KR101706389B1 - Composition for inhibiting angiogenesis, VEGF or HIF1-alpha - Google Patents
Composition for inhibiting angiogenesis, VEGF or HIF1-alpha Download PDFInfo
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- KR101706389B1 KR101706389B1 KR1020100102816A KR20100102816A KR101706389B1 KR 101706389 B1 KR101706389 B1 KR 101706389B1 KR 1020100102816 A KR1020100102816 A KR 1020100102816A KR 20100102816 A KR20100102816 A KR 20100102816A KR 101706389 B1 KR101706389 B1 KR 101706389B1
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Abstract
본 발명은 라폰티게닌을 유효성분으로 함유하는 신생혈관형성억제용 조성물, VEGF 억제용 조성물, HIF-1알파 억제용 조성물, 종양, 황반변성, 당뇨, 당뇨병성 망막병증, 건선, 류마티스성 관절염 또는 만성 염증 등의 치료, 개선 또는 예방용 조성물을 제공한다. 본 발명의 조성물은 함유되는 유효성분에 의해 신생혈관형성억제, VEGF 억제, HIF-1알파 억제, 종양, 황반변성, 당뇨, 당뇨병성 망막병증, 건선, 류마티스성 관절염 또는 만성 염증 등의 치료, 개선 또는 예방에 효과적이라는 장점을 갖는다.The present invention relates to a composition for inhibiting angiogenesis, an agent for inhibiting VEGF, a composition for inhibiting HIF-1 alpha, a tumor, macular degeneration, diabetes, diabetic retinopathy, psoriasis, rheumatoid arthritis or rheumatoid arthritis, Chronic inflammation, and the like. The composition of the present invention can be used to treat, improve, or prevent neovascularization, VEGF suppression, HIF-1 alpha suppression, tumor, macular degeneration, diabetes, diabetic retinopathy, psoriasis, rheumatoid arthritis, Or prevention.
Description
본 발명은 신생혈관형성 억제, VEGF 억제 또는 HIF1-알파 억제용 조성물에 관한 것으로, 보다 상세하게는 라폰티게닌을 유효성분으로 함유하는 조성물에 관한 것이다.The present invention relates to a composition for inhibiting angiogenesis, VEGF inhibition or HIF1-alpha inhibition, and more particularly, to a composition containing raffotigenin as an active ingredient.
신생혈관형성(Angiogenesis)은 기존 혈관으로부터 새로운 혈관이 생성되는 기작을 의미하며, 정상적인 생리조건에서는 거의 일어나지 않는 엄격히 조절되는 현상이나 수정란 발생과정에서 배아가 발달될 때와 성인의 경우 상처가 치유될 때 그리고 여성의 생식주기에서 생식기 계통의 변화 등에서 일어난다. 성인의 경우 모세혈관의 내피세포는 상대적으로 잘 분열하지 않으며 분열속도는 보통 수개월 내지 수년이다. 혈관신생은 혈관신생은 여러 종류의 세포와 수용성 인자 및 세포외 기질(extracellular matrix) 성분과의 상호작용에 의한 복잡한 과정으로 일어난다.Angiogenesis refers to the mechanism by which new blood vessels are generated from existing blood vessels. It is a tightly controlled phenomenon that rarely occurs under normal physiological conditions, or when the embryo develops during the development of the embryo and when the wound heals in the adult And changes in the reproductive system in the female reproductive cycle. In adults, capillary endothelial cells do not divide relatively well, and the rate of cleavage is usually from months to years. Angiogenesis is a complex process in which angiogenesis is mediated by the interaction of various types of cells with water soluble and extracellular matrix components.
그러나 이렇게 엄격히 조절되는 현상이지만 신생혈관 형성이 과하게 진행될 경우 여러가지 질환이 유발된다. 종양에서의 신생혈관은 다른 장기로의 이동통로를 제공하여 전이가 쉽게 이루어지게 만들며, 종양뿐 아니라 연령관련 황반변성(age-related macular degeneration), 당뇨병성 망막병증(diabetic retinopathy), 건선(psoriasis), 류마티스 관절염(rheumatoid arthritis), 만성염증(chronic inflammation)과 같은 질환에 결정적인 역할을 하는 것으로 알려져 있다. 혈관신생에 중요한 역할을 담당하는 인자로 VEGF(Vascular endothelial growth factor)가 알려져 있으며, 상기 VEGF는 HIF1-알파(Hypoxia-inducible factor 1, alpha)라는 전자조절인자에 의해 조절 가능한 것으로 알려져 있다.However, this is a strictly controlled phenomenon, but when the neovascularization is over-developed, various diseases are caused. Neovascularization in the tumor provides a pathway to other organs and facilitates metastasis. In addition to tumors, age-related macular degeneration, diabetic retinopathy, psoriasis, , Rheumatoid arthritis, chronic inflammation, and the like. VEGF (Vascular Endothelial Growth Factor) is known to play an important role in angiogenesis and it is known that VEGF can be regulated by Hp1-alpha (Hypoxia-
따라서, 신생혈관 억제제, HIF1-알파 억제제 및 그와 관련된 질환 또는 증세의 치료, 개선 또는 예방을 위한 기술 개발이 필요하다.Therefore, there is a need to develop techniques for the treatment, improvement or prevention of neovascularization inhibitors, HIF1-alpha inhibitors and the diseases or conditions associated therewith.
한편, 라폰티게닌(rhapontigenin)은 신생혈관 억제, HIF1-알파 억제 및 황반변성 등과 관련성에 대해 알려지지 않았다.On the other hand, rhapontigenin is not known for its relevance to neovascularization, HIF1-alpha suppression and macular degeneration.
본 발명이 해결하려는 과제는 신생혈관형성억제용 조성물을 제공하는 것이다.A problem to be solved by the present invention is to provide a composition for inhibiting angiogenesis.
또한, 본 발명이 해결하려는 과제는 VEGF 억제용 조성물을 제공하는 것이다.In addition, a problem to be solved by the present invention is to provide a composition for inhibiting VEGF.
또한, 본 발명이 해결하려는 과제는 HIF-1알파 억제용 조성물을 제공하는 것이다.In addition, a problem to be solved by the present invention is to provide a composition for inhibiting HIF-1 alpha.
