KR102381517B1 - Composition containing Selaginella involvens extract, Orostachys japonica extract and lapachol for prevention or treatment of cancer - Google Patents
Composition containing Selaginella involvens extract, Orostachys japonica extract and lapachol for prevention or treatment of cancer Download PDFInfo
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- KR102381517B1 KR102381517B1 KR1020210073704A KR20210073704A KR102381517B1 KR 102381517 B1 KR102381517 B1 KR 102381517B1 KR 1020210073704 A KR1020210073704 A KR 1020210073704A KR 20210073704 A KR20210073704 A KR 20210073704A KR 102381517 B1 KR102381517 B1 KR 102381517B1
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- cancer
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Abstract
본 발명은 부처손 추출물, 바위솔 추출물 및 라파콜을 포함하는 암의 예방 또는 치료용 조성물에 관한 것으로, 본 발명의 부처손 추출물, 바위솔 추출물 및 라파콜을 포함하는 조성물은 세포독성이 낮고 부작용이 없으며, MMP-2 및 MMP-9의 활성화 및 발현을 억제하며, MMP억제제인 TIMP-1의 발현을 증가시키고, 암세포의 세포 침윤을 억제시켜, 암의 예방 또는 치료용 조성물 및 암의 예방 또는 개선용 식품 조성물로 유용할 수 있다.The present invention relates to a composition for preventing or treating cancer comprising the extract of Buchusone, rock pine extract and rapachol. -Inhibits the activation and expression of -2 and MMP-9, increases the expression of TIMP-1, an MMP inhibitor, and inhibits cell invasion of cancer cells, and a composition for preventing or treating cancer and a food composition for preventing or improving cancer can be useful as
Description
본 발명은 부처손 추출물, 바위솔 추출물 및 라파콜을 포함하는 암의 예방 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing or treating cancer comprising an extract of butchersone, a rock pine extract, and rapachol.
암은 세계적으로 높은 사망률을 보이고 있으며, 서구 사회에서는 심혈관 질환 다음으로 가장 일반적인 사망원인이다. 특히, 인구의 고령화와 더불어 흡연 인구의 증가, 및 대기 오염으로 인해 폐암이 증가하고 있으며, 식생활이 서구화되어 고지방식의 섭취가 일반화되고, 환경오염물질의 급격한 증가, 음주량의 증가 등으로 대장암, 유방암, 전립선암 등이 지속적으로 증가 추세에 있다. 이러한 실정에서 암의 조기예방 및 치료를 가능하게 하여 인간 건강의 증진, 건강한 삶의 질 향상 및 인류보건 증진에 기여할 수 있는 항암 물질의 창출이 절실히 요구되고 있다. 악성 종양은 대부분의 경우 하나의 장기 (폐, 간, 신장, 위, 대장, 직장 등)에서 발생한 후 처음 발생한 원발 부위인 장기로부터 다른 조직으로 퍼져 나가는데, 이렇게 원발 부위로부터 다른 조직으로 퍼져 나가는 것을 전이 (metastasis)라 한다. 전이는 악성 종양의 진행에 수반되는 현상으로, 악성 종양 세포가 증식하고 암이 진행함에 따라 전이에 필요한 새로운 유전 형질을 획득한 후 혈관과 림프선으로 침윤하고 혈액과 림프를 따라 순환하다가 다른 조직에 정착한 후 증식하게 된다. 최근 연구 결과에서 전이와 관련된 유전 형질들이 밝혀지고 있으며, 원발 조직의 유전자 검사를 통해 차후 타장기로의 전이를 통한 재발 고위험군을 유추할 수 있게 된다. 이러한 전이 초기 단계에서 단백질분해효소인 매트릭스 메탈로프로티나아제 (MMP, matrix metalloproteinase)는 암세포가 세포외기질과 기저막을 분해하여 암세포의 침윤을 유도하고 전이하는데 중요한 역할을 하며 지금까지 20종 이상이 분리, 확인되었다. MMP는 아연을 보조효소로 사용하는 엔도프로티나아제(endoproteinase)로, 콜라겐분해효소 (collagenase), 젤라틴분해효소 (gelatinase), 스트로멜라이신(stromelysins), Membrane-type MMP로 나뉘어진다. 특히, 이들 MMP 중에서도 MMP-2 (72 kDa type IV collagenase; gelatinase A)와 MMP-9 (92 kDa type IV collagenase; gelatinase B)는 기저막의 중요 성분인 ype IV collagen을 분해하는 효소로, 암의 이동과 전이에 가장 직접적인 관련이 있으며 재발 및 사망률 증가와 상관관계가 있는 것으로 알려져 있다 (Nabeshima, K et al, Pathol Int, 52, 255-264, 2002). 또한, MMP-9의 프로모터 영역에는 전사인자인 AP-1과 NF-κB 결합 영역을 가지고 있으므로 TNF-α와 같은 싸이토카인이나 PMA (phorbol 12-mysistate 13-acetate)와 같은 암 유발 자극원이 이들 AP-1과 NF-κB 등의 전사인자의 활성을 유도하여 MMP-9의 발현 및 활성을 증가시키는 것으로 알려져 있다(Sato H, et al, Oncogene, 19, pp2904-2912, 2000; Lee S O, et al, Biochem Biophys Res Commun, 354, pp165-171, 2007).Cancer has a high mortality rate worldwide and is the second most common cause of death after cardiovascular disease in Western societies. In particular, lung cancer is increasing due to an aging population, an increase in the smoking population, and air pollution, and a high-fat diet is common due to a westernized diet. Breast cancer, prostate cancer, etc. continue to increase. In this situation, there is an urgent need for the creation of anticancer substances that can contribute to the promotion of human health, the improvement of the quality of healthy life, and the promotion of human health by enabling the early prevention and treatment of cancer. In most cases, malignant tumors develop in one organ (lung, liver, kidney, stomach, large intestine, rectum, etc.) and then spread to other tissues from the primary site where they first occurred. It is called metastasis. Metastasis is a phenomenon accompanying the progression of malignant tumors. As malignant tumor cells proliferate and cancer progresses, they acquire new genetic traits necessary for metastasis, then infiltrate into blood vessels and lymph glands, circulate through blood and lymph, and settle in other tissues. After that, it will proliferate. Recent research results have revealed genetic traits related to metastasis, and it is possible to infer a high-risk group for recurrence through metastasis to other organs through genetic testing of the primary tissue. In this early stage of metastasis, matrix metalloproteinase (MMP), a proteolytic enzyme, plays an important role in inducing invasion and metastasis of cancer cells by decomposing the extracellular matrix and basement membrane of cancer cells. separated and confirmed. MMP is an endoproteinase using zinc as a coenzyme, and is divided into collagenase, gelatinase, stromelysins, and Membrane-type MMP. In particular, among these MMPs, MMP-2 (72 kDa type IV collagenase; gelatinase A) and MMP-9 (92 kDa type IV collagenase; gelatinase B) are enzymes that degrade ype IV collagen, an important component of the basement membrane, and are and metastasis, and is known to correlate with an increase in recurrence and mortality (Nabeshima, K et al, Pathol Int, 52, 255-264, 2002). In addition, since the promoter region of MMP-9 has the transcription factors AP-1 and NF-κB binding regions, cytokines such as TNF-α or cancer-causing stimulants such as PMA (phorbol 12-mysistate 13-acetate) are these APs. It is known to increase the expression and activity of MMP-9 by inducing the activity of transcription factors such as -1 and NF-κB (Sato H, et al, Oncogene, 19, pp2904-2912, 2000; Lee SO, et al , Biochem Biophys Res Commun, 354, pp165-171, 2007).
