KR101731214B1 - Pharmaceutical composition for preventing or treating breast cancer comprising cudratricusxanthone A - Google Patents
Pharmaceutical composition for preventing or treating breast cancer comprising cudratricusxanthone A Download PDFInfo
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- KR101731214B1 KR101731214B1 KR1020160067991A KR20160067991A KR101731214B1 KR 101731214 B1 KR101731214 B1 KR 101731214B1 KR 1020160067991 A KR1020160067991 A KR 1020160067991A KR 20160067991 A KR20160067991 A KR 20160067991A KR 101731214 B1 KR101731214 B1 KR 101731214B1
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- breast cancer
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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- A—HUMAN NECESSITIES
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- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
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Abstract
Description
쿠드라트리구스잔톤 A(Cudratricusxanthone A; CTXA)를 유효성분으로 함유하는 유방암 예방 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing or treating breast cancer, which contains Cudratricus xanthone A (CTXA) as an active ingredient.
유방암은 미국에서는 여성암 중 1위, 우리나라에서는 3위를 차지하는 가장 보편적인 암으로 매년 약 2만 명의 여성들이 유방암에 걸리며, 환자 발생도 매년 증가하는 추세이다. 유방암의 치료는 조기 진단시 외과적 절제술로 치료가 가능하나 많은 환자에서 폐, 뼈, 간 등의 전이 형태로 재발된다.Breast cancer is the most common cancer in the United States, which is the most common cancer in the United States, and the third most common cancer in Korea. About 20,000 women each year are affected by breast cancer. The treatment of breast cancer can be treated by surgical resection in early diagnosis, but recurrence occurs in lung, bone, and liver in many patients.
암 세포의 전이는 세포를 둘러싸고 있는 조직으로 침투해 들어가는 세포 침윤 과정이 필수적이며 이는 악성 암세포의 특징 중 하나이다. 암세포의 침윤성은 세포외 기질(extracellular matrix; ECM)과 기저막(basement membrane)을 분해하는 단백질 분해과정과 분해된 매트릭스(matrix)를 통하여 이동하는 세포 이동성(migration)이 관여한다. ECM을 분해하는 단백질 분해 효소 중 대표적인 것이 매트릭스 메탈로프로티에이즈(matrix metalloproteinase; MMP)이며, 이 중 특히 MMP-2와 MMP-9이 세포 침윤성에 중요한 역할을 한다.Cancer cell metastasis is an essential process of cell infiltration that penetrates into the surrounding tissue and is one of the characteristics of malignant cancer cells. The invasiveness of cancer cells is involved in the proteolytic process that breaks down the extracellular matrix (ECM) and basement membrane, and cell migration through the degraded matrix. Among the proteolytic enzymes that degrade ECM, matrix metalloproteinase (MMP) is a typical example, and MMP-2 and MMP-9 play an important role in cell invasion.
이에 따라서, 최근에는 유방암을 포함한 다양한 암종에서 MMP-9 신호 전달 경로를 새로운 항암 타겟으로 한 연구 및 치료제 개발이 진행되고 있다.Recently, research and development of a new anti-cancer target of MMP-9 signal transduction pathway in various cancer types including breast cancer are being developed.
현대 의학의 대표적 암 치료법에는 외과적 수술요법, 생물요법, 방사선요법, 항암물질 투여에 의한 화학요법 등이 있다. 화학요법은 항암제를 경구나 주사로 투여하여 암세포의 증식을 억제하는 방법으로서, 화학요법이 가지는 장점은 몸의 어떤 부위에 생긴 암이라도 약물이 도달할 수 있고 전이된 암을 치료할 수 있다는 것으로, 현재 화학요법은 전이성 암 치료에 표준요법으로 사용되고 있다. 물론 화학요법으로 전이된 암을 완치시킬 수 있는 것은 아니지만 증상을 완화시켜 수명을 연장시켜주는 중요한 역할을 한다. 현재까지 천연물 유래의 항암제 중 가장 널리 사용되고 있는 항암제는 택솔 (taxol)로서 유방암, 난소암의 치료에 사용되고 있으나, 이러한 화학요법제는 부작용, 항암제 내성 등의 문제점을 가지고 있다.Typical cancer treatment methods in modern medicine include surgical surgery, biotherapy, radiation therapy, and chemotherapy by administration of anticancer agents. Chemotherapy is a method of inhibiting the proliferation of cancer cells by administering an anticancer drug by injection or injection. The advantage of chemotherapy is that the cancer can be reached by any part of the body and the cancer can be treated. Chemotherapy has been used as a standard therapy for metastatic cancer treatment. Of course, it is not possible to cure metastatic cancer by chemotherapy, but it plays an important role in alleviating symptoms and prolonging the life span. Up to now, anticancer drugs which are most widely used among anticancer drugs derived from natural products have been used as taxol in the treatment of breast cancer and ovarian cancer, but these chemotherapeutic agents have problems such as side effects, anticancer drug resistance and the like.
본 발명은 쿠드라트리구스잔톤 A(Cudratricusxanthone A; CTXA)를 유효성분으로 함유하는 조성물을 유방암 예방 또는 치료용 약학조성물 또는 건강식품으로 제공하고자 한다.The present invention provides a composition containing Cudratricus xanthone A (CTXA) as an active ingredient as a pharmaceutical composition for the prevention or treatment of breast cancer or a health food.
본 발명은 쿠드라트리구스잔톤 A(Cudratricusxanthone A; CTXA)를 유효성분으로 함유하는 유방암 예방 또는 치료용 약학조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating breast cancer, which contains Cudratricus xanthone A (CTXA) as an active ingredient.
또한, 본 발명은 쿠드라트리구스잔톤 A(Cudratricusxanthone A; CTXA)를 유효성분으로 함유하는 유방암 개선용 건강식품을 제공한다.The present invention also provides a health food for improving breast cancer, which contains Cudratricus xanthone A (CTXA) as an active ingredient.
본 발명에 따르면, 쿠드라트리구스잔톤 A(CTXA)가 처리된 유방암세포에서 쿠드라트리구스잔톤 A의 농도 의존적으로 유방암 세포의 세포사멸이 증가되었으며, PMA(phorbol 12-myristate 12-actate)에 의해 유도되는 유방암 세포 이동 및 침윤을 효과적으로 억제하는 것이 확인됨에 따라, 쿠드라트리구스잔톤 A(CTXA)를 유효성분으로 함유하는 조성물은 유방암 예방 또는 치료용 약학조성물 및 건강식품으로 사용될 수 있다.According to the present invention, the cell death of breast cancer cells was increased in a dose-dependent manner in a dose-dependent manner in a breast cancer cell treated with quadratureglus xanthone A (CTXA), and induced by PMA (phorbol 12-myristate 12-actate) (CTXA) as an active ingredient can be used as a pharmaceutical composition for the prevention or treatment of breast cancer and as a health food.