또한, 본 발명이 해결하려는 과제는 암, 연령 관련 황반변성, 당뇨병성 망막병증, 건선, 류마티스성 관절염, 또는 만성 염증 중에서 선택된 하나 이상의 치료, 개선 또는 예방용 조성물을 제공하는 것이다.In addition, the object to be solved by the present invention is to provide a composition for at least one treatment, improvement or prevention selected from cancer, age-related macular degeneration, diabetic retinopathy, psoriasis, rheumatoid arthritis, or chronic inflammation.
본 발명은 라폰티게닌(rhapontigenin)의 신규 용도, 즉, 신생혈관형성(Angiogenesis)억제용도, VEGF(Vascular endothelial growth factor) 억제용도, HIF-1알파(Hypoxia-inducible factor 1, alpha) 억제용도 및 종양, 황반변성, 당뇨, 당뇨병성 망막병증, 건선, 류마티스성 관절염 또는 만성 염증 중에서 선택된 하나 이상의 치료, 개선 또는 예방용도를 제공한다.The present invention relates to novel uses of rhapontigenin, namely, inhibition of angiogenesis, use of VEGF (Vascular Endothelial Growth Factor) inhibitors, inhibition of HIF-1 alpha (Hypoxia-
본 발명에 있어서, 라폰티게닌(IUPAC Name: 5-[(E)-2-(3-hydroxy-4-methoxyphenyl)ethenyl]benzene-1,3-diol)은 구입(예를 들어, Cayman Chemical Company, USA; Item Number : 13293)하거나 합성할 수 있다.In the present invention, the lupontigenin (IUPAC Name: 5 - [(E) -2- (3-hydroxy-4-methoxyphenyl) ethenyl] benzene- , USA; Item Number: 13293) or synthesized.
상기 종양은 암일 수 있으며, 예를 들어 고형암으로 전립선암, 대장암, 유방암, 또는 섬유육종 중에서 선택된 하나 이상일 수 있다. 상기 황반변성은 연령 관련 황반변성일 수 있다.The tumor may be a cancer, and may be, for example, one or more selected from prostate cancer, colon cancer, breast cancer, or fibrosarcoma as solid cancer. The macular degeneration may be age-related macular degeneration.
또한, 본 발명은 라폰티게닌을 유효성분으로 함유하는 신생혈관형성억제용 조성물을 제공한다.The present invention also provides a composition for inhibiting angiogenesis, which comprises lapontigenin as an active ingredient.
상기 신생혈관형성억제는 저산소 상태에서 유도되는 신생혈관 형성을 억제하는 것일 수 있다.The inhibition of neovascularization may be to inhibit neovascularization induced in hypoxic conditions.
상기 신생혈관형성억제는 VEGF(Vascular endothelial growth factor) 억제 또는 HIF-1알파(Hypoxia-inducible factor 1, alpha) 억제 중에서 선택된 하나 이상에 의할 수 있다.The angiogenesis inhibition may be at least one selected from VEGF (vascular endothelial growth factor) inhibition or HIP-1 alpha (Hypoxia-
상기 조성물은 신생혈관형성억제에 의해 종양, 황반변성, 당뇨, 당뇨병성 망막병증, 건선, 류마티스성 관절염 또는 만성 염증 중에서 선택된 하나 이상의 치료, 개선 또는 예방에 효과를 나타낼 수 있다(Folkman, J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med, 1:27-31,1995. 등 참조). 상기 종양은 암일 수 있으며, 예를 들어 고형암으로 전립선암, 대장암, 유방암, 또는 섬유육종 중에서 선택된 하나 이상일 수 있다. 상기 황반변성은 연령 관련 황반변성일 수 있다.The composition may be effective for at least one treatment, improvement or prevention selected from tumor angiogenesis inhibition, diabetic retinopathy, diabetic retinopathy, psoriasis, rheumatoid arthritis or chronic inflammation by inhibiting angiogenesis (Folkman, J. Angiogenesis in cancer, vascular, rheumatoid and other disease, Nat Med, 1: 27-31, 1995, etc.). The tumor may be a cancer, and may be, for example, one or more selected from prostate cancer, colon cancer, breast cancer, or fibrosarcoma as solid cancer. The macular degeneration may be age-related macular degeneration.
본 발명의 조성물은 식품 조성물 또는 약학 조성물일 수 있다.The composition of the present invention may be a food composition or a pharmaceutical composition.
또한, 본 발명은 라폰티게닌을 유효성분으로 함유하는 VEGF(Vascular endothelial growth factor) 억제용 조성물을 제공한다.The present invention also provides a composition for inhibiting vascular endothelial growth factor (VEGF) comprising lapontigenin as an active ingredient.
상기 조성물은 VEGF 억제에 의해 종양, 황반변성, 당뇨, 당뇨병성 망막병증, 건선, 류마티스성 관절염 또는 만성 염증 중에서 선택된 하나 이상의 치료, 개선 또는 예방에 효과를 나타낼 수 있다(Ferrara, N., Gerber, H. P., and LeCouter, J. The biology of VEGF and its receptors. Nat Med, 9:669-676,2003. 등 참조). 상기 종양은 암일 수 있으며, 예를 들어 고형암으로 전립선암, 대장암, 유방암, 또는 섬유육종 중에서 선택된 하나 이상일 수 있다. 상기 황반변성은 연령 관련 황반변성일 수 있다.The composition may be effective for at least one treatment, improvement or prevention selected from tumor, macular degeneration, diabetes, diabetic retinopathy, psoriasis, rheumatoid arthritis or chronic inflammation by VEGF inhibition (Ferrara, N., Gerber, HP, and LeCouter, J. The biology of VEGF and its receptors. Nat Med, 9: 669-676, 2003.). The tumor may be a cancer, and may be, for example, one or more selected from prostate cancer, colon cancer, breast cancer, or fibrosarcoma as solid cancer. The macular degeneration may be age-related macular degeneration.
본 발명의 조성물은 식품 조성물 또는 약학 조성물일 수 있다.The composition of the present invention may be a food composition or a pharmaceutical composition.