이에, 본 발명자들은 인체에 부작용을 일으키지 않으면서 암전이를 예방하거나 억제할 수 있는 천연 추출물을 찾고자 노력한 결과, 부처손 추출물, 바위솔 추출물 및 라파콜을 각각 단독 또는 2종을 사용하는 경우보다, 부처손 추출물, 바위솔 추출물 및 라파콜을 모두 혼합하여 사용할 경우, MMP-2 및 MMP-9의 활성화 및 발현을 억제하며, MMP억제제인 TIMP-1의 발현을 증가시키고, 암세포의 세포 침윤을 억제하는 효과가 현저한 것을 확인함에 따라 본 발명을 완성하였다.Accordingly, the present inventors tried to find a natural extract capable of preventing or inhibiting cancer metastasis without causing side effects to the human body. , rock sol extract, and Rapachol, inhibit the activation and expression of MMP-2 and MMP-9, increase the expression of TIMP-1, an MMP inhibitor, and have a remarkable effect in inhibiting cell invasion of cancer cells By confirming that, the present invention was completed.
본 발명의 목적은 암의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.It is an object of the present invention to provide a pharmaceutical composition for preventing or treating cancer.
본 발명의 다른 목적은 암의 예방 또는 개선용 건강식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a health food composition for preventing or improving cancer.
본 발명의 또다른 목적은 암의 예방 또는 개선용 건강기능식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a health functional food composition for the prevention or improvement of cancer.
상기 목적을 달성하기 위하여,In order to achieve the above object,
본 발명은 부처손(Selaginella involvens) 추출물; 바위솔(Orostachys japonica) 추출물; 및 라파콜(lapachol); 을 포함하는 암의 예방 또는 치료용 약학적 조성물을 제공한다.The present invention Buchuson (Selaginella involves) extract; extract of Orostachys japonica; and lapachol; It provides a pharmaceutical composition for preventing or treating cancer comprising a.
또한, 본 발명은 부처손(Selaginella involvens) 추출물; 바위솔(Orostachys japonica) 추출물; 및 라파콜(lapachol);을 포함하는 암의 예방 또는 개선용 건강식품 조성물을 제공한다.In addition, the present invention Buddhason (Selaginella involves) extract; extract of Orostachys japonica; and Rapachol (lapachol); provides a health food composition for preventing or improving cancer, including.
나아가 본 발명은 부처손(Selaginella involvens) 추출물; 바위솔(Orostachys japonica) 추출물; 및 라파콜(lapachol);을 포함하는 암의 예방 또는 개선용 건강기능식품 조성물을 제공한다.Furthermore, the present invention is Buchuson (Selaginella involve) extract; extract of Orostachys japonica; And Rapachol (lapachol); provides a health functional food composition for the prevention or improvement of cancer, including.
본 발명의 부처손 추출물, 바위솔 추출물 및 라파콜을 포함하는 조성물은 세포독성이 낮고 부작용이 없으며, MMP-2 및 MMP-9의 활성화 및 발현을 억제하며, MMP억제제인 TIMP-1의 발현을 증가시키고, 암세포의 세포 침윤을 억제시켜, 암의 예방 또는 치료용 조성물 및 암의 예방 또는 개선용 식품 조성물로 유용할 수 있다.The composition comprising the extract of the present invention, the extract of Buchusson, the extract of rock pine, and Rapachol has low cytotoxicity and no side effects, inhibits the activation and expression of MMP-2 and MMP-9, and increases the expression of TIMP-1, an MMP inhibitor, and By inhibiting cell invasion of cancer cells, it may be useful as a composition for preventing or treating cancer and a food composition for preventing or improving cancer.
도 1은 HT1080 세포에서 본 발명의 실시예 1 내지 9 및 비교예 1 내지 6의 세포독성 효과를 나타낸 것이다.
도 2는 PMA로 자극된 HT1080 세포에서 본 발명의 실시예 1 내지 9 및 비교예 1 내지 6의 MMP-2 및 MMP-9 활성에 대한 효과를 나타낸 것이다.
도 3a는 세포 전이와 관련된 MMP-2 및 MMP-9 단백질 발현에 대한 본 발명의 실시예 1 내지 9 및 비교예 1 내지 6의 효과를 나타낸 것이다.
도 3b는 세포 전이와 관련된 TIMP-1의 단백질 발현에 대한 본 발명의 실시예 1 내지 9 및 비교예 1 내지 6의 효과를 나타낸 것이다.
도 4a는 HT1080 세포의 핵에서 NF-κB 발현에 대한 본 발명의 실시예 1 내지 9 및 비교예 1 내지 6의 효과를 나타낸 것이다.
도 4b는 HT1080 세포의 핵에서 AP-1의 일부인 c-fos의 발현에 대한 본 발명의 실시예 1 내지 9 및 비교예 1 내지 6의 효과를 나타낸 것이다.
도 5는 본 발명의 실시예 1 내지 9 및 비교예 1 내지 6을 처리한 HT1080 세포에서의 TIMP-1 발현을 면역형광 분석한 결과이다.
도 6a는 HT1080 세포에서 MMP-2 유전자 발현에 대한 본 발명의 실시예 1 내지 9 및 비교예 1 내지 6의 효과를 나타낸 것이다.
도 6b는 HT1080 세포에서 MMP-9 유전자 발현에 대한 본 발명의 실시예 1 내지 9 및 비교예 1 내지 6의 효과를 나타낸 것이다.
도 7은 VEGF로 자극된 HT1080 세포에서 세포침윤에 대한 본 발명의 실시예 1 내지 9 및 비교예 1 내지 6의 효과를 나타낸 것이다.1 shows the cytotoxic effect of Examples 1 to 9 and Comparative Examples 1 to 6 of the present invention in HT1080 cells.
2 shows the effect on MMP-2 and MMP-9 activity of Examples 1 to 9 and Comparative Examples 1 to 6 of the present invention in HT1080 cells stimulated with PMA.
Figure 3a shows the effect of Examples 1 to 9 and Comparative Examples 1 to 6 of the present invention on the expression of MMP-2 and MMP-9 proteins associated with cell metastasis.
Figure 3b shows the effect of Examples 1 to 9 and Comparative Examples 1 to 6 of the present invention on the protein expression of TIMP-1 associated with cell metastasis.
Figure 4a shows the effect of Examples 1 to 9 and Comparative Examples 1 to 6 of the present invention on the NF-κB expression in the nucleus of HT1080 cells.
4B shows the effects of Examples 1 to 9 and Comparative Examples 1 to 6 of the present invention on the expression of c-fos, which is a part of AP-1, in the nucleus of HT1080 cells.
5 is a result of immunofluorescence analysis of TIMP-1 expression in HT1080 cells treated with Examples 1 to 9 and Comparative Examples 1 to 6 of the present invention.
Figure 6a shows the effect of Examples 1 to 9 and Comparative Examples 1 to 6 of the present invention on MMP-2 gene expression in HT1080 cells.
Figure 6b shows the effect of Examples 1 to 9 and Comparative Examples 1 to 6 of the present invention on MMP-9 gene expression in HT1080 cells.