도 1은 쿠드라트리구스잔톤 A(Cudratricusxanthone A; CTXA)의 화합물 구조이다.
도 2는 CTXA의 세포 생존력을 확인한 결과로, MCF-7 세포(A) 및 MDA-MB-231 세포(B)에 CTXA (1-50 μM)를 처리하여 24시간 동안 배양하고, 세포 생존력을 확인한 결과이다. *p<0.05 vs. control.
도 3은 MCF-7 및 MDA-MB-231 세포의 형태에 미치는 CTXA의 효과를 확인한 결과로, 1, 5, 10 및 20 μM 농도의 CTXA를 MCF-7(A) 및 MDA-MB-231(B) 세포에 24시간 동안 처리하고 세포의 형태를 광학현미경으로 확인한 결과이다(＊200).
도 4는 CTXA의 세포사멸(apoptosis) 효과를 확인한 결과로, 도 4A는 사람 유방암 세포인 MCF-7 및 MDA-MB-231 세포에 1, 5, 10 및 20 μM CTXA를 24시간 동안 처리한 후 아넥신 V 및 PI로 염색하고 유세포 분석기로 사멸된 세포를 확인한 결과이며, 도 4B는 CTXA에 의해 사멸이 유도된 세포를 백분율로 나타낸 그래프이다.
도 5는 세포사멸과 관련된 단백질 발현에 미치는 CTXA의 영향을 확인한 결과로, 1, 5, 10 및 20 μM 농도의 CTXA를 MCF-7(A) 및 MDA-MB-231(B) 세포에 24시간 동안 처리한 후, Bax, Bcl-2, 카스파제(caspase)-3, 절단된 카스파제(cleaved caspase)-3, PARP 및 절단된 PARP(cleaved PARP)의 수준을 웨스턴 블롯 분석으로 확인한 결과이다.
도 6은 CTXA가 PMA(phorbol 12-myristate 12-actate)에 의해 유도되는 MM-9 발현을 억제하는 효과를 확인한 결과로, PMA가 처리된 MCF-7(도 6A 및 6C) 및 MDA-MB-231(도 6C) 세포에 0, 1, 2.5, 5 및 10 μM 농도의 CTXA를 24시간 동안 처리한 후, 세포 용해물을 이용하여 웨스턴 블롯 및 젤라틴 자이모그래피 분석을 수행한 결과이다.
도 7은 CTXA가 PMA(phorbol 12-myristate 12-actate)에 의해 유도되는 유방암 세포의 침윤을 억제하는 효과를 확인한 마트리겔 침윤 분석 결과로, 도 7A 및 7B는 PMA 100 nM가 처리된 MCF-7 및 MDA-MB-231 세포에 1, 5 및 10 μM 농도의 CTXA를 24시간 동안 처리한 후, 필터의 아래부분의 세포를 고정한 후 염색하여 확인한 결과이며, 도 7C 및 7D는 필터를 통과하여 침윤한 세포 수를 확인한 결과로, 세번 반복 실험한 결과를 평균 ± 표준오차로 나타낸 그래프이다.
도 8은 CTXA가 PMA(phorbol 12-myristate 12-actate)에 의해 유도되는 유방암 세포의 이동을 억제하는 효과를 확인한 결과로, 도 8A 및 8B는 MCF-7 및 MDA-MB-231 세포를 6 웰에 분주하고 하룻밤 동안 배양한 후, PMA 및 CTXA 5 μM을 24시간 동안 처리하고 세포 이동을 현미경으로 확인한 결과이며, 도 8C 및 8D는 ProgRes CapturePro program(v.2.8.0)을 이용하여 세포가 존재하지 않는 공간으로 이동한 세포수를 계수하여 그래프로 나타낸 결과이다.
도 9는 MCF-7 및 MDA-MB-231 세포에서 CTXA의 MAPK 신호과정 억제 효과를 확인한 결과로, MCF-7 및 MDA-MB-231 세포를 무혈청배지에서 24시간 배양하고 0, 1, 2.5, 5 및 10 μM 농도의 CTXA를 2시간 동안 처리한 후, 100 nM PMA를 15분간 처리한 세포를 수집하여 인산화 특이적 항체를 이용한 웨스턴 블롯을 수행하여 phosphor-JNK, p38 및 ERK1/2 수준을 확인한 결과, 유방암 세포에서 CTXA가 p38/JNK의 활성을 효과적으로 억제하는 것을 확인한 결과이다.
도 10은 MCF-7 및 MDA-MB-231 세포에서 CTXA가 IκBα 신호과정을 억제하는 효과를 확인한 결과로, MCF-7 및 MDA-MB-231 세포를 무혈청배지에서 24시간 배양하고 0, 1, 2.5, 5 및 10 μM 농도의 CTXA를 2시간 동안 처리한 후, 100 nM PMA를 15분간 처리한 세포를 수집하고 인산화 특이적 항체를 이용하여 인산화된 IκBα 수준을 확인한 웨스턴 블롯 분석결과이다.
도 11은 CTXA에 의해 유도되는 유방암 세포의 세포사멸 및 전이 억제 과정을 나타낸 모식도이다.Figure 1 shows the compound structure of Cudratricus xanthone A (CTXA).
FIG. 2 shows CTXA cell viability. As a result, CTXA (1-50 μM) was treated with MCF-7 cells (A) and MDA-MB-231 cells (B) for 24 hours and cell viability Results. * p < control.
FIG. 3 shows the effect of CTXA on the morphology of MCF-7 and MDA-MB-231 cells. CTXA at concentrations of 1, 5, 10 and 20 μM was administered to MCF-7 (A) and MDA-MB- B) cells for 24 hours, and the morphology of the cells was confirmed by optical microscopy (* 200).
FIG. 4A shows the results of examining the apoptosis effect of CTXA. FIG. 4A shows that human breast cancer cells MCF-7 and MDA-MB-231 cells were treated with 1, 5, 10 and 20 μM CTXA for 24 hours Annexin V and PI and stained with a flow cytometry analyzer. FIG. 4B is a graph showing the percentage of cells induced to be killed by CTXA.
FIG. 5 shows the effect of CTXA on the expression of proteins involved in cell death, showing that CTXA at concentrations of 1, 5, 10 and 20 μM was inhibited in MCF-7 (A) and MDA-MB-231 Bax, Bcl-2, caspase-3, cleaved caspase-3, PARP, and cleaved PARP levels after Western blot analysis.