본 발명은 라폰티게닌을 유효성분으로 함유하는 HIF-1알파(Hypoxia-inducible factor 1, alpha) 억제용 조성물을 제공한다.The present invention provides a composition for inhibiting HIF-1 alpha (Hypoxia-
상기 조성물은 HIF-1알파 억제에 의해 종양, 황반변성, 당뇨, 당뇨병성 망막병증, 건선, 류마티스성 관절염 또는 만성 염증 중에서 선택된 하나 이상의 치료, 개선 또는 예방에 효과를 나타낼 수 있다(Harris, A. L. Hypoxia--a key regulatory factor in tumour growth. Nat Rev Cancer, 2:38-47,2002.; Semenza, G. L. Targeting HIF-1 for cancer therapy. Nat Rev Cancer, 3:721-732,2003. 등 참조). 상기 종양은 암일 수 있으며, 예를 들어 고형암으로 전립선암, 대장암, 유방암 또는 섬유육종 중에서 선택된 하나 이상일 수 있다. 상기 황반변성은 연령 관련 황반변성일 수 있다.The composition may be effective for at least one treatment, improvement or prevention selected from HIF-1 alpha inhibition, such as tumor, macular degeneration, diabetes, diabetic retinopathy, psoriasis, rheumatoid arthritis or chronic inflammation (Harris, AL Hypoxia Nat Rev Cancer, 2: 38-47, 2002; Semenza, GL Targeting HIF-1 for cancer therapy, Nat Rev Cancer, 3: 721-732, 2003.). The tumor may be a cancer, and may be, for example, one or more selected from prostate cancer, colon cancer, breast cancer or fibrosarcoma as a solid cancer. The macular degeneration may be age-related macular degeneration.
본 발명의 조성물은 식품 조성물 또는 약학 조성물일 수 있다.The composition of the present invention may be a food composition or a pharmaceutical composition.
또한, 본 발명은 라폰티게닌을 유효성분으로 함유하는 종양, 황반변성, 당뇨, 당뇨병성 망막병증, 건선, 류마티스성 관절염 또는 만성 염증 중에서 선택된 하나 이상의 치료, 개선 또는 예방용 조성물을 제공한다. 상기 종양은 암일 수 있으며, 예를 들어 고형암으로 전립선암, 대장암, 유방암 또는 섬유육종 중에서 선택된 하나 이상일 수 있다. 상기 황반변성은 연령 관련 황반변성일 수 있다.The present invention also provides a composition for treating, improving or preventing at least one selected from tumors containing lapontigenin as an active ingredient, macular degeneration, diabetes, diabetic retinopathy, psoriasis, rheumatoid arthritis or chronic inflammation. The tumor may be a cancer, and may be, for example, one or more selected from prostate cancer, colon cancer, breast cancer or fibrosarcoma as a solid cancer. The macular degeneration may be age-related macular degeneration.
상기 치료, 개선 또는 예방은 신생혈관형성억제, VEGF(Vascular endothelial growth factor) 억제 또는 HIF-1알파(Hypoxia-inducible factor 1, alpha) 억제 중에서 선택된 하나 이상에 의할 수 있다.The treatment, improvement or prevention may be at least one selected from inhibition of angiogenesis, inhibition of VEGF (vascular endothelial growth factor) or inhibition of HIF-1 alpha (Hypoxia-
본 발명의 조성물은 식품 조성물 또는 약학 조성물일 수 있다.The composition of the present invention may be a food composition or a pharmaceutical composition.
본 발명의 조성물은 투여를 위해서 유효성분 이외에 추가로 약학적, 및/또는 식품학적으로 허용되는 담체를 1종 이상 포함하여 제제화할 수 있다.The composition of the present invention may be formulated to contain at least one pharmaceutically acceptable and / or pharmaceutically acceptable carrier in addition to the active ingredient for administration.
약학적 및/또는 식품학적으로 허용되는 담체는 식염수, 멸균수, 링거액, 완충 식염수, 덱스트로즈 용액, 말토덱스트린 용액, 글리세롤, 에탄올 및 이들 성분 중 하나 이상을 혼합하여 사용할 수 있으며, 필요에 따라 항산화제, 완충액, 정균제 등 다른 통상의 첨가제를 첨가할 수 있다. 또한 희석제, 분산제, 계면활성제, 용매, 붕해제, 감미제, 결합제, 피복제, 팽창제, 윤활제, 활택제 또는 향미제를 부가적으로 첨가할 수 있다. 더 나아가 당 분야의 적절한 방법으로 또는 Remington's Pharmaceutical Science(최근판), Mack Publishing Company, Easton PA에 개시되어 있는 방법을 이용하여 각 질환에 따라 또는 성분에 따라 바람직하게 제제화 할 수 있다.The pharmaceutically and / or pharmacologically acceptable carrier may be a mixture of one or more of saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, Antioxidants, buffers, bacteriostats, and other conventional additives may be added. In addition, diluents, dispersants, surfactants, solvents, disintegrants, sweeteners, binders, coating agents, swelling agents, lubricants, lubricants or flavors may additionally be added. Further, it can be suitably formulated according to each disease or ingredient, using methods disclosed in the art or by methods disclosed in Remington's Pharmaceutical Science (recent edition), Mack Publishing Company, Easton PA.
본 발명의 약학적 조성물의 제제 형태는 과립제, 산제, 정제, 피복정, 캡슐제, 좌제, 액제, 시럽, 즙, 현탁제, 유제, 점적제 또는 주사 가능한 액제 및 활성 화합물의 서방출형 제제 등이 될 수 있다.Formulations of the pharmaceutical compositions of the present invention may be in the form of granules, powders, tablets, coated tablets, capsules, suppositories, solutions, syrups, juices, suspensions, emulsions, .
