seen from the above results that EBA has the effect of inhibiting the survival and colony formation of lung cancer cells through induction of apoptosis.
상기 진술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다.The description of the present invention stated above is for illustration, and those of ordinary skill in the art to which the present invention pertains can understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. There will be. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive.
Claims (6)
상기 약학적 조성물은 비수용체 티로신 키나아제인 Src를 억제하는 것을 특징으로 하는, 약학적 조성물.The method of claim 1,
The pharmaceutical composition is characterized in that it inhibits Src, which is a non-receptor tyrosine kinase, a pharmaceutical composition.
상기 식품 조성물은 비수용체 티로신 키나아제인 Src를 억제하는 것을 특징으로 하는, 식품 조성물.5. The method of claim 4,
The food composition is characterized in that it inhibits the non-receptor tyrosine kinase Src, the food composition.
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