7 shows the effects of Examples 1 to 9 and Comparative Examples 1 to 6 of the present invention on cell invasion in HT1080 cells stimulated with VEGF.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
암의 예방 또는 치료용 약학적 조성물Pharmaceutical composition for preventing or treating cancer
본 발명은 부처손(Selaginella involvens) 추출물; 바위솔(Orostachys japonica) 추출물; 및 라파콜(lapachol); 을 포함하는 암의 예방 또는 치료용 약학적 조성물을 제공한다. The present invention Buchuson (Selaginella involves) extract; extract of Orostachys japonica; and lapachol; It provides a pharmaceutical composition for preventing or treating cancer comprising a.
본 발명의 일실시예에 있어서, 상기 조성물은 부처손 추출물 50 중량부를 기준으로 바위솔 추출물 15 내지 55 중량부 및 라파콜 5 내지 45 중량부 포함하여 사용할 수 있으며, 바람직하게 상기 조성물은 부처손 추출물 50 중량부를 기준으로 바위솔 추출물 20 내지 45 중량부 및 라파콜 5 내지 25 중량부 포함하여 사용할 수 있으며, 보다 바람직하게는 상기 조성물은 부처손 추출물 50 중량부를 기준으로 바위솔 추출물 35 내지 45 중량부 및 라파콜 5 내지 15 중량부 포함하여 사용할 수 있다.In one embodiment of the present invention, the composition may be used in an amount of 15 to 55 parts by weight of rock pine extract and 5 to 45 parts by weight of Raphachol, based on 50 parts by weight of the extract of Butchersone, and preferably, the composition comprises 50 parts by weight of the extract of Butchersone. 20 to 45 parts by weight of rock pine extract and 5 to 25 parts by weight of Raphachol may be used as a basis, and more preferably, the composition comprises 35 to 45 parts by weight of Rock pine extract and 5 to 15 parts by weight of Raphachol based on 50 parts by weight of Butchersone extract. It can be used including parts by weight.
본 발명의 일실시예에 있어서, 상기 조성물은 MMP-2 및 MMP-9의 활성화 및 발현을 억제하며, MMP억제제인 TIMP-1의 발현을 증가시키고, 암세포의 세포 침윤을 억제시켜 암전이를 억제할 수 있다.In one embodiment of the present invention, the composition inhibits the activation and expression of MMP-2 and MMP-9, increases the expression of TIMP-1, an MMP inhibitor, and inhibits cancer metastasis by inhibiting cell invasion of cancer cells can do.
본 발명의 일실시예에 있어서, 상기 암은 뇌종양, 양성성상세포종, 악성성상세포종, 뇌하수체 선종, 뇌수막종, 뇌림프종, 핍지교종, 두개내인종, 상의세포종, 뇌간종양, 두경부 종양, 후두암, 구인두암, 비강암, 부비동암, 비인두암, 침샘암, 하인두암, 갑상선암, 흉부종양, 소세포성 폐암, 비소세포성 폐암, 흉선암, 종격동 종양, 식도암, 유방암, 남성유방암, 복부종양, 위암, 간암, 담낭암, 담도암, 췌장암, 소장암, 대장암, 항문암, 방광암, 신장암, 남성생식기종양, 음경암, 요도암, 전립선암, 여성생식기종양, 자궁경부암, 자궁내막암, 난소암, 자궁육종, 질암, 여성 외부생식기암, 여성요도암, 피부암, 골수종, 백혈병 및 악성림프종으로 이루어진 군으로부터 선택된 1종 이상인 것을 특징으로 한다.In one embodiment of the present invention, the cancer is brain tumor, benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, cerebral lymphoma, oligodendroglioma, intracranial race, ependymoma, brain stem tumor, head and neck tumor, laryngeal cancer, oropharyngeal cancer, Nasal sinus cancer, sinus cancer, nasopharyngeal cancer, salivary gland cancer, hypopharyngeal cancer, thyroid cancer, chest tumor, small cell lung cancer, non-small cell lung cancer, thymus cancer, mediastinal tumor, esophageal cancer, breast cancer, male breast cancer, abdominal tumor, stomach cancer, liver cancer, gallbladder cancer, Biliary tract cancer, pancreatic cancer, small intestine cancer, colorectal cancer, anal cancer, bladder cancer, kidney cancer, male genital tumor, penile cancer, urethral cancer, prostate cancer, female genital tumor, cervical cancer, endometrial cancer, ovarian cancer, uterine sarcoma, vaginal cancer , female external genital cancer, female urethral cancer, skin cancer, myeloma, characterized in that at least one selected from the group consisting of leukemia and malignant lymphoma.
본 발명의 조성물은 임상 투여시에 경구 및 비경구의 여러 가지 제형으로 투여될 수 있으며, 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 제조된다.The composition of the present invention may be administered in various oral and parenteral formulations during clinical administration, and when formulated, commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, etc. is manufactured
경구투여를 위한 고형 제제에는 정제, 환자, 산제, 과립제, 캡슐제, 트로키제 등이 포함되며, 이러한 고형 제제는 하나 이상의 본 발명의 조성물에 적어도 하나 이상의 부형제 예를 들면, 전분, 탄산칼슘, 수크로스(sucrose), 락토오스(lactose) 또는 젤라틴 등을 섞어 조제된다. 또한, 단순한 부형제 외에 마그네슘 스티레이트 탈크 같은 윤활제들도 사용된다. 경구 투여를 위한 액상 제제로는 현탁제, 내용액제, 유제 또는 시럽제 등이 해당되는데, 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다.Solid preparations for oral administration include tablets, patients, powders, granules, capsules, troches, and the like, and such solid preparations include at least one excipient in one or more compositions of the present invention, for example, starch, calcium carbonate, water It is prepared by mixing sucrose, lactose, or gelatin. In addition to simple excipients, lubricants such as magnesium stearate talc are also used. Liquid formulations for oral administration include suspensions, solutions, emulsions, or syrups. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. can
비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁용제, 유제, 동결건조제제, 좌제 등이 포함된다. 비수성용제, 현탁용제로는 프로필렌글리콜, 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, 글리세롤, 젤라틴 등이 사용될 수 있다.Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspension solutions, emulsions, lyophilized formulations, suppositories, and the like. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, gelatin, and the like can be used.
또한, 본 발명의 조성물의 인체에 대한 효과적인 투여량은 환자의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질환 정도에 따라 달라질 수 있으며, 일반적으로 약 0.001-100 mg/kg/일이며, 바람직하게는 0.01-35 mg/kg/일이다. 몸무게가 70㎏인 성인 환자를 기준으로 할 때, 일반적으로 0.07-7000 mg/일이며, 바람직하게는 0.7-2500 ㎎/일이며, 의사 또는 약사의 판단에 따라 일정시간 간격으로 1일 1회 내지 수회로 분할 투여할 수도 있다.In addition, the effective dosage for the human body of the composition of the present invention may vary depending on the patient's age, weight, sex, dosage form, health status and disease degree, and is generally about 0.001-100 mg/kg/day, preferably Usually 0.01-35 mg/kg/day. Based on an adult patient weighing 70 kg, it is generally 0.07-7000 mg/day, preferably 0.7-2500 mg/day, and once a day at regular time intervals according to the judgment of a doctor or pharmacist It may be administered in several divided doses.