본 발명의 약학적 조성물은 목적에 따라 정맥내, 동맥내, 복강내, 근육내, 흉골내, 경피, 비측내, 흡입, 국소, 직장, 경구, 안구내 또는 피내 경로 등을 통해 통상적인 방식으로 투여할 수 있다.The pharmaceutical composition of the present invention may be administered orally or parenterally in a conventional manner depending on the purpose, such as intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, transdermal, intranasal, inhalation, topical, rectal, Lt; / RTI >
본 발명에 있어서, 유효성분의 투여량은 체중 60kg 성인기준으로 1mg/kg ~ 3.2mg/kg의 범위 내에서 조절할 수 있다. 다만, 투여될 최적의 투여량은 당업자에 의해 쉽게 결정될 수 있으며, 질환의 종류, 질환의 중증도, 조성물에 함유된 유효성분 및 다른 성분의 함량, 제형의 종류, 및 환자의 연령, 체중, 일반 건강 상태, 성별 및 식이, 투여 시간, 투여 경로 및 조성물의 분비율, 치료기간, 동시 사용되는 약물을 비롯한 다양한 인자에 따라 조절될 수 있다.In the present invention, the dose of the active ingredient can be adjusted within the range of 1 mg / kg to 3.2 mg / kg on the basis of adult weighing 60 kg. However, the optimal dose to be administered can be easily determined by those skilled in the art, and can be easily determined by a person skilled in the art and depends on various factors such as the type of disease, the severity of the disease, the content of the active ingredient and other ingredients contained in the composition, The age, body weight, sex, diet, time of administration, route of administration and fraction of the composition, duration of treatment, concurrent medication, and the like.
본 발명의 식품 조성물의 제형은 통상의 방법에 따라 제조하며, 담체와 함께 건조한 후 캡슐화하거나 기타 정제, 과립, 분말, 음료, 죽 등의 형태로 제형화할 수 있으며, 상기 기재한 것 외에도 모든 식품 형태로 제조 가능하다.The formulation of the food composition of the present invention may be prepared by a conventional method and may be formulated in the form of capsules or other tablets, granules, powders, beverages, porridge, etc. after drying together with the carrier. .
본 발명의 식품조성물은 건강기능식품 조성물일 수 있다.The food composition of the present invention may be a health functional food composition.
본 발명의 조성물 내에서 유효성분의 함량은 조성물 총 중량에 대하여 0.3~72중량%의 양으로 함유될 수 있다.The content of the active ingredient in the composition of the present invention may be contained in an amount of 0.3 to 72% by weight based on the total weight of the composition.
또한, 본 발명은 본 발명의 조성물 중 유효성분을 투여가 필요한 인간을 포함한 포유류에게 투여하는 단계를 포함하는 신생혈관생성억제방법, VEGF(Vascular endothelial growth factor)억제방법, HIF-1알파(Hypoxia-inducible factor 1, alpha) 억제방법, 종양, 황반변성, 당뇨, 당뇨병성 망막병증, 건선, 류마티스성 관절염 또는 만성 염증 중에서 선택된 하나 이상의 치료, 개선 또는 예방법을 제공한다.The present invention also relates to a method for inhibiting angiogenesis, a method for inhibiting vascular endothelial growth factor (VEGF), a method for inhibiting HIF-1 alpha (Hypoxia- improvement or prophylaxis of one or more selected from the group consisting of inflammation, inflammation, inflammation, inflammation,
본 발명의 용도, 조성물 및 방법에서 언급된 사항은 서로 모순되지 않는 한 동일하게 적용된다.The matters referred to in the uses, compositions and methods of the present invention apply equally as long as they are not mutually contradictory.
본 발명의 조성물은 함유되는 유효성분에 의해 신생혈관형성억제, VEGF 억제, HIF-1알파 억제, 및 종양, 황반변성, 당뇨, 당뇨병성 망막병증, 건선, 류마티스성 관절염 또는 만성 염증 등의 치료, 개선 또는 예방에 효과적이다.The composition of the present invention can be used for treatment of neovascularization inhibition, VEGF inhibition, HIF-1 alpha suppression and tumor, macular degeneration, diabetes, diabetic retinopathy, psoriasis, rheumatoid arthritis or chronic inflammation, Improvement or prevention.
도 1은 시간경과에 따른 라폰티게닌의 VEGF 억제 효과를 확인한 그래프이다.
도 2는 라폰티게닌의 HIF-1알파 발현 억제 효과를 확인한 웨스턴 블럿 결과를 나타낸 사진이다.
도 3은 라폰티게닌의 HIF-1알파 발현 억제 효과를 확인한 웨스턴 블럿 결과를 나타낸 사진이다.
도 4는 라폰티게닌의 VEGF 억제 효과를 확인한 그래프이다.
도 5는 라폰티게닌의 VEGF 억제 효과를 확인한 사진이다.FIG. 1 is a graph showing the VEGF inhibitory effect of raffotigenin over time. FIG.
FIG. 2 is a photograph showing the result of western blot confirming the effect of inhibiting HIF-1 alpha expression of laportigenin.
3 is a photograph showing Western blot results confirming the effect of inhibiting HIF-1 alpha expression of laportigenin.
4 is a graph showing the VEGF inhibitory effect of laportigenin.
5 is a photograph showing the VEGF inhibitory effect of laportigenin.
본 발명의 이해를 돕기 위하여 실시예, 제조예를 제시한다. 하기의 실시예, 제조예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 실시예, 제조예에 의해 본 발명의 내용이 한정되는 것은 아니다.Examples and production examples are provided to facilitate understanding of the present invention. The following examples and preparation examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the examples and the production examples.
하기 실시예에서 별도 언급이 없는 한, 시약은 (주)성우라이프사이언스(경기도 의정부시, 대한민국)에서 구입한 것을 사용하였다.In the following examples, reagents purchased from Sungwoo Life Science Co., Ltd. (Uijeongbu, Gyeonggi-do, Korea) were used unless otherwise noted.
하기 실시예 중 실험결과에 대한 T-검정을 실시하여 유의차가 1% 미만 (p<0.01), 0.1% 미만 (p<0.001) 또는 0.01% 미만(p<0.0001)일 때 통계적 유의성이 있는 것으로 판정하였다.A T-test was conducted to determine the statistical significance when the difference in significance was less than 1% (p <0.01), less than 0.1% (p <0.001) or less than 0.01% (p <0.0001) Respectively.
각각의 도에서 *,# 는 p<0.01 이고, **,## 는 p<0.001 이며,***,### 는 p<0.0001 이다. ##,###는 정상 산소분압상태와 저산소상태에서의 VEGF발현양에 대한 유의차를 표시한다.