FIG. 6 shows that the CTXA inhibited the expression of MM-9 induced by PMA (phorbol 12-myristate 12-actate), indicating that PMA-treated MCF-7 (FIGS. 6A and 6C) and MDA- 231 (FIG. 6C) cells treated with CTXA at concentrations of 0, 1, 2.5, 5 and 10 μM for 24 hours, followed by western blotting and gelatin zymography analysis using cell lysate.
7 shows results of Matrigel infiltration analysis that confirmed the effect of CTXA on the inhibition of breast cancer cell infiltration induced by PMA (phorbol 12-myristate 12-actate). Figs. 7A and 7B show that MCF-7 treated with 100 nM PMA And MDA-MB-231 cells were treated with CTXA at concentrations of 1, 5, and 10 μM for 24 hours, and the cells at the lower part of the filter were fixed and stained. FIGS. 7C and 7D show the results As a result of confirming the number of cells, it is a graph showing the results of three repeated experiments as the mean ± standard error.
8A and 8B show the effect of CTXA on phorbol 12-myristate 12-actate induced breast cancer cell migration inhibition. FIGS. 8A and 8B show that MCF-7 and MDA-MB- And cultured overnight. The cells were treated with 5 [mu] M of PMA and CTXA for 24 hours, and the cell migration was confirmed by microscopy. Figures 8C and 8D show the results of cell proliferation using ProgRes CapturePro program (v.2.8.0) The number of cells migrated to a space that does not exist is counted and shown as a graph.
FIG. 9 shows that MCF-7 and MDA-MB-231 cells were cultured in serum-free medium for 24 hours and inhibited the MAPK signaling of CTXA in MCF-7 and MDA-MB- , 5 and 10 μM of CTXA for 2 hours, and then treated with 100 nM PMA for 15 minutes. Western blotting using a phosphorylation-specific antibody was performed to detect phosphor-JNK, p38 and ERK1 / 2 levels As a result, it was confirmed that CTXA effectively inhibited the activity of p38 / JNK in breast cancer cells.
FIG. 10 shows that MCF-7 and MDA-MB-231 cells were cultured in a serum-free medium for 24 hours, and 0, 1 , CTXA at concentrations of 2.5, 5, and 10 μM for 2 hours, followed by collection of cells treated with 100 nM PMA for 15 minutes and detection of phosphorylated IκBα levels using phosphorylation-specific antibodies.
FIG. 11 is a schematic view showing the process of inhibiting CTXA-induced apoptosis and metastasis of breast cancer cells.
본 발명은 쿠드라트리구스잔톤 A(Cudratricusxanthone A; CTXA)를 유효성분으로 함유하는 유방암 예방 또는 치료용 약학조성물을 제공할 수 있다.The present invention can provide a pharmaceutical composition for the prevention or treatment of breast cancer containing Cudratricus xanthone A (CTXA) as an active ingredient.
상기 쿠드라트리구스잔톤 A는 세포사멸 억제인자인 Bcl-2의 발현을 억제하고 세포사멸 유도인자인 Bax를 활성화시켜 유방암세포의 세포사멸을 유도할 수 있다.The above-mentioned coduratrix suzantone A inhibits the expression of Bcl-2, a cell death suppressor, and activates Bax, a cell death inducer, to induce apoptosis of breast cancer cells.
본 발명의 일실시예에 따르면, 유방암 세포주인 MCF-7 및 MDA-MB-231 세포에 CTXA (1, 5, 10 및 20 μM)를 24시간 동안 처리하고 아넥신 V 및 PI로 이중 염색한 후 사멸된 세포(Annexin V+/PI-)의 수를 유세포분석기로 확인한 결과, 도 4A 및 4B와 같이 CTXA가 처리된 세포군의 사멸된 세포 백분율이 대조군과 비교하여 매우 증가된 것을 확인할 수 있었다.According to one embodiment of the present invention, CTXA (1, 5, 10 and 20 μM) was treated for 24 hours in breast cancer cell lines MCF-7 and MDA-MB-231 and double stained with Annexin V and PI The number of dead cells (Annexin V + / PI-) was confirmed by flow cytometry. As shown in FIGS. 4A and 4B, the percentage of dead cells in the CTXA-treated cell group was significantly increased as compared with the control group.
상기 CTXA의 세포사멸 기전을 확인한 결과, 도 5A 및 도 5B와 같이 CTXA (1, 5, 10 및 20 μM)가 처리된 MCF-7 및 MDA-MB-231 세포에서 카스파제-3의 활성화, 절단된 카스파제-3, PARP 및 PARP의 절단이 유도된 것을 확인됨에 따라, CTXA에 의해 유도된 세포사멸은 미토콘드리아의 관여에 의한 것으로 확인되었으며, 상기 CTXA에 의해 유도되는 세포사멸은 미토콘드리아 막 보전을 조절하는 단백질인 Bcl-2의 발현을 저하시키는 반면, Bax 단백질의 발현을 증가시켜 유방암 세포의 세포사멸을 증가시키는 것을 확인할 수 있었다.As shown in FIGS. 5A and 5B, activation of caspase-3 in MCF-7 and MDA-MB-231 cells treated with CTXA (1, 5, 10 and 20 μM) It was confirmed that CTXA-induced apoptosis was due to the involvement of mitochondria, and that the CTXA-induced apoptosis induced
또한, 상기 쿠드라트리구스잔톤 A는 MMP-9 발현 억제 및 MAPK와 IκBα 신호과정을 억제하여 유방암 세포의 전이를 억제할 수 있다.In addition, the above-mentioned quadratureglucosone A inhibits MMP-9 expression and inhibits MAPK and IκBα signaling, thereby inhibiting the metastasis of breast cancer cells.
본 발명의 다른 일실시예에 따르면, 마트리겔 침윤 분석을 통한 MCF-7 및 MDA-MB-231 세포의 이동 및 침윤을 확인한 결과, 도 7과 같이 PMA가 처리되지 않은 대조군과 비교하여 PMA가 처리된 MCF-7 및 MDA-MB-231 세포군의 이동 및 침윤이 증가된 것을 확인된 반면, CTXA 10μM가 처리된 MCF-7 및 MDA-MB-231 세포군에서는 PMA에 의해 유도되는 MCF-7 및 MDA-MB-231 세포 침윤이 거의 억제된 것을 확인할 수 있었다.According to another embodiment of the present invention, migration and infiltration of MCF-7 and MDA-MB-231 cells through matrigel invasion analysis were examined. As a result, compared with the control group not treated with PMA, And MDA-MB-231 cells in the MCF-7 and MDA-MB-231 cell lines treated with 10 μM of CTXA, whereas the MCF-7 and MDA- MB-231 cell infiltration was almost suppressed.