암의 예방 또는 개선용 건강식품 또는 건강기능식품 조성물Health food or health functional food composition for preventing or improving cancer
본 발명은 부처손(Selaginella involvens) 추출물; 바위솔(Orostachys japonica) 추출물; 및 라파콜(lapachol);을 포함하는 암의 예방 또는 개선용 건강식품 또는 건강기능식품 조성물을 제공한다.The present invention Buchuson (Selaginella involves) extract; extract of Orostachys japonica; And lapachol (lapachol); provides a health food or health functional food composition for the prevention or improvement of cancer, including.
본 발명의 일실시예에 있어서, 상기 조성물은 부처손 추출물 50 중량부를 기준으로 바위솔 추출물 15 내지 55 중량부 및 라파콜 5 내지 45 중량부 포함하여 사용할 수 있으며, 바람직하게 상기 조성물은 부처손 추출물 50 중량부를 기준으로 바위솔 추출물 20 내지 45 중량부 및 라파콜 5 내지 25 중량부 포함하여 사용할 수 있으며, 보다 바람직하게는 상기 조성물은 부처손 추출물 50 중량부를 기준으로 바위솔 추출물 35 내지 45 중량부 및 라파콜 5 내지 15 중량부 포함하여 사용할 수 있다.In one embodiment of the present invention, the composition may be used in an amount of 15 to 55 parts by weight of rock pine extract and 5 to 45 parts by weight of Raphachol, based on 50 parts by weight of the extract of Butchersone, and preferably, the composition comprises 50 parts by weight of the extract of Butchersone. 20 to 45 parts by weight of rock pine extract and 5 to 25 parts by weight of Raphachol may be used as a basis, and more preferably, the composition comprises 35 to 45 parts by weight of Rock pine extract and 5 to 15 parts by weight of Raphachol based on 50 parts by weight of Butchersone extract. It can be used including parts by weight.
본 발명의 부처손(Selaginella involvens) 추출물; 바위솔(Orostachys japonica) 추출물; 및 라파콜(lapachol)을 건강기능식품 및 건강식품 조성물로 사용하는 경우, 식품의 종류에는 특별한 제한은 없다. 본 발명의 부처손(Selaginella involvens) 추출물; 바위솔(Orostachys japonica) 추출물; 및 라파콜(lapachol)을 첨가할 수 있는 식품의 예로는 드링크제, 육류, 소시지, 빵, 비스킷, 떡, 초콜릿, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 알코올 음료 및 비타민 복합제, 유제품 및 유가공 제품 등이 있으며, 통상적인 의미에서의 건강기능식품 및 건강식품 조성물을 모두 포함한다.The extract of the present invention (Selaginella involve); extract of Orostachys japonica; And when lapachol (lapachol) is used as a health functional food and health food composition, the type of food is not particularly limited. The extract of the present invention (Selaginella involve); extract of Orostachys japonica; And examples of foods to which lapachol can be added include drinks, meat, sausages, bread, biscuits, rice cakes, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream. , various soups, beverages, alcoholic beverages and vitamin complexes, dairy products, and dairy products, and includes all health functional foods and health food compositions in the ordinary sense.
본 발명에 따른 부처손(Selaginella involvens) 추출물; 바위솔(Orostachys japonica) 추출물; 및 라파콜(lapachol)을 함유하는 건강기능식품 및 건강식품 조성물은 식품에 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 부처손(Selaginella involvens) 추출물; 바위솔(Orostachys japonica) 추출물; 및 라파콜(lapachol)의 혼합량은 그의 사용 목적(예방 또는 개선용)에 따라 적합하게 결정될 수 있다. 일반적으로, 건강기능식품 및 건강식품 조성물 중의 상기 조성물의 양은 전체 식품 중량의 0.1 내지 90 중량부로 가할 수 있다. 그러나 건강 유지를 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하일 수 있으며, 안전성 면에서 아무런 문제가 없기 때문에 부처손(Selaginella involvens) 추출물; 바위솔(Orostachys japonica) 추출물; 및 라파콜(lapachol)은 상기 범위 이상의 양으로도 사용될 수 있다.an extract of Selaginella involves an extract according to the present invention; extract of Orostachys japonica; And lapachol (lapachol) containing health functional food and health food composition may be added to food as it is or used together with other food or food ingredients, and may be appropriately used according to a conventional method. Selaginella involve extract; extract of Orostachys japonica; And the mixing amount of lapachol may be suitably determined according to the purpose of its use (for prevention or improvement). In general, the amount of the composition in the health functional food and health food composition may be added in an amount of 0.1 to 90 parts by weight based on the total weight of the food. However, in the case of long-term intake for health maintenance or health control, the amount may be less than the above range, and since there is no problem in terms of safety, Selaginella involvens extract; extract of Orostachys japonica; And lapachol (lapachol) may be used in an amount above the above range.
본 발명의 건강기능식품 및 건강식품 조성물은 지시된 비율로 필수 성분으로서 본 발명 부처손(Selaginella involvens) 추출물; 바위솔(Orostachys japonica) 추출물; 및 라파콜(lapachol)을 함유하는 외에는 다른 성분에는 특별한 제한이 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스 등; 및 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리트라이톨 등의 당알코올이다. 상술한 것 이외의 향미제로서 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진등) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 건강기능식품 및 건강식품 조성물 100 당 일반적으로 약 1 내지 20 g, 바람직하게는 약 5 내지 12 g이다.The health functional food and health food composition of the present invention contains the present invention Buchuson (Selaginella involvens) extract as an essential ingredient in the indicated ratio; extract of Orostachys japonica; and lapachol (lapachol), other ingredients are not particularly limited, and may contain various flavoring agents or natural carbohydrates as additional ingredients like conventional beverages. 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 flavoring agents other than those described above, natural flavoring agents (taumatin, stevia extract (eg, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The ratio of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 health functional food and health food composition of the present invention.
상기 외에 본 발명의 부처손(Selaginella involvens) 추출물; 바위솔(Orostachys japonica) 추출물; 및 라파콜(lapachol)을 함유하는 건강기능식품 및 건강식품 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그 밖에 본 발명의 건강기능식품 및 건강식품 조성물은 천연 과일쥬스 및 과일쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다.In addition to the above, the extract of the present invention (Selaginella involve); extract of Orostachys japonica; And lapachol (lapachol) containing health functional food and health food composition is various nutrients, vitamins, minerals (electrolytes), synthetic flavoring agents and flavoring agents such as natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.) , pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like. In addition, the health functional food and health food composition of the present invention may contain natural fruit juice, fruit juice for the production of fruit juice drinks, and vegetable drinks.
이하 본 발명을 실시예에 의하여 더욱 상세하게 설명한다. 이들 실시예는 단지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 범위가 이들 실시예에 국한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail by way of Examples. These examples are merely for illustrating the present invention in more detail, and it will be apparent to those of ordinary skill in the art that the scope of the present invention is not limited to these examples.
<재료준비><Preparation of materials>
DMEM(Dulbecco's modified Eagle's medium), 트립신(trypsin)-EDTA, 페니실린/스트렙토마이신/암포테리신(각각 10000 U/ml, 10000 g/ml, 및 2500 g/ml) 및 FBS(fetal bovine serum)은 Gibco BRL, Life Technologies (NY, USA)로부터 구입하였다. HT1080세포는 ATCC에서 구입하였고, MTT 시약, 라파콜 및 기타 물질은 Sigma Chemical Co. (St. Louis, MO, USA)에서 구입하였다. DMEM (Dulbecco's modified Eagle's medium), trypsin-EDTA, penicillin/streptomycin/amphotericin (10000 U/ml, 10000 g/ml, and 2500 g/ml, respectively) and fetal bovine serum (FBS) from Gibco BRL, was purchased from Life Technologies (NY, USA). HT1080 cells were purchased from ATCC, MTT reagent, Raphachol and other materials were obtained from Sigma Chemical Co., Ltd. (St. Louis, MO, USA).