In each figure, *, # are p <0.01, **, ## are p <0.001, ***, ### are p <0.0001. ##, ### indicates a significant difference between the normal oxygen partial pressure state and the amount of VEGF expression in the hypoxic state.
<실시예 1> 라폰티게닌의 VEGF 억제 효과 확인Example 1 Confirmation of VEGF Inhibitory Effect of Laportigenin
인간전립선암세포주인 PC-3(한국세포주은행, 서울, 대한민국)에 라폰티게닌(5uM 농도)을 4시간, 12시간, 24시간 동안 각각 처리 후, VEGF ELISA kit(invitrogen, USA)를 이용하여 사용설명서에 따라 VEGF 양을 측정하였다. 라폰티게닌(한국화학연구원 유시용박사팀에게서 입수함, 대전, 대한민국)은 디메틸설폭사이드에 용해된 것을 사용하였다.(5 uM concentration) was treated with human VEGF ELISA kit (Invitrogen, USA) for 4 hours, 12 hours, and 24 hours after treatment with human prostate cancer cell line PC-3 The amount of VEGF was measured according to the instructions. Lapontigenin (available from Dr. Yu Xingyuan, Ph.D., Korea Research Institute of Chemical Technology, Taejon, Korea) was dissolved in dimethylsulfoxide.
라폰티게닌을 처리하지 않은 것을 제외하고 동일하게 준비한 인간전립선암세포주를 대조군으로 사용하였다.A similarly prepared human prostate cancer cell line was used as a control except that lapontigenin was not treated.
그 결과를 도 1에 나타내었다. 도 1은 시간경과에 따른 라폰티게닌의 VEGF 억제 효과를 확인한 그래프로, x축은 라폰티게닌(Rha) 처리 유무(0: 무처리, 5: 5uM 농도 처리)를 나타내고, y축은 VEGF발현량(pg/ml)을 나타낸다.The results are shown in Fig. FIG. 1 is a graph showing the VEGF inhibitory effect of raffotigenin over time. The x axis represents the presence or absence (0: no treatment, 5: 5 uM concentration treatment) of raffotigenin (Rha) treatment and the y axis represents the VEGF expression level pg / ml).
도 1에서 보는 바와 같이 시간에 따라 인간전립선암세포에서 VEGF의 발현량은 증가하며, 라폰티게닌 처리에 의해 그 발현량이 대조군에 비해 감소함을 알 수 있다. 따라서, 라폰티게닌에 의해 VEGF의 발현을 억제할 수 있으며, 그에 따라 신생혈관형성 억제, 암 등의 종양, 황반변성, 당뇨, 당뇨병성 망막병증, 건선, 류마티스성 관절염 또는 만성 염증 등 중에서 선택된 하나 이상의 치료, 개선 또는 예방 등이 가능함을 알 수 있다.
As shown in FIG. 1, the expression level of VEGF is increased in human prostate cancer cells over time, and the expression level of the VEGF is decreased by the treatment with laportigenin compared with the control. Accordingly, the expression of VEGF can be inhibited by laportigenin, and thus, a neovascularization inhibition, a tumor such as cancer, macular degeneration, diabetes, diabetic retinopathy, psoriasis, rheumatoid arthritis or chronic inflammation It can be seen that the above treatment, improvement, or prevention is possible.
<실시예 2> 라폰티게닌의 HIF-1알파 억제 효과 확인Example 2 Confirmation of HIF-1 Alpha Inhibitory Effect of Rafontigenin
저산소상태에서 발현이 증가되는 HIF-1알파가 라폰티게닌에 의해 억제되는 것을 확인하기 위하여, 인간전립선암세포주(PC-3)의 세포추출물을 이용하여 웨스턴 블럿을 수행하였다. 라폰티게닌과 인간전립선암세포주는 실시예 1에서와 동일한 방법으로 준비한 것을 사용하였다.Western blot was performed using cellular extracts of human prostate cancer cell line (PC-3) in order to confirm that HIF-1 alpha, which increases expression in hypoxic state, is inhibited by lapontigenin. The lapontigenin and human prostate cancer cell lines were prepared in the same manner as in Example 1.
인간전립선암세포(PC-3)를 지름이 100mm인 배양접시에서 정상분압상태와 저산소상태(94% N2 / 5% CO2 / 1% O2)에서 각각 배양하였다. 그 후, 라폰티게닌을 1~10uM의 농도로 4시간 동안 처리한 후, 각각의 세포로부터 protease inhibitors{10μg/ml Aprotinin, 10μg/ml Leupeptin, 10mM Iodoacetamide, 1% PMSF(phenylmethylsulphonyl fluoride), 10μg/ml Pepstatin A}와 phosphatase inhibitors {1mM NaF, 1mM Na3VO4 }가 포함된 RIPA(radio immunoprecipitation assay) buffer {50mM Tris(trishydroxymethylaminomethane), 300mM NaCl, 5mM EDTA(ethylenediaminetetraacetic acid), 0.5% Triton X-100}를 사용하여 세포 용해하여 세포추출물을 준비하였다. 분리한 세포추출물 90μg을 전기영동한 후, 겔로부터 니트로셀룰로오스 멤브레인으로 단백질을 웨스턴블롯킷(Bio-Rad, USA)을 이용하여 제조사의 사용설명서에 따라 이동시켰다. 단백질이 붙어 있는 니트로셀룰로오스 멤브레인에 HIF-1알파를 인지할 수 있는 HIF-1알파에 대한 1차 항체(BD Transduction Laboratories, USA; Catalog Number : 610958) 로 섭씨 4도에서 20시간 반응시켰다. 반응이 끝나면 세척하고, 1차 항체와 결합하는 2차 항체(AbDserotec, USA; Catalog Number : STAR70)로 상온(섭씨 20도)에서 1시간 동안 반응시켰다. 이어서 2차 항체를 인지할 수있는 용액(ECL Western blotting detection reagent, Amersham, USA)으로 2~10분간 암실에서 반응시킨 다음, X-ray 필름에 감광하여 단백질의 발현정도를 측정하였다. 