상기 세포 전이 억제 기전을 확인한 결과, 도 6과 같이 PMA 100nm가 처리된 MCF-7 및 MDA-MB-231 세포 및 각각의 조건 배지에서 MMP-9 발현이 촉진된 반면, CTXA가 처리된 세포군에서는 CTXA 농도 의존적으로 MMP-9 수준이 감소된 것을 확인할 수 있었으며, MCF-7 및 MDA-MB-231 세포에서 MAPK 신호과정을 확인한 결과, 도 9와 같이 PMA에 의해 유도되는 ERK1/2, p38 및 JNK의 인산화가 CTXA에 의해 효과적으로 억제되는 것이 확인되었다. As shown in FIG. 6, MMP-9 expression was promoted in MCF-7 and MDA-MB-231 cells treated with
또한, 도 10과 같이 PMA로 자극된 유방암 세포 내 IκBα 인산화 역시 매우 효과적으로 억제되는 것을 확인할 수 있었다.In addition, as shown in FIG. 10, it was confirmed that IκBα phosphorylation in breast cancer cells stimulated by PMA was also effectively inhibited.
상기 결과로부터 CTXA는 MMP-9의 발현을 감소시키고, MAPK 신호과정뿐만 아니라, NF-κB 신호과정을 효과적으로 저해하여 유방암 세포의 전이를 억제하는 것을 확인할 수 있었다.From the above results, it was confirmed that CTXA reduces the expression of MMP-9 and effectively inhibits the NF-κB signal process as well as the MAPK signal process, thereby inhibiting the metastasis of breast cancer cells.
상기 약학조성물은 약학조성물 총 100 중량부에 대하여, 쿠드라트리구스잔톤 A를 0.01 내지 90 중량부로 함유할 수 있다.The pharmaceutical composition may contain 0.01 to 90 parts by weight of quadrathlyxanthone A per 100 parts by weight of the total amount of the pharmaceutical composition.
본 발명의 한 구체예에서, 상기 쿠드라트리구스잔톤 A를 유효성분으로 함유하는 유방암 예방 또는 치료용 약학조성물은 통상적인 방법에 따라 주사제, 과립제, 산제, 정제, 환제, 캡슐제, 좌제, 겔, 현탁제, 유제, 점적제 또는 액제로 이루어진 군에서 선택된 어느 하나의 제형을 사용할 수 있다.In one embodiment of the present invention, the pharmaceutical composition for preventing or treating breast cancer containing the above-mentioned quadraturegluzanone A as an active ingredient can be administered orally or parenterally in the form of injections, granules, powders, tablets, pills, capsules, suppositories, Any one of the formulations selected from the group consisting of suspensions, emulsions, drops, and liquid preparations can be used.
본 발명의 다른 구체예에서, 쿠드라트리구스잔톤 A를 유효성분으로 함유하는 유방암 예방 또는 치료용 약학조성물은 약학조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제, 붕해제, 감미제, 피복제, 팽창제, 윤활제, 활택제, 향미제, 항산화제, 완충액, 정균제, 희석제, 분산제, 계면활성제, 결합제 및 윤활제로 이루어진 군에서 선택되는 하나 이상의 첨가제를 추가로 포함할 수 있다.In another embodiment of the present invention, the pharmaceutical composition for preventing or treating breast cancer, wherein the composition contains quadrupuloguszanthone A as an active ingredient, may be formulated with suitable carriers, excipients, disintegrants, sweeteners, , At least one additive selected from the group consisting of lubricants, lubricants, flavors, antioxidants, buffers, bacteriostats, diluents, dispersants, surfactants, binders and lubricants.
구체적으로 담체, 부형제 및 희석제는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 사용할 수 있으며, 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 조성물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 칼슘카보네이트, 수크로스 또는 락토오스, 젤라틴 등을 섞어 조제할 수 있다. 또한 단순한 부형제 이외에 마그네슘 스티레이트, 탈크 같은 윤활제들도 사용할 수 있다. 경구를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 있으며 흔히 사용되는 단순 희석제인 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, 좌제 등이 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기재로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.Specific examples of carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, Cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. Solid formulations for oral administration may be in the form of tablets, pills, powders, granules, capsules These solid preparations can be prepared by mixing at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, gelatin, etc., into the composition. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, syrups and the like, and various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included in addition to water and liquid paraffin which are commonly used simple diluents. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. As the suppository base, witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like can be used.
본 발명의 일실시예에 따르면 상기 약학 조성물은 정맥내, 동맥내, 복강내, 근육내, 동맥내, 복강내, 흉골내, 경피, 비측내, 흡입, 국소, 직장, 경구, 안구내 또는 피내 경로를 통해 통상적인 방식으로 대상체로 투여할 수 있다.According to one embodiment of the present invention, the pharmaceutical composition may be administered orally, intraarterally, intraperitoneally, intramuscularly, intraarterally, intraperitoneally, intrasternally, transdermally, nasally, inhaled, topically, rectally, ≪ / RTI > can be administered to the subject in a conventional manner.
상기 쿠드라트리구스잔톤 A의 바람직한 투여량은 대상체의 상태 및 체중, 질환의 종류 및 정도, 약물 형태, 투여경로 및 기간에 따라 달라질 수 있으며 당업자에 의해 적절하게 선택될 수 있다. 본 발명의 일실시예에 따르면 이에 제한되는 것은 아니지만 1일 투여량이 0.01 내지 200 mg/kg, 구체적으로는 0.1 내지 200 mg/kg, 보다 구체적으로는 0.1 내지 100 mg/kg 일 수 있다. 투여는 하루에 한 번 투여할 수도 있고 수회로 나누어 투여할 수도 있으며, 이에 의해 본 발명의 범위가 제한되는 것은 아니다.The preferred dosage of the above-mentioned quadraturegluzosone A may vary depending on the condition and body weight of the subject, the kind and degree of disease, the drug form, the administration route and the period, and can be appropriately selected by those skilled in the art. According to one embodiment of the present invention, the daily dose may be 0.01 to 200 mg / kg, specifically 0.1 to 200 mg / kg, more specifically 0.1 to 100 mg / kg, though it is not limited thereto. The administration may be performed once a day or divided into several times, and thus the scope of the present invention is not limited thereto.
본 발명에 있어서, 상기 '대상체'는 인간을 포함하는 포유동물일 수 있으나, 이들 예에 한정되는 것은 아니다.In the present invention, the 'subject' may be a mammal including a human, but is not limited thereto.
또한, 본 발명은 쿠드라트리구스잔톤 A(Cudratricusxanthone A; CTXA)를 유효성분으로 함유하는 유방암 개선용 건강식품을 제공할 수 있다.In addition, the present invention can provide a health food for improving breast cancer containing Cudratricus xanthone A (CTXA) as an active ingredient.