<준비예 1><Preparation example 1>
본 실험에 사용된 부처손 및 바위솔 주정추출물은 다음과 같은 방법으로 추출하였다. 먼저, 시료를 흐르는 물에 깨끗이 세척한 다음 완전히 자연 건조시켰다. 세척·건조된 시료를 믹서기로 분쇄하여 분말로 제조 후 주정에 3일간 추출하고 여과하였다. 각 여과된 여액을 감압 농축하여 분말 형태의 시료 주정추출물을 획득하였다. The alcohol extracts of Buchusson and Rock pine used in this experiment were extracted in the following way. First, the sample was thoroughly washed in running water and then completely dried naturally. The washed and dried sample was pulverized with a mixer to make a powder, extracted in alcohol for 3 days, and filtered. Each filtered filtrate was concentrated under reduced pressure to obtain a sample alcohol extract in powder form.
<실시예 및 비교예> 바위솔 추출물, 부처손 추출물 및 라파콜 복합물의 제조<Examples and Comparative Examples> Preparation of extracts of rock pine, butchersone extract, and Raphacol complex
상기 제조된 바위솔 추출물, 부처손 추출물 및 라파콜을 하기 표 1의 중량비로 혼합하고, 실시예 1 내지 9 및 비교예 1 내지 6의 복합물을 제조하였다.The prepared rock pine extract, butcherson extract and raphachol were mixed in the weight ratios shown in Table 1 below, and the composites of Examples 1 to 9 and Comparative Examples 1 to 6 were prepared.
<실험예 1> 바위솔 추출물, 부처손 추출물 및 라파콜 복합물의 HT1080 세포에 대한 세포독성 <Experimental Example 1> Cytotoxicity to HT1080 cells of rock pine extract, butchersone extract and Raphachol complex
HT1080 세포의 세포독성 수준은 Hansen et al., 1989에 기술된 3-(4,5-dimethyl-2-yl)-2,5-diphenyltetrazolium bromide (MTT) 방법을 사용하여 측정하였다. 구체적으로 HT1080 세포에서 96 well plate에 5Х104 cells/well이 되게 0.18 mL 분주하고, 상기 실시예 1 내지 9 및 비교예 1 내지 6을 0.02 mL 첨가한 후 37℃, 5% CO2incubator에서 24시간 배양하였다. 여기에 5 mg/mL 농도로 제조한 MTT 용액 0.02 mL 첨가하여 4시간 배양한 후 배양액을 제거하고 각 well당 DMSO 0.15 mL를 가하여 실온에서 30분간 반응시킨 뒤 ELISA reader로 540nm에서 흡광도를 측정하였다. 세포 독성 측정은 시료용액의 첨가군와 무첨가군의 흡광도 감소율로 나타내었으며, 분석 값들은 3회 반복 실험한 값의 mean±S.D.로 나타내었고, p값이 0.01 미만인 경우 유의한 차이가 있는 것으로 평가하였다(p<0.01).The level of cytotoxicity in HT1080 cells was measured using the 3-(4,5-dimethyl-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method described in Hansen et al., 1989. Specifically, 0.18 mL of HT1080 cells were dispensed in a 96-well plate to 5Х10 4 cells/well, and 0.02 mL of Examples 1 to 9 and Comparative Examples 1 to 6 was added, followed by incubation at 37°C, 5% CO2 incubator for 24 hours. . Here, 0.02 mL of MTT solution prepared at a concentration of 5 mg/mL was added, incubated for 4 hours, the culture medium was removed, and 0.15 mL of DMSO was added to each well, reacted for 30 minutes at room temperature, and absorbance was measured at 540 nm with an ELISA reader. The cytotoxicity measurement was expressed as the absorbance reduction rate of the group with and without the addition of the sample solution, and the analysis values were expressed as mean±SD of the value repeated three times, and a significant difference was evaluated when the p value was less than 0.01 ( p<0.01).
세포독성을 측정한 결과 도 1에 나타낸 바와 같이, 모두 70% 이상의 생존율을 보였다.As a result of measuring the cytotoxicity, as shown in FIG. 1, all showed a survival rate of 70% or more.
<실험예 2> 바위솔 추출물, 부처손 추출물 및 라파콜 복합물의 젤라틴 자이모그래피(Gelatin zymography) 분석<Experimental Example 2> Gelatin zymography analysis of rock pine extract, butchersone extract and Raphachol complex
본 발명의 바위솔 추출물, 부처손 추출물 및 라파콜을 포함하는 복합물의 MMP-2와 MMP-9의 활성화에 대한 효과를 확인하기 위해 젤라틴 자이모그래피 분석을 수행하였다. 동일한 양의 총 단백질을 함유하는 조건화된 배지를 1.5mg/ml 젤라틴을 함유하는 폴리아크릴아미드 겔의 각 웰에 로딩하고, 비환원조건에서 전기영동하였다. 각각의 실험에 대해 상이한 단백질 양을 젤라틴 자이모그래피 분석에 사용하였다. 젤라틴융해성 밴드는 청색 배경에서 투명한 부분으로 관찰이 되었고, 밴드 강도는 ImageMaster Software (Amersham Pharmacia Bioscience, NJ, USA)를 사용하여 측정하였다. Gelatin zymography analysis was performed to confirm the effect on the activation of MMP-2 and MMP-9 of the complex containing the rock pine extract of the present invention, butchersone extract, and Rapachol. Conditioned medium containing the same amount of total protein was loaded into each well of a polyacrylamide gel containing 1.5 mg/ml gelatin and electrophoresed under non-reducing conditions. Different protein amounts were used for gelatin zymography analysis for each experiment. The gelatin soluble band was observed as a transparent part on a blue background, and the band intensity was measured using ImageMaster Software (Amersham Pharmacia Bioscience, NJ, USA).
그 결과, 도 2에 나타낸 바와 같이, 비활성 형태의 proMMP-2 형태는 PMA 처리 군에서 활성형태인 MMP-2로 전환되는 것이 관찰되었으며, 또한, 비교예 1 내지 6(바위솔 추출물, 부처손 추출물 및 라파콜 각각 단독 혹은 2종의 혼합 사용) 대비 본 발명의 실시예 1 내지 9를 세포에 처리할 경우 MMP-9 및 MMP-2의 활성이 현저히 저해되는 것을 확인하였다. 상기 결과는 본 발명의 바위솔 추출물, 부처손 추출물 및 라파콜을 포함하는 복합물이 암전이와 관련된 MMP-2 및 MMP-9의 활성화를 억제할 수 있음을 나타낸다.As a result, as shown in FIG. 2 , it was observed that the inactive form of proMMP-2 was converted to the active form of MMP-2 in the PMA-treated group, and Comparative Examples 1 to 6 (bawisol extract, butcherson extract, and rapa) It was confirmed that when cells were treated with Examples 1 to 9 of the present invention, the activity of MMP-9 and MMP-2 was significantly inhibited compared to the use of each cole alone or a mixture of two types). The above results indicate that the complex containing the rock pine extract of the present invention, the butchersone extract and rapachol can inhibit the activation of MMP-2 and MMP-9 associated with cancer metastasis.