이 때 동일한 필터에 대해 세포에 동일한 양으로 발현된다고 알려진 단백질인 베타-액틴에 대한 항체로 웨스턴 블럿을 수행하여, HIF-1알파의 발현량을 보정해 주었다.Human prostate cancer cells (PC-3) were cultured in a 100-mm-diameter culture dish in a normal partial pressure state and a hypoxic state (94% N 2 /5% CO 2 /1% O 2 ). After treatment with laportigenin at a concentration of 1 to 10 uM for 4 hours, protease inhibitors (10 μg / ml Aprotinin, 10 μg / ml Leupeptin, 10 mM Iodoacetamide, 1% PMSF (phenylmethylsulphonyl fluoride) ml Pepstatin a} and phosphatase inhibitors {1mM NaF, 1mM Na 3 VO 4} the RIPA (radio immunoprecipitation assay) buffer { 50mM Tris (trishydroxymethylaminomethane), 300mM NaCl, 5mM EDTA (ethylenediaminetetraacetic acid), 0.5% Triton X-100 containing the } To prepare a cell extract. After 90 μg of the separated cell extract was electrophoresed, proteins were transferred from the gel to the nitrocellulose membrane using a Western blot kit (Bio-Rad, USA) according to the manufacturer's instructions. To the nitrocellulose membrane to which the protein was attached, a HIF-1 alpha-sensitive primary antibody (BD Transduction Laboratories, USA; Catalog Number: 610958) capable of recognizing HIF-1 alpha was reacted at 4 ° C for 20 hours. After the reaction, the cells were washed and reacted with a secondary antibody (AbDserotec, USA; Catalog Number: STAR70) for 1 hour at room temperature (20 ° C). Subsequently, the cells were reacted with a secondary antibody-recognizing solution (ECL Western blotting detection reagent, Amersham, USA) in a dark room for 2 to 10 minutes, and then exposed to X-ray film to measure protein expression. At this time, Western blot was performed on the same filter with an antibody against beta-actin, which is a protein known to be expressed in the same amount in cells, and the amount of HIF-1 alpha expression was corrected.
또한, 전립선암세포주 LNCap(American Type Culture Collection ATCC, USA), 대장암세포주 SW620(한국세포주은행, 서울, 대한민국), 유방암세포주 MCF-7(한국세포주은행, 서울, 대한민국), 섬유육종세포주 HT1080(한국세포주은행, 서울, 대한민국)에 대해서도 PC3세포주에서와 동일한 방법으로 처리하여 웨스턴블럿을 실시하였다.The breast cancer cell line MCF-7 (Korea Cell Line Bank, Seoul, Korea), the fibrous sarcoma cell line HT1080 (Korean Cell Line Bank, Seoul, Korea), the prostate cancer cell line LNCap (American Type Culture Collection ATCC, USA), the colon cancer cell line SW620 Korean Cell Line Bank, Seoul, Korea) were also subjected to Western blotting in the same manner as in the PC3 cell line.
그 결과를 도 2와 도 3에 나타내었다. 도 2와 도 3은 라폰티게닌(Rha)의 HIF-1알파 발현 억제 효과를 확인한 웨스턴 블럿 결과를 나타낸 사진이다. 도 2와 도 3에서 '-'는 저산소상태(Hypoxia)가 아닌 상태 즉, 정상분압상태를 나타내고, '+'는 저산소상태를 나타낸다. 도 2에서 1.0, 0.9, 0.3, 0.2, 0.2는 'Image J'프로그램(National Institutes of Health, USA)을 사용하여 측정한 HIF-1α의 이미지 측정값을 숫자로 표현한 값으로, 저산소 상태에서 라폰티게닌을 처리하지 않았을 때 발현된 HIF-1α의 측정 정도를 1.0으로 기준하여, 나머지 값을 계산한 것이다. 도 2와 도 3에서 보는 바와 같이, 정상분압상태에서 배양한 암세포의 경우, HIF-1알파의 발현이 거의 되지 않으나, 저산소상태에서 배양한 암세포에서 혈관신생촉진인자인 HIF-1알파의 발현이 현저히 증가함을 알 수 있다. 또한, 도 2에서 보는 바와 같이, 라폰티게닌에 의해 농도 의존적으로 HIF-1알파의 발현이 억제됨을 확인할 수 있다. 따라서, 라폰티게닌에 의해 HIF-1알파를 억제할 수 있으며, 그에 따라 신생혈관형성 억제, 암등의 종양, 황반변성, 당뇨, 당뇨병성 망막병증, 건선, 류마티스성 관절염 또는 만성 염증 등 중에서 선택된 하나 이상의 치료, 개선 또는 예방 등이 가능함을 알 수 있다.
The results are shown in Fig. 2 and Fig. FIG. 2 and FIG. 3 are photographs showing Western blotting results confirming the effect of inhibiting HIF-1 alpha expression of laportigenin (Rha). In FIG. 2 and FIG. 3, '-' indicates a state other than Hypoxia, that is, a normal partial pressure state, and '+' indicates a hypoxic state. In FIG. 2, 1.0, 0.9, 0.3, 0.2, and 0.2 represent numerical values of HIF-1α measured using the 'Image J' program (National Institutes of Health, USA) The remaining values were calculated based on the degree of measurement of HIF-1α expressed in the absence of treatment with the genin at 1.0. As shown in FIG. 2 and FIG. 3, the expression of HIF-1 alpha in the cancer cells cultured under the normal partial pressure state is hardly observed, but the expression of HIF-1 alpha, which is an angiogenesis promoting factor, It can be seen that the increase is remarkable. Further, as shown in FIG. 2, it can be confirmed that the expression of HIF-1 alpha is inhibited by raffotigenin in a concentration-dependent manner. Thus, it is possible to inhibit HIF-1 alpha by raffotigenin and thus to inhibit HIF-1 alpha, thereby inhibiting angiogenesis, tumors such as cancer, macular degeneration, diabetes, diabetic retinopathy, psoriasis, rheumatoid arthritis or chronic inflammation It can be seen that the above treatment, improvement, or prevention is possible.