상기 건강식품은 상기 쿠드라트리구스잔톤 A 이외에 다른 식품 또는 식품 첨가물과 함께 사용되고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효성분의 혼합양은 그의 사용 목적 예를 들어 예방, 건강 또는 치료적 처치에 따라 적합하게 결정될 수 있다.The health food is used together with food or food additives other than the above-mentioned cadrugluxzantone A, and can be suitably used according to a conventional method. The amount of the active ingredient to be mixed can be suitably determined according to its use purpose, for example, prevention, health or therapeutic treatment.
상기 건강식품에 함유된 화합물의 유효용량은 상기 치료제의 유효용량에 준해서 사용할 수 있으나, 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 범위 이하일 수 있으며, 유효성분은 안전성 면에서 아무런 문제가 없기 때문에 상기 범위 이상의 양으로도 사용될 수 있음은 확실하다.The effective dose of the compound contained in the above-mentioned health food may be used in accordance with the effective dose of the therapeutic agent, but may be less than the above range for health and hygiene purposes or for long-term intake for health control purposes, It is clear that the component can be used in an amount of more than the above range since there is no problem in terms of safety.
상기 건강식품의 종류에는 특별한 제한이 없고, 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제등을 들 수 있다.There is no particular limitation on the type of the health food, and examples thereof include meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, Drinks, alcoholic beverages and vitamin complexes.
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 당업계에서 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.
<< 실험예Experimental Example 1> 추출물 준비 1> Preparation of extract
꾸지뽕 뿌리를 대구 약령시에서 구입하였으며, 상기 꾸지뽕 뿌리로부터 쿠드라트리구스잔톤 A(Cudratricusxanthone A; CTXA)를 분리하여 사용하였다.Cucumber root was purchased from Myonghwa City, Daegu, and Cudratricus xanthone A (CTXA) was isolated from the cucumber root.
<< 실험예Experimental Example 2> 세포 배양 및 처리 2> Cell culture and treatment
사람 유방암 세포주인 MCF-7 및 MDA-MB-231 세포를 KCLB(Korean Cell Line Bank)에서 얻었으며, 상기 MCF-7 및 MDA-MB-231 세포를 10% 태아소혈청(fetal bovine serum; FBS)과 항생제(페니실린/스트렙토마이신)가 포함된 DMEM(Dulbecco’s modified Eagle’s medium) 및 RPMI 1640 배지를 이용하여 37℃, 5% CO2가 포함된 가습 조건에서 배양하였다.MCF-7 and MDA-MB-231 cells were obtained from KCLB (Korean Cell Line Bank). The MCF-7 and MDA-MB-231 cells were cultured in 10% fetal bovine serum (FBS) And Dulbecco's modified Eagle's medium containing antibiotics (penicillin / streptomycin) and RPMI 1640 medium at 37 ° C and 5
<< 실험예Experimental Example 3> 세포 생존도 분석 3> Cell viability analysis
96웰 플레이트에 각 세포를 웰 당 1＊104 cells/㎖씩 분주하고 다양한 농도의 쿠드라트리구스잔톤 A(CTXA)를 18시간 동안 37℃, 5% CO2가 포함된 가습 조건에서 처리하였다.Each cell was plated at a concentration of 1 × 10 4 cells / ml in a 96-well plate, and various concentrations of quadratureglus xanthone A (CTXA) were treated for 18 hours at 37 ° C. in humidified condition containing 5% CO 2 .
상기 방법으로 처리된 세포 부유물 1㎖에 MTT(3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) 10㎕를 첨가하여 4시간 동안 반응시킨 후, 배지를 제거하고 DMSO(dimethylsulfoxide) 100㎕를 첨가한 후, microplate reader (Tecan Trading AG, Switzerland)를 이용하여 595nm로 분광학적 흡광도를 측정하였다. 세포 생존력은 대조군의 상대 백분율로 나타내었다. 10 μl of MTT (3- [4,5-dimethylthiazol-2-yl] -2,5-diphenyl tetrazolium bromide) was added to 1 ml of the cell suspension, and the reaction was carried out for 4 hours. After adding 100 μl of DMSO (dimethylsulfoxide), the spectrophotometric absorbance was measured at 595 nm using a microplate reader (Tecan Trading AG, Switzerland). Cell viability was expressed as relative percentage of control.
<< 실험예Experimental Example 4> 침윤분석(Invasion assay) 4> Invasion assay
BD BioCoatTM MatrigelTM Invasion Chamber (BD Biosciences, USA)를 이용하여 제조사의 설명서에 따라 침윤분석을 수행하였다.BD BioCoat TM Matrigel TM Invasion chamber (BD Biosciences, USA) was used to perform invasion analysis according to the manufacturer's instructions.
배지 0.5 ㎖로 코팅한 마트리겔을 37℃, 5% CO2 습식 배양기에서 2시간 동안 재수화시킨 후, 다양한 농도의 CTXA가 담겨있는 바닥 웰의 상위 챔버에 세포를 2＊104 cells/0.5 ㎖로 분주하였다.Matrigel coated with 0.5 ml of the medium was rehydrated in a 5% CO 2 humidified incubator at 37 ° C. for 2 hours. Then, the cells were transferred to upper chambers of the bottom wells containing various concentrations of CTXA at a concentration of 2 × 10 4 cells / 0.5 ml ≪ / RTI >
상기 챔버를 22시간 동안 배양한 후 위쪽 챔버의 세포를 고정하고 톨루이딘 블루(Toluidine blue) 용액으로 염색하고, inverted microscope (Leica Microsystems CMS GmbH, Germany)를 이용하여 막의 네 부분을 무작위로 선정하여 침윤한 세포를 계수하였다.After incubating the chamber for 22 hours, cells in the upper chamber were fixed, stained with a toluidine blue solution, and four sections of the membrane were randomly selected and infiltrated using an inverted microscope (Leica Microsystems CMS GmbH, Germany) Cells were counted.
<< 실험예Experimental Example 5> 상처 치유 분석(Wound healing assay) 5> Wound healing assay
6웰 플레이트에 세포를 접종하고 세포가 합류되도록 하룻밤 동안 배양하였다. 상기 배양된 세포를 200 ㎕ 피펫 팁으로 긁어 상처를 제작하고, 배지로 세척한 후 다양한 농도의 CTXA가 포함된 무혈청배지로 교체하였다.Cells were inoculated in 6 well plates and incubated overnight. The cultured cells were scratched by scraping with a 200 μl pipette tip, washed with medium, and replaced with serum-free medium containing various concentrations of CTXA.
24시간 후, 현미경을 이용하여 CTXA 농도에 따른 세포의 이동을 확인하고, 그 결과를 영역당 이동한 세포 수의 평균으로 나타내었다.Twenty-four hours later, cell migration was determined by CTXA concentration using a microscope and the results were expressed as the average number of cells migrated per region.