<실험예 3> 웨스턴 블롯 분석(Western blot analysis)<Experimental Example 3> Western blot analysis
표준절차에 따라 웨스턴 블롯 분석을 수행하였다. 실시예 1 내지 9 및 비교예 1 내지 6으로 처리된 세포를 RIPA lysis buffer (Sigma Chemical Co., St. Louis, MO, USA)으로 용해시켰다. 세포 용해물을 4-20% Novex®gel (Invitrogen, USA)에서 분리하고, 니트로셀룰로오스 멤브레인(nitrocellulose membrane)위에 electro transferred하고 10% 탈지우유로 차단하였다. Western blot analysis was performed according to standard procedures. Cells treated with Examples 1 to 9 and Comparative Examples 1 to 6 were lysed with RIPA lysis buffer (Sigma Chemical Co., St. Louis, MO, USA). The cell lysate was separated on 4-20% Novex® gel (Invitrogen, USA), electro-transferred on a nitrocellulose membrane, and blocked with 10% skim milk.
anti-MMP-2, anti-MMP-9, anti-TIMP-1, anti-NF-κp50, anti-c-FOS, anti-β및 이차 항체 (Santa Cruz BiotechnologufInc, CA, USA)를 사용하여 화학발광 ECL 분석 키트 (Amersham Pharmacia Biosciences, NJ, USA)를 사용하여 각각의 단백질을 제조자의 지시에 따라 검출하였다. AlphaEase®image analysis software (Alpha Innotech, CA, USA)를 사용하여 단백질 밴드를 시각화하였다.Chemiluminescence using anti-MMP-2, anti-MMP-9, anti-TIMP-1, anti-NF-κp50, anti-c-FOS, anti-β and secondary antibodies (Santa Cruz Biotechnologuf Inc, CA, USA) Each protein was detected using an ECL assay kit (Amersham Pharmacia Biosciences, NJ, USA) according to the manufacturer's instructions. Protein bands were visualized using AlphaEase® image analysis software (Alpha Innotech, CA, USA).
그 결과, 도 3a에 나타낸 바와 같이, 실시예 1 내지 9 및 비교예 1 내지 6을 처리한 모든 세포에서 MMP-9 및 MMP-2의 발현이 억제되었으며, 도 3b에 나타낸 바와 같이, TIMP-1의 발현이 증가되었으며, 특히, 비교예 1 내지 6(바위솔 추출물, 부처손 추출물 및 라파콜 각각 단독 혹은 2종의 혼합 사용) 대비 본 발명의 실시예 1 내지 9를 세포에 처리할 경우 MMP-9 및 MMP-2의 단백질 발현이 현저히 억제되고, TIMP-1의 발현이 현저히 증가되는 것을 확인하였다. As a result, as shown in FIG. 3a, the expression of MMP-9 and MMP-2 was inhibited in all cells treated with Examples 1 to 9 and Comparative Examples 1 to 6, and as shown in FIG. 3b, TIMP-1 was increased, and, in particular, when cells were treated with Examples 1 to 9 of the present invention compared to Comparative Examples 1 to 6 (each alone or a mixture of bawisol extract, butcherson extract and Raphachol), MMP-9 and It was confirmed that the protein expression of MMP-2 was significantly suppressed, and the expression of TIMP-1 was significantly increased.
또한, MMP-9 유전자 발현의 하향 조절이 c-fos 및 c-jun으로 구성된 AP-1 전사 인자의 차단과 p50 및 p65으로 구성된 NF-κ전사 인자의 차단에 의한 것인지 여부를 핵에서 웨스턴 블럿 분석을 사용하여 조사하였다.In addition, Western blot analysis in the nucleus to determine whether downregulation of MMP-9 gene expression is due to blockade of the AP-1 transcription factor composed of c-fos and c-jun and the NF-κ transcription factor composed of p50 and p65. was used to investigate.
간단히 말하면, 세포를 얼음 냉각된 PBS 1 ml로 수확하고 4 ℃에서 5000 rpm으로 1 분간 원심분리 하였다. 세포 펠렛을 10 mM HEPES, pH7.9, 10mM KCl, 0.1mM EDTA, 0.1mM EGTA, 1mM DTT(dithiothreitol), 및 1 mM PMSF(phenylmethylsulfonyl fluoride)를 함유하는 0.4 ㎖의 완충액 A로 15분 동안 얼음에서 용해시켰다. 그런 다음 10 % Nonidet P-40 용액 25ml를 가하고 샘플을 15초간 볼텍싱한 후 4℃에서, 15,000 rpm으로 5분간 원심분리 하였다. 그런 다음 펠렛을 0.5 ml의 완충액 A로 1회 세척하고, 20mM HEPES, pH7.9, 0.4M NaCl, 1mM EDTA, 1mM EGTA, 1mM DTT 및 1 mM PMSF로 구성된 50 ml의 완충액 B에 재현 탁시켰다. 용해된 핵을 30분 동안 얼음 위에 놓은 후 4℃에서 15,000 rpm으로 5 분간 원심분리 하였다. 핵 단백질 농도는 DC Protein Assay (BioRad, Hercules, CA, USA)에 의해 결정되었다. 실험전까지 -80 ℃에서 보관하였다. Briefly, cells were harvested with 1 ml of ice-cold PBS and centrifuged at 4 °C at 5000 rpm for 1 min. The cell pellet was incubated with 0.4 ml of buffer A containing 10 mM HEPES, pH7.9, 10 mM KCl, 0.1 mM EDTA, 0.1 mM EGTA, 1 mM dithiothreitol (DTT), and 1 mM phenylmethylsulfonyl fluoride (PMSF) on ice for 15 min. dissolved. Then, 25 ml of 10% Nonidet P-40 solution was added, and the sample was vortexed for 15 seconds, followed by centrifugation at 4°C and 15,000 rpm for 5 minutes. The pellet was then washed once with 0.5 ml of Buffer A and resuspended in 50 ml of Buffer B consisting of 20 mM HEPES, pH7.9, 0.4M NaCl, 1 mM EDTA, 1 mM EGTA, 1 mM DTT and 1 mM PMSF. The lysed nuclei were placed on ice for 30 minutes and then centrifuged at 15,000 rpm at 4°C for 5 minutes. Nuclear protein concentrations were determined by DC Protein Assay (BioRad, Hercules, CA, USA). It was stored at -80 °C until the experiment.
그 결과, 도 4에 나타낸 바와 같이, PMA 처리군에 비해 p50 및 p65의 단백질 발현이 감소됨을 발견하였다. 그러나, 본 발명의 바위솔 추출물, 부처손 추출물 및 라파콜을 포함하는 복합물은 AP-1의 일부인 c-fos의 발현에 대한 억제 효과를 나타내지 않았다. 이러한 결과는 MMP-9 발현이 NF-κ전사 인자에 의해 조절될 수 있음을 나타낸다.As a result, as shown in FIG. 4 , it was found that the protein expression of p50 and p65 was reduced compared to the PMA-treated group. However, the complex containing the rock pine extract, butcherson extract and rapachol of the present invention did not show an inhibitory effect on the expression of c-fos, which is a part of AP-1. These results indicate that MMP-9 expression can be regulated by the NF-κ transcription factor.