<실시예 3> 저산소상태에서 발현 증가하는 VEGF 억제 효과 확인Example 3 Confirmation of VEGF Inhibitory Effect on Expression in Hypoxia
저산소상태에서 발현이 증가하는 VEGF가 라폰티게닌에 의해 발현이 억제되는 것을 하기 방법으로 확인하였다. 인간전립선암세포(PC-3)와 VEGF ELISA kit는 실시예 1에서와 동일한 방법으로 준비하였다.It was confirmed by the following method that the expression of VEGF, which increases in the hypoxic state, is inhibited by laportigenin. The human prostate cancer cells (PC-3) and the VEGF ELISA kit were prepared in the same manner as in Example 1.
인간전립선암세포를 지름이 100mm인 배양접시에서 정상분압상태와 저산소상태(94% N2 / 5% CO2 / 1% O2)에서 각각 배양하였다. 그 후, 라폰티게닌을 5μM의 농도로 4, 12, 24시간 동안 처리한 후, 각각의 세포배양액을 수거하였다. 세포배양액 중 VEGF양을 VEGF ELISA kit로 제조사의 사용설명서에 따라 측정하였다. 라폰티게닌을 처리하지 않고, 정상분압상태에서 배양한 것을 제외하고 동일하게 준비한 인간전립선암세포를 대조군으로 하였다.Human prostate cancer cells were cultured in a 100 mm diameter culture dish in a normal partial pressure state and a hypoxic state (94% N 2 /5% CO 2 /1% O 2 ). Thereafter, the laportigenin was treated at a concentration of 5 [mu] M for 4, 12, and 24 hours, and each cell culture solution was collected. The amount of VEGF in the cell culture was measured by a VEGF ELISA kit according to the manufacturer's instructions. Human prostate cancer cells prepared in the same manner as above except that the cells were cultured under a normal partial pressure condition without treatment with lapontigenin was used as a control.
그 결과를 도 4에 나타내었다. 도 4는 라폰티게닌이 저산소상태에서 발현이 증가한 VEGF를 억제하는 효과를 확인한 그래프로, x축은 라폰티게닌(Rha) 처리 유무(0: 무처리, 5: 5μM 농도 처리)와 저산소상태 유무(-: 정상분압상태, +:저산소상태)를 나타내고, y축은 VEGF발현량(pg/ml)을 나타낸다. 도 4는 좌측부터 우측방향으로 각각 4시간, 12시간, 24시간 처리시 결과를 나타낸다.The results are shown in Fig. FIG. 4 is a graph showing the effect of inhibition of VEGF by increased expression of laportigenin in a hypoxic state. The x-axis shows the presence or absence of Raphson (Rha) treatment (0: no treatment, 5: -: normal partial pressure state, +: hypoxic state), and the y-axis represents VEGF expression amount (pg / ml). FIG. 4 shows the results when processing from 4 hours, 12 hours, and 24 hours from left to right respectively.
도 4에서 보는 바와 같이 시간에 따라 인간전립선암세포에서 VEGF의 발현량은 증가하며, 라폰티게닌 처리에 의해 그 발현량이 대조군에 비해 감소함을 알 수 있다. 또한, 저산소상태에서 배양한 세포의 경우 VEGF 분비량이 정상분압상태에서 배양한 세포와는 대조적으로 현저히 증가됨을 확인할 수 있으며, 이 때 라폰티게닌 처리시 VEGF의 분비량이 회복되는 것으로부터, 라폰티게닌은 저산소상태에서 유도되는 VEGF의 분비량을 감소시키는 효과를 가짐을 확인할 수 있다. 따라서, 라폰티게닌에 의해 VEGF를 억제할 수 있으며, 그에 따라 신생혈관형성 억제, 암 등의 종양, 황반변성, 당뇨, 당뇨병성 망막병증, 건선, 류마티스성 관절염 또는 만성 염증 등 중에서 선택된 하나 이상의 치료, 개선 또는 예방 등이 가능함을 알 수 있다.
As shown in FIG. 4, the expression level of VEGF is increased in human prostate cancer cells over time, and the expression level of the VEGF is decreased by the treatment with raffontigenin compared with the control. In addition, in the case of cells cultured under hypoxic condition, the amount of VEGF secretion is significantly increased in contrast to the cells cultured under normal partial pressure. Since the secretion amount of VEGF is restored upon treatment with laportigenin, Can reduce the secretion amount of VEGF induced in the hypoxic state. Therefore, it is possible to inhibit VEGF by raffotigenin, and thus, to treat at least one selected from neovascularization inhibition, tumors such as cancer, macular degeneration, diabetes, diabetic retinopathy, psoriasis, rheumatoid arthritis or chronic inflammation , Improvement, or prevention.
<실시예 4> 라폰티게닌의 VEGF 억제 효과 확인Example 4 Confirmation of VEGF Inhibitory Effect of Laportigenin
라폰티게닌의 VEGF억제 효과를 생체 외 실험 중 가장 생체내(in vivo) 조건과 유사한 상태에서 확인하기 위해 메트리젤상의 인간제대정맥내피세포(Human Umbilical Vein Endothelial Cells; HUVEC)의 튜브 형성 실험을 실시하였다. 상기 실험은 신생혈관 형성에 있어서 특징인 튜브 형성(tube formation)에 관한 실험이다. Tube formation experiments of human Umbilical Vein Endothelial Cells (HUVEC) on metrizel were performed to confirm the VEGF inhibitory effect of laportigenin in the most in vivo conditions in vitro Respectively. The experiment is an experiment on tube formation, which is characteristic of neovascularization.
라폰티게닌은 실시예 1에서와 동일한 방법으로 준비하였다.Raphontigenin was prepared in the same manner as in Example 1.