<< 실험예Experimental Example 6> 6> 웨스턴Western 블롯Blot 분석 analysis
용해 버퍼에 세포를 부유시켜 세포 용해물을 준비하였다.Cell lysates were prepared by suspending cells in lysis buffer.
동량의 단백질을 10% SDS-PAGE(sodium dodecyl sulfate-polyacrylamied gel electrophoresis)에 분리시키고, PVDF(polyvinylidene difluoride) 막으로 옮겼다.The same amount of protein was separated by 10% SDS-PAGE (sodium dodecyl sulfate-polyacrylamid gel electrophoresis) and transferred to PVDF (polyvinylidene difluoride) membrane.
상기 막을 5% 탈지유(skim milk)로 차단시키고 일차 항체 및 홀스래디쉬 퍼옥사이드가 결합된 이차 항체를 연속하여 인큐베이트하였다.The membrane was blocked with 5% skim milk and the primary antibody and the secondary antibody conjugated with horseradish peroxides were successively incubated.
상기 막을 TBS-T 버퍼로 15분씩 3번 세척하고, Western BrightTM ECL Western blotting detection kit (Advansta Inc., USA)를 이용하여 제조사의 설명서대로 상기 면역블롯 막을 인큐베이트한 후 imagequantTM LAS4000 (Fujifilm Life Science, Japan)로 시각화하였다.The film is washed for 15 minutes three times with TBS-T buffer, Bright Western TM ECL Western blotting detection kit (Advansta Inc. , USA) and then incubated in the manufacturer's instructions to stop the bait imagequant immunoblot using a TM LAS4000 (Fujifilm Life Science, Japan).
<< 실험예Experimental Example 7> 젤라틴 7> Gelatin 자이모그래피Zymography 분석(Gelatin Analysis (Gelatin zymographyzymography assay) assay)
젤라틴 자이모그래피 분석을 이용하여 MMP-9의 효소 활성을 확인하기 위해, 세포가 합류되도록 24시간 동안 배양한 후 무혈청 배지로 유지시켰다.To confirm the enzymatic activity of MMP-9 using gelatin-zymography analysis, cells were incubated for 24 hours to be confluent and maintained in serum-free medium.
24시간 자극 후 조건 배지를 수집하여 비환원 버퍼와 혼합하고 0.1 % (wt/vol) 젤라틴이 포함된 10 % 폴리아크릴아마이드 겔에 전기영동하였다.After 24 hour stimulation, conditioned medium was collected, mixed with non-reducing buffer, and electrophoresed on a 10% polyacrylamide gel containing 0.1% (wt / vol) gelatin.
상기 겔을 2.5 % 트리톤 X-100, 50 mM Tris-HCl (pH 7.5), 150 mM NaCl, 5 mM CaCl2, 1 mM ZnCl2 및 40 mmol/NaN3이 포함된 버퍼로 세척하였으며, 세척된 겔을 45% (vol/vol) 메탄올 및 1% (vol/vol) 아세트산에 포함된 0.25 %(wt/vol) 쿠마시브릴리언트블루(Coomassie brilliant blue)로 염색하였다.The gel is 2.5% Triton X-100, 50 mM Tris- HCl (pH 7.5), 150 mM NaCl, 5
<< 실험예Experimental Example 8> 8> 아넥신Annexin V & PI 염색 V & PI staining
fluorescein isothiocyanate (FITC)-Annexin V staining kit (BD Biosciences, San Jose, CA, USA)를 이용하여 제조사의 설명서대로 아넥신 V 염색을 수행하였다.Annexin V staining kit (BD Biosciences, San Jose, Calif., USA) was used for staining with fluorescein isothiocyanate (FITC) -Annexin V staining kit.
간략하게, CTXA가 처리된 세포를 PBS로 세척하고 아넥신 V와 PI(propidium iodide)가 포함된 1×결합 버퍼에 재부유시킨 후 flow cytometry (BD Biosciences)를 이용하여 형광강도를 측정하였다.Briefly, CTXA-treated cells were washed with PBS and resuspended in 1 × binding buffer containing Annexin V and PI (propidium iodide), and fluorescence intensity was measured using flow cytometry (BD Biosciences).
<< 실시예Example 1> 암세포 생존 억제 효과 확인 1> Confirm survival inhibition effect of cancer cells
MCF-7 및 MDA-MB-231 세포를 96-웰 플레이트에 웰 당 1＊104 세포로 분주하고 1 - 50 μM 농도의 CTXA를 처리하여 5% CO2, 37℃ 조건에서 24시간 동안 배양하였다.MCF-7 and MDA-MB-231 cells were plated in 96-well plates at 1 × 10 4 cells per well and treated with CTXA at a concentration of 1 to 50 μM for 24 hours at 5% CO 2 and 37 ° C. .
24시간 배양 후, 최종농도가 0.5 ㎎/㎖인 MTT 용액을 4시간 동안 처리하고 형성된 포르마잔(formazan)을 DMSO(dimethylsulfoxide)으로 용해시켰다.After culturing for 24 hours, the MTT solution having a final concentration of 0.5 mg / ml was treated for 4 hours, and the formazan formed was dissolved in DMSO (dimethylsulfoxide).
microplate reader(Tecan Trading AG, Switzerland)를 이용하여 595㎚에서 혼합물의 흡광도를 확인하고, 세포 생존도를 대조군에 대한 상대적인 생존 세포의 백분율로 나타내었다.The absorbance of the mixture was determined at 595 nm using a microplate reader (Tecan Trading AG, Switzerland) and the cell viability was expressed as a percentage of the viable cells relative to the control.
그 결과, 도 2와 같이 CTXA 농도의존적으로 MCF-7 및 MDA-MB-231 세포의 세포 생존이 억제되는 것을 확인할 수 있었다.As a result, it was confirmed that the cell survival of MCF-7 and MDA-MB-231 cells was inhibited depending on CTXA concentration as shown in FIG.
<< 실시예Example 2> 세포사멸 유도 효과 확인 2> Confirmation of induction of cell death
앞선 실험에서 확인된 CTXA에 의해 유도된 세포독성이 세포사멸(apoptosis)에 의한 결과인지를 확인하기 위해, FACS(fluorescence activated cell sorter) 분석을 수행하였다.A fluorescence activated cell sorter (FACS) assay was performed to confirm that the cytotoxicity induced by CTXA in the previous experiment was the result of apoptosis.
MCF-7 및 MDA-MB-231 세포에 CTXA (1, 5, 10 및 20 μM)를 24시간 동안 처리하고 세포 사멸된 세포(Annexin V+/PI-)의 수를 정량하기 위해, 아넥신 V 및 PI로 이중 염색한 후 유세포분석기로 확인하였다. In order to treat CTXA (1, 5, 10 and 20 μM) in MCF-7 and MDA-MB-231 cells for 24 hours and to quantify the number of apoptotic cells (Annexin V + / PI-), Annexin V and PI was double stained and confirmed by flow cytometry.