<실험예 4> 면역현광 분석법(Immunofluorescence assay)을 이용한 단백질 발현 분석<Experimental Example 4> Protein expression analysis using immunofluorescence assay
본 발명의 바위솔 추출물, 부처손 추출물 및 라파콜을 포함하는 복합물이 TIMP-1의 발현에 영향을 줄 수 있는지 확인하기 위해, HT1080 세포를 슬라이드 챔버에 접종하고 37 ℃에서 밤새 배양하였다. 이어서, 세포를 실시예 3, 7 및 9로 처리하고 PMA로 자극하였다. 배양 24 시간 후, 세포를 실온에서 15 분 동안 10 % 포르말린으로 고정시킨 다음, 0.5 % tween 20 (0.5 % PBS T-20)을 함유하는 PBS로 투과성을 만들고 0.1 % PBS T-20으로 3 회 세척하였다. 세포는 상온에서 24 시간 동안 항 -TIMP-1 일차 항체로 5 % Donkey normal serum 및 면역형광 염색으로 전처리 과정을 거친다. 그 후, 세포를 0.1 % PBS T-20으로 5 분간 3 회 세척하고, 2차 항체 (donkey anti- rabbit conjugated FITC) (FITC 1 : 200)를 실온에서 1시간 동안 처리하였다. 이어서, 세포를 0.1 % PBS T-20으로 3 회 세척하고 PB를 5 분 동안 각각 1 회 세척하였다. 마지막으로, 슬라이드는 DAPI 솔루션에 의해 확산되었고 Axio Scope A1 현미경 (Carl Zeiss, Goettingen, Germany)을 사용하여 분석하였다.In order to determine whether the complex containing the extract of the present invention, the extract of baekseol extract, the extract of Buchuson and Rapachol can affect the expression of TIMP-1, HT1080 cells were inoculated into a slide chamber and cultured at 37°C overnight. Cells were then treated with Examples 3, 7 and 9 and stimulated with PMA. After 24 h of incubation, cells were fixed in 10% formalin for 15 min at room temperature, then permeabilized with PBS containing 0.5% tween 20 (0.5% PBS T-20) and washed 3 times with 0.1% PBS T-20. did Cells are pretreated with 5% Donkey normal serum and immunofluorescent staining with anti-TIMP-1 primary antibody for 24 hours at room temperature. Thereafter, the cells were washed 3 times for 5 minutes with 0.1% PBS T-20, and treated with a secondary antibody (donkey anti-rabbit conjugated FITC) (FITC 1: 200) at room temperature for 1 hour. Then, the cells were washed 3 times with 0.1% PBS T-20 and PB was washed once each for 5 min. Finally, slides were spread by DAPI solution and analyzed using an Axio Scope A1 microscope (Carl Zeiss, Goettingen, Germany).
그 결과, 도 5에 나타낸 바와 같이, 아무것도 처리하지 않은(Blank) 군보다 높은 PMA 처리 군에서 CY3 형광(적색)을 갖는 TIMP-1 단백질 발현이 관찰되었으며, 본 발명의 바위솔 추출물, 부처손 추출물 및 라파콜을 포함하는 복합물은 PMA 처리 그룹과 비교하여 TIMP-1 발현 수준을 증가시켰다. 이러한 결과는 MMP-9 발현의 감소가 증가된 TIMP-1 발현에 기인함을 나타낸다.As a result, as shown in FIG. 5, expression of TIMP-1 protein having CY3 fluorescence (red) was observed in the PMA-treated group higher than that of the untreated (Blank) group, and the present invention's rock pine extract, butcherson extract and rapa Complexes with Cole increased TIMP-1 expression levels compared to the PMA-treated group. These results indicate that the decrease in MMP-9 expression is due to increased TIMP-1 expression.
<실험예 5> RT-PCR을 이용한 유전자 발현 분석<Experimental Example 5> Gene expression analysis using RT-PCR
RT-PCR을 위해, 세포로부터 준비된 총 RNA 1 μg을 역전사시켜 AMV 역전사 효소 (USB coporation, OH, USA)를 사용하여 제1가닥 cDNA를 생성시켰다. MMP-2, MMP-9 및 G3PDH mRNA를 증폭하기 위해 Whatman thermocycler (Biometra, Kent, UK)에서 중합 효소 연쇄 반응을 수행하였다. 목적 cDNA를 증폭 시키는데 사용된 프라이머 서열은 MMP-2 (정방향 프라이머 : 5'-TGCTGAAGGA CACACTAAAGAAGA-3 ', 역방향 프라이머 : 5'-TTGCCATCCTTCTCAA AGTTGTAGG-3'), MMP-9 (정방향 프라이머 : 5 5-CTTGTCGCT GTCAAAGTTCG-3) 및 glycer aldehyde -3-phosphate dehydro genase (G3PDH) (순방향 프라이머 : 5-TGAAGGTCGGTG TG AACGGATT TGGC-3, 역전사 프라이머 : TTCATCTTCC AAGG CC AATC- : 5-CATGTAGGCCA TGAGGTCCACCAC-3) 2 % agarose gel에서 전기영동한 PCR 산물을 ethidium bromide 염색으로 시각화하고 AlphaEase®겔 이미지 분석 소프트웨어 (Alpha Innotech, CA, USA)를 사용하여 정량화하였다.For RT-PCR, 1 μg of total RNA prepared from cells was reverse transcribed and first-strand cDNA was generated using AMV reverse transcriptase (USB coporation, OH, USA). Polymerase chain reaction was performed in a Whatman thermocycler (Biometra, Kent, UK) to amplify MMP-2, MMP-9 and G3PDH mRNA. The primer sequences used to amplify the target cDNA were MMP-2 (forward primer: 5'-TGCTGAAGGA CACACTAAAGAAGA-3', reverse primer: 5'-TTGCCATCCTTCTCAA AGTTGTAGG-3'), MMP-9 (forward primer: 5 5-CTTGTCGCT) GTCAAAGTTCG-3) and glycer aldehyde-3-phosphate dehydrogenase (G3PDH) (forward primer: 5-TGAAGGTCGGTG TG AACGGATT TGGC-3, reverse transcription primer: TTCATCTTCC AAGG CC AATC-: 5-CATGTAGGCCA TGAGGTCCACCAC-3) in 2% agarose gel The electrophoresed PCR products were visualized with ethidium bromide staining and quantified using AlphaEase® gel image analysis software (Alpha Innotech, CA, USA).
그 결과, 도 6에 나타낸 바와 같이, PMP 처리군에 비해 MMP-9 유전자 발현 수준이 유의하게 감소하였다. 특히, 비교예 1 내지 6(바위솔 추출물, 부처손 추출물 및 라파콜 각각 단독 혹은 2종의 혼합 사용) 대비 본 발명의 실시예 1 내지 9를 세포에 처리할 경우 MMP-9 유전자 발현 수준이 현저히 감소하는 것을 확인하였다. 또한, MMP-2 유전자 발현의 수준은 PMA 처치군에 비하여 감소하였으며, 특히, 비교예 1 내지 6(바위솔 추출물, 부처손 추출물 및 라파콜 각각 단독 혹은 2종의 혼합 사용) 대비 본 발명의 실시예 1 내지 9를 세포에 처리할 경우 MMP-2 유전자 발현 수준이 현저히 감소하는 것을 확인하였다. 상기의 결과는 본 발명의 바위솔 추출물, 부처손 추출물 및 라파콜을 포함하는 복합물이 MMP-2 및 MMP-9의 유전자 발현을 감소시킬 수 있음을 나타낸다.As a result, as shown in FIG. 6 , the MMP-9 gene expression level was significantly reduced compared to the PMP treatment group. In particular, when cells were treated with Examples 1 to 9 of the present invention, compared to Comparative Examples 1 to 6 (bawisol extract, butcherson extract, and Raphachol each alone or a mixture of two), the MMP-9 gene expression level was significantly reduced. confirmed that. In addition, the level of MMP-2 gene expression was decreased compared to the PMA treatment group, and in particular, Example 1 of the present invention compared to Comparative Examples 1 to 6 (bawisol extract, butcherson extract, and Raphachol, either alone or in combination of two) It was confirmed that the MMP-2 gene expression level was significantly reduced when the cells were treated with 9 to 9. The above results indicate that the complex containing the rock pine extract of the present invention, the butchersone extract and raphachol can reduce the gene expression of MMP-2 and MMP-9.