메트리젤(BD Bioscience, USA)이 코팅된 24 웰 플레이트(well plate)에 인간제대정맥내피세포(HUVECs; 경희대학교 암예방소재개발연구센터, 서울, 한국)를 분주하였다. 각각의 군으로 나누어, 일 군에 대하여 실시예 3에서와 같은 방법으로 저산소 상태(94% N2 / 5% CO2 / 1% O2)에서 12시간 배양한 인간 전립선암 세포 배양액을 처리하였고, 다른 한 군에 대하여 실시예 3에서와 같은 방법으로 저산소 상태(94% N2 / 5% CO2 / 1% O2)에서 라폰티게닌을 5μM의 농도로 처리하여 12시간 배양한 전립선암 세포 배양액을 처리하였다. 양성대조군에는 VEGF를 20ng/ml 처리하였다. 각 군은 정상 산소분압 상태에서 4시간 배양하였다. 그 후, 위상차 현미경을 이용하여 각각의 세포 중 튜브형성 정도를 관찰하였다. 그 결과를 도 5에 나타내었다. 도 5는 라폰티게닌의 VEGF 억제 효과를 확인한 사진으로, 좌측은 양성 대조군, 가운데는 저산소 상태 배양액 처리군, 우측은 저산소 상태에서 라폰티게닌(Rha) 처리한 배양액 처리군에 대한 결과이다. 도 5에서 보는 바와 같이 VEGF에 의해 관 형성이 또렷하게 만들어진 것을 관찰할 수 있으며, 저산소 상태에서 VEGF를 분비하도록 배양한 세포 배양액 처리군 역시 관모양이 형성되었음을 확인할 수 있다. 그러나, 라폰티게닌 처리한 세포 배양액 처리군의 경우 관모양 형태를 나타내지 않음을 알 수 있다. 따라서, 라폰티게닌은 신생혈관 형성을 억제함을 알 수 있으며, 바람직하게는 고형암에서와 같이 저산소상태에서 유도되는 혈관신생을 효과적으로 억제할 수 있음을 알 수 있다. 또한, 라폰티게닌에 의해 VEGF를 억제할 수 있으며, 그에 따라 암 등의 종양, 황반변성, 당뇨, 당뇨병성 망막병증, 건선, 류마티스성 관절염 또는 만성 염증 등 중에서 선택된 하나 이상의 치료, 개선 또는 예방 등이 가능함을 알 수 있다.
Human umbilical vein endothelial cells (HUVECs; Kyung Hee University Cancer Prevention Materials Development Research Center, Seoul, Korea) were dispensed into a 24 well plate coated with Metrizel (BD Bioscience, USA). Each group was treated with human prostate cancer cell culture medium cultured for 12 hours in a hypoxic state (94% N 2 /5% CO 2 /1% O 2 ) in the same manner as in Example 3, The other group was treated with 5 μM of laportigenin in a hypoxic state (94% N 2 /5% CO 2 /1% O 2 ) in the same manner as in Example 3, and cultured for 12 hours to obtain a prostate cancer cell culture Lt; / RTI > Positive controls were treated with 20 ng / ml of VEGF. Each group was incubated for 4 hours under normal oxygen partial pressure. Then, the degree of tube formation in each cell was observed using a phase contrast microscope. The results are shown in Fig. FIG. 5 is a photograph showing the VEGF inhibitory effect of laportigenin. The results are shown in the case of the positive control group on the left, the group treated with the hypoxic culture medium in the center, and the group treated with the Lafontigene (Rha) treatment in the hypoxic condition on the right. As shown in FIG. 5, it can be seen that the tube formation is made clear by VEGF, and that the cell culture medium treated to secrete VEGF in a hypoxic state also has a tubular shape. However, it can be seen that the cell culture treated group treated with laportigenin does not show a tubular shape. Thus, it can be seen that laportigenin inhibits angiogenesis, and preferably inhibits angiogenesis induced in a hypoxic state as in solid tumors. It is also possible to inhibit VEGF by lapontigenin, thereby treating, improving or preventing one or more selected from tumors such as cancer, macular degeneration, diabetes, diabetic retinopathy, psoriasis, rheumatoid arthritis or chronic inflammation This is possible.
<제조예 1> 약학 조성물의 제조≪ Preparation Example 1 > Preparation of pharmaceutical composition
실시예 1에서와 동일한 방법으로 준비한 라폰티게닌 120mg, 옥수수 전분 100mg, 유당 100mg, 스테아린산 마그네슘 2mg을 젤라틴 캡슐에 충전하여 캡슐제를 제조하였다.
120 mg of laportigenin prepared in the same manner as in Example 1, 100 mg of corn starch, 100 mg of lactose, and 2 mg of magnesium stearate were filled in gelatin capsules to prepare capsules.
<제조예 2> 식품 조성물의 제조≪ Preparation Example 2 > Preparation of food composition
실시예 1-1에서와 동일한 방법으로 준비한 라폰티게닌(4중량 %), 액상과당(0.5중량%), 올리고당(2중량%), 설탕(2중량%), 및 식염(0.5중량%)에 물을 추가하여 잔량을 맞춘 후 균질하게 배합하여 순간 살균을 하여 건강음료를 제조하였다.(4% by weight), liquid fructose (0.5% by weight), oligosaccharide (2% by weight), sugar (2% by weight) and sodium chloride (0.5% by weight) prepared in the same manner as in Example 1-1 Water was added to adjust the remaining amount, and homogeneously mixed and sterilized instantly to prepare a health drink.
Claims (14)
상기 치료 또는 예방 효과는 신생혈관형성억제에 의한 것인, 조성물.A composition for treating or preventing at least one selected from macular degeneration, psoriasis, rheumatoid arthritis, or chronic inflammation, which comprises lapontigenin as an active ingredient,
Wherein said therapeutic or prophylactic effect is by inhibition of angiogenesis.
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| WO2020113759A1 (en) * | 2018-12-03 | 2020-06-11 | Zhuhai Qiwei Bio-Technology Ltd. | Method of treating age-related macular degeneration |
| CN113226020A (en) * | 2018-11-14 | 2021-08-06 | 珠海岐微生物科技有限公司 | Animal models, screening methods and treatment methods for intraocular diseases or disorders |
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| Bioorganic & Medicinal Chemistry Letters, 2004, vol. 14, pp. 3841~3845* |
| 학위논문(최하나, 건국대학교 대학원, 동물생명공학과 2010. 8]* |
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| CN113226020A (en) * | 2018-11-14 | 2021-08-06 | 珠海岐微生物科技有限公司 | Animal models, screening methods and treatment methods for intraocular diseases or disorders |
| WO2020113759A1 (en) * | 2018-12-03 | 2020-06-11 | Zhuhai Qiwei Bio-Technology Ltd. | Method of treating age-related macular degeneration |
| WO2020113373A1 (en) * | 2018-12-03 | 2020-06-11 | Zhuhai Qiwei Bio-Technology Ltd. | Method of treating age-related macular degeneration |
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