그 결과, 도 4A 및 4B와 같이 CTXA가 처리된 세포군에서 사멸된 세포의 백분율이 대조군과 비교하여 매우 증가된 것을 확인할 수 있었다.As a result, as shown in FIGS. 4A and 4B, it was confirmed that the percentage of cells killed in the CTXA-treated cell group was greatly increased as compared with the control.
<< 실시예Example 3> 세포사멸 기전 확인 3> Confirmation of cell death mechanism
카스파제(Caspases)는 세포사멸 기전의 주요 구성 요소로, 미토콘드리아 및 카스파제 신호기전은 상호 연관적이다(Yang et al. 2015, 1)인데, 본 발명의 도 5A 및 도 5B를 참고하면, CTXA(1, 5, 10 및 20 μM)가 처리된 MCF-7 및 MDA-MB-231 세포에서 카스파제-3의 활성화, 절단된 카스파제-3, PARP 및 PARP의 절단이 유도된 것을 확인할 수 있었다.Caspases are a major component of the apoptotic mechanism and mitochondrial and caspase signaling mechanisms are interrelated (Yang et al. 2015, 1). Referring to Figures 5A and 5B of the present invention, CTXA It was confirmed that activation of caspase-3, cleaved caspase-3, PARP and PARP cleavage were induced in MCF-7 and MDA-MB-231 cells treated with (1, 5, 10 and 20 μM) .
상기 결과로부터 CTXA에 의해 유도된 세포사멸은 미토콘드리아의 관여에 의한 것으로 확인되었다.From the above results, it was confirmed that CTXA-induced apoptosis was due to the involvement of mitochondria.
한편, Bcl-2 및 Bax 단백질은 미토콘드리아 막 보전을 조절하는 단백질로, CTXA이 Bcl-2 그룹 및 Bax 단백질의 발현에 영향을 미치는 것으로 확인되었다.On the other hand, Bcl-2 and Bax proteins are proteins that regulate mitochondrial membrane integrity and CTXA has been shown to affect the expression of Bcl-2 group and Bax protein.
상기 결과로부터 CTXA는 항-세포사멸 단백질인 Bcl-2의 발현을 저하시키고, Bax 단백질에 의해 유도되는 세포사멸을 증가시키는 것을 확인할 수 있었다.From the above results, it was confirmed that CTXA decreased the expression of Bcl-2, an anti-apoptotic protein, and increased Bax protein-induced cell death.
<< 실시예Example 4> 4> PMAPMA (( phorbolphorbol 12- 12- myristatemyristate 12- 12- actateactate )에 의해 유도되는 ) MMPMMP -9 분비 억제효과 확인-9 Confirmation of secretion inhibition
MMP-9의 발현은 유방암을 포함한 다양한 암질환과 매우 높은 연관성을 나타내는데, PMA에 의해 유도되는 MMP-9의 활성 및 분비에 있어 CTXA의 영향을 웨스턴 블롯 및 젤라틴 자이모그래피 분석으로 확인하였다.Expression of MMP-9 is highly correlated with various cancers including breast cancer. The effect of CTXA on the activity and secretion of MMP-9 induced by PMA was confirmed by Western blotting and gelatin zymography analysis.
그 결과, 도 6과 같이 PMA 100nm가 처리된 MCF-7 및 MDA-MB-231 세포 및 각각의 조건 배지에서 MMP-9 발현이 촉진된 반면, CTXA가 처리된 세포군에서는 CTXA 농도 의존적으로 MMP-9 수준이 감소된 것을 확인할 수 있었다.As a result, MMP-9 expression was promoted in MCF-7 and MDA-MB-231 cells treated with
상기 결과로부터 CTXA는 PMA에 의해 유도되는 MMP-9 발현을 억제하는 것을 확인할 수 있었다.From the above results, it was confirmed that CTXA inhibits the expression of MMP-9 induced by PMA.
<< 실시예Example 5> 5> PMAPMA (( phorbolphorbol 12- 12- myristatemyristate 12- 12- actateactate )에 의해 유도되는 침윤 억제효과 확인) Induced infiltration inhibition effect
마트리겔 침윤 분석을 통한 MCF-7 및 MDA-MB-231 세포의 이동 및 침윤을 확인한 결과, 도 7과 같이 PMA가 처리되지 않은 대조군과 비교하여 PMA가 처리된 MCF-7 및 MDA-MB-231 세포군의 이동 및 침윤이 증가된 것을 확인할 수 있었다.7 and MDA-MB-231 cells through the Matrigel invasion assay. As shown in FIG. 7, the PMA-treated MCF-7 and MDA-MB-231 cells Cell migration and invasion were increased.
CTXA를 앞선 생존도 분석 실험에서 확인된 세포 독성을 나타내지 않는 농도범위(1~10μM)로 상기 MCF-7 및 MDA-MB-231 세포군에 처리한 결과, 도 7과 같이 CTXA 10μM 이 처리된 세포군에서는 PMA에 의해 유도되는 MCF-7 및 MDA-MB-231 세포 침윤이 거의 억제된 것을 확인할 수 있었다.CTXA was treated with the above MCF-7 and MDA-MB-231 cell groups in a concentration range (1 to 10 μM) that did not exhibit the cytotoxicity confirmed by the previous survival assay. As a result, as shown in FIG. 7, It was confirmed that the infiltration of MCF-7 and MDA-MB-231 cells induced by PMA was almost suppressed.
상기 결과로부터 CTXA는 세포 침윤억제를 통하여 항-종양 효과를 나타내는 것이 확인되었다.From the above results, it was confirmed that CTXA showed an anti-tumor effect through inhibition of cell invasion.
<< 실시예Example 6> 6> PMAPMA (( phorbolphorbol 12- 12- myristatemyristate 12- 12- actateactate )에 의해 유도되는 세포 이동 억제효과 확인) Induced cell migration inhibition
세포 이동 및 운동성은 원발성 종양의 전이에 있어 중요한 침투 전략으로, CTXA가 MCF-7 및 MDA-MB-231 세포와 같은 유방암세포의 전이능을 억제할 수 있는지 확인하기 위해, 상처 치유 분석을 수행하였다.Cell migration and motility were an important penetration strategy for primary tumor metastasis and wound healing assays were performed to determine if CTXA could inhibit the metastatic potential of breast cancer cells such as MCF-7 and MDA-MB-231 cells .
그 결과, 도 8과 같이 5 μM CTXA가 처리된 실험군에서는 세포가 존재하지 않은 공간 안으로의 세포이동이 대략 20 ~ 30 % 억제된 것을 확인할 수 있었다.As a result, it was confirmed that cell migration into a cell-free space was inhibited by about 20 to 30% in the experimental group treated with 5 μM CTXA as shown in FIG.
<< 실시예Example 7> 7> PMAPMA (( phorbolphorbol 12- 12- myristatemyristate 12- 12- actateactate )에 의해 유도되는 ) IκBaIκBa 및 MAPK 신호과정 억제 효과 확인 And inhibition of MAPK signal processing
CTXA가 MAPK 및 IκBα 신호과정을 억제하는지 확인하였다.CTXA inhibited MAPK and IκBα signaling.
MCF-7 및 MDA-MB-231 세포에서 MAPK 신호과정을 확인한 결과, 도 9와 같이 PMA에 의해 유도되는 ERK1/2, p38 및 JNK의 인산화가 CTXA에 의해 효과적으로 억제되는 것이 확인되었다. 또한, 도 10과 같이 PMA로 자극된 유방암 세포 내 IκBα 인산화 역시 매우 효과적으로 억제되는 것을 확인할 수 있었다.As a result of confirming the MAPK signal process in MCF-7 and MDA-MB-231 cells, it was confirmed that phosphorylation of ERK1 / 2, p38 and JNK induced by PMA was effectively inhibited by CTXA as shown in Fig. In addition, as shown in FIG. 10, it was confirmed that IκBα phosphorylation in breast cancer cells stimulated by PMA was also effectively inhibited.
상기 결과로부터 CTXA는 MAPK 신호과정뿐만 아니라, NF-κB 신호과정을 효과적으로 억제하는 것을 확인할 수 있었다.From the above results, it was confirmed that CTXA effectively inhibited the NF-κB signal process as well as the MAPK signal process.
한편, 본 발명에 따른 쿠드라트리구스잔톤 A는 목적에 따라 여러 형태로 제제화가 가능하다. 하기에서는 본 발명에 따른 쿠드라트리구스잔톤 A를 활성성분으로 함유시킨 몇몇 제제화 방법을 예시한 것으로 본 발명이 이에 한정되는 것은 아니다.Meanwhile, according to the present invention, the quadratureglus xanthone A can be formulated into various forms according to the purpose. Hereinafter, some formulations containing quadratureglus xanthone A according to the present invention as an active ingredient are exemplified, but the present invention is not limited thereto.
<제제예 1> 약학조성물의 처방예Formulation Example 1 Prescription Example of Pharmaceutical Composition
<제제예 1-1> 주사제의 제조≪ Formulation Example 1-1 > Preparation of injection
쿠드라트리구스잔톤 A 10 mg, 소디움 메타비설파이트 3.0 mg, 메틸파라벤 0.8 mg, 프로필파라벤 0.1 mg 및 주사용 멸균증류수 적량을 혼합하고 통상의 방법으로 최종 부피가 2 ㎖이 되도록 제조한 후, 2 ㎖ 용량의 앰플에 충전하고 멸균하여 주사제를 제조하였다.10 mg of quadratureglucanthon A, 3.0 mg of sodium metabisulfite, 0.8 mg of methylparaben, 0.1 mg of propylparaben, and an appropriate amount of sterilized distilled water for injection are mixed and made to a final volume of 2 ml by a conventional method, Dose ampoule and sterilized to prepare an injection.
<제제예 1-2> 정제의 제조≪ Formulation Example 1-2 > Preparation of tablets
쿠드라트리구스잔톤 A 10 mg, 유당 100 mg, 전분 100 mg 및 스테아린산 마그네슘 적량을 혼합하고 통상의 정제 제조방법에 따라 타정하여 정제를 제조하였다.10 mg of cuprothioglucinol A, 100 mg of lactose, 100 mg of starch and an appropriate amount of magnesium stearate, and tableted according to a conventional tablet preparation method.
<제제예 1-3> 캡슐제의 제조≪ Formulation Example 1-3 > Preparation of capsules
쿠드라트리구스잔톤 A 10 mg, 유당 50 ㎎, 전분 50 ㎎, 탈크 2 ㎎ 및 스테아린산 마그네슘 적량을 혼합하고 통상의 캡슐제 제조방법에 따라 젤라틴 캡슐에 충전하여 캡슐제를 제조하였다.10 mg of lidocaine, 50 mg of lecithin, 50 mg of starch, 2 mg of talc, and magnesium stearate, and the mixture was filled in gelatin capsules according to a conventional capsule preparation method to prepare capsules.
<제제예 2> 건강식품의 제조≪ Formulation Example 2 > Preparation of health food
쿠드라트리구스잔톤 A 0.5 ㎎, 비타민 혼합물 적량(비타민 A 아세테이트 70 ㎍, 비타민 E 1.0 ㎎, 비타민 B 1 0.13 ㎎, 비타민 B 2 0.15 ㎎, 비타민 B 6 0.5 ㎎, 비타민 B 12 0.2 ㎍, 비타민 C 10 ㎎, 비오틴 10 ㎍, 니코틴산아미드 1.7 ㎎, 엽산 50 ㎍, 판토텐산 칼슘 0.5 ㎎) 및 무기질 혼합물 적량(황산제1철 1.75 ㎎, 산화아연 0.82㎎, 탄산마그네슘 25.3 ㎎, 제1인산칼륨 15 ㎎, 제2인산칼슘 55 ㎎, 구연산칼륨 90㎎, 탄산칼슘 100 ㎎, 염화마그네슘 24.8 ㎎)을 혼합한 다음 과립을 제조하고 통상의 방법에 따라 건강식품을 제조하였다.(Vitamin A acetate: 70,, vitamin E: 1.0 mg, vitamin B: 0.13 mg, vitamin B 2: 0.15 mg, vitamin B 6: 0.5 mg, vitamin B 12: 0.2 쨉 g, vitamin C 10 (1.75 mg of ferrous sulfate, 0.82 mg of zinc oxide, 25.3 mg of magnesium carbonate, 15 mg of potassium phosphate, 15 mg of potassium phosphate), 1 g of sodium chloride, 10 mg of biotin, 1.7 g of nicotinamide, 50 g of folic acid and 0.5 mg of calcium pantothenate 55 mg of calcium diphosphate, 90 mg of potassium citrate, 100 mg of calcium carbonate, and 24.8 mg of magnesium chloride) were mixed to prepare a granule, and a health food was prepared according to a conventional method.
이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.While the present invention has been particularly shown and described with reference to specific embodiments thereof, those skilled in the art will appreciate that such specific embodiments are merely preferred embodiments and that the scope of the present invention is not limited thereby. something to do. It is therefore intended that the scope of the invention be defined by the claims appended hereto and their equivalents.
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