<실험예 6> 시험관 내 세포 침윤 분석<Experimental Example 6> In vitro cell invasion assay
세포 침윤 분석은 Chemicon®의 프로토콜에 따라 수행되었다. Cell Invasion Assay Kit (ECM550)은 24-well tissue culture plate와 12 개의 cell culture inserts로 구성된 Invasion Chamber를 이용하였다. 인서트는 8ml의 공극 크기의 폴리카보네이트 멤브레인을 포함하며, 그 위에 ECMatrix 용액의 얇은층이 적용된다(ECM 층은 멤브레인 기공을 막아 비 침습성 세포가 이동하지 못하도록 차단하고, 반면에 침습성 세포는 ECM 층을 통해 이동함). 300μl의 무혈청 배지에 HT1080 세포를 각 삽입물에 첨가하고 10 % 소태아혈청(chemoattractant)을 함유하는 배지 500μl를 하부 챔버에 첨가하였다. 세포가 접착하도록 고착되면, 세포를 본 발명의 바위솔 추출물, 부처손 추출물 및 라파콜을 포함하는 복합물로 처리하고 VEGF로 자극하였다. 챔버를 5% CO와 37℃에서 24시간 동안 배양하였다. ECM 겔층뿐만 아니라 침입이없는 세포는 면봉을 사용하여 제거하였다. 반대로, 막의 하부 표면상의 침입 세포는 20분동안 염색용액에 인서트를 침지함으로써 염색되었다. 그런 다음 염색된 세포를 10% 아세트산에 녹여 정량하고 염료/용질 혼합물의 일정량을 96- 웰 플레이트에 옮겨 560 nm에서 OD를 비색 측정하였다. Cell invasion assays were performed according to Chemicon®'s protocol. The Cell Invasion Assay Kit (ECM550) used an Invasion Chamber consisting of a 24-well tissue culture plate and 12 cell culture inserts. The insert contains a polycarbonate membrane with a pore size of 8 ml, on which a thin layer of ECMatrix solution is applied (the ECM layer blocks the membrane pores and prevents non-invasive cells from migrating, whereas the invasive cells cover the ECM layer. moved through). HT1080 cells were added to each insert in 300 μl of serum-free medium and 500 μl of medium containing 10% fetal bovine serum (chemoattractant) was added to the lower chamber. When the cells were adhered to adhesion, the cells were treated with a complex containing the extract of the present invention, the extract of rock pine, butchersone extract, and rapachol, and stimulated with VEGF. The chamber was incubated at 37° C. with 5% CO for 24 hours. Cells without invasion as well as the ECM gel layer were removed using a cotton swab. Conversely, invading cells on the lower surface of the membrane were stained by immersing the inserts in the staining solution for 20 min. Then, the stained cells were dissolved in 10% acetic acid and quantified, and a certain amount of the dye/solute mixture was transferred to a 96-well plate and the OD was colorimetrically measured at 560 nm.
암 전이에 대한 본 발명의 바위솔 추출물, 부처손 추출물 및 라파콜을 포함하는 복합물의 세포 침윤에 대한 효과를 확인한 결과, 도 7에 나타낸 바와 같이, VEGF 처리군에서의 침입 세포의 염색은 아무것도 처리하지 않은(Blank) 군에 비해 약 157 % 증가하였다. 이를 토대로 VEGF를 양성대조군으로 사용하였으며, 본 발명의 바위솔 추출물, 부처손 추출물 및 라파콜을 포함하는 복합물이 처리된 실시예 1 내지 9의 경우 VEGF 처리된 그룹과 비교하여 세포 침윤에 대한 억제 효과를 보였으며, 비교예 1 내지 6 대비 세포 침윤에 대한 억제 효과가 현저한 것을 확인하였다. 상기 결과로 인해 본 발명의 바위솔 추출물, 부처손 추출물 및 라파콜을 포함하는 복합물이 세포 침윤을 억제함으로써 암 전이를 억제할 수 있음을 나타낸다.As a result of confirming the effect on cell invasion of the complex containing the rock pine extract of the present invention, butchersone extract and Rapachol on cancer metastasis, as shown in FIG. 7 , the staining of the invading cells in the VEGF-treated group was not treated (Blank) increased about 157% compared to the group. Based on this, VEGF was used as a positive control group, and in Examples 1 to 9, in which the complex containing the rock pine extract, Buchuson extract and Raphachol of the present invention was treated, compared to the VEGF-treated group, the inhibitory effect on cell infiltration was shown. It was confirmed that the inhibitory effect on cell infiltration was remarkable compared to Comparative Examples 1 to 6. The above results indicate that the complex containing the rock pine extract, the butchersone extract and raphachol of the present invention can inhibit cancer metastasis by inhibiting cell invasion.
<통계분석><Statistical Analysis>
자료는 Student 's t test (대조군과 비교)와 MEGFL을 이용하여 분석하였다. 데이터는 세번의 독립적인 실험으로부터 평균값 ± 표준편차를 구하였다 (* P < 0.05, ** < 0.01, *** P < 0.001).Data were analyzed using Student's t test (compared to control group) and MEGFL. Data were obtained as mean ± standard deviation from three independent experiments (* P < 0.05, ** < 0.01, *** P < 0.001).
이제까지 본 발명에 대하여 그 바람직한 실시예들을 중심으로 살펴보았다. 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자는 본 발명이 본 발명의 본질적인 특성에서 벗어나지 않는 범위에서 변형된 형태로 구현될 수 있음을 이해할 수 있을 것이다. 그러므로 개시된 실시예들은 한정적인 관점이 아니라 설명적인 관점에서 고려되어야 한다. 본 발명의 범위는 전술한 설명이 아니라 특허청구범위에 나타나 있으며, 그와 동등한 범위 내에 있는 모든 차이점은 본 발명에 포함된 것으로 해석되어야 할 것이다.So far, the present invention has been looked at with respect to preferred embodiments thereof. Those of ordinary skill in the art to which the present invention pertains will understand that the present invention can be implemented in a modified form without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments are to be considered in an illustrative rather than a restrictive sense. The scope of the present invention is indicated in the claims rather than the foregoing description, and all differences within the scope equivalent thereto should be construed as being included in the present invention.
Claims (6)
바위솔(Orostachys japonica) 추출물 20-40 중량부; 및
라파콜(lapachol) 9-11 중량부;를 포함하는 암 전이 억제용 약학적 조성물.
Based on 50 parts by weight of Selaginella involvens extract;
20-40 parts by weight of Orostachys japonica extract; and
9-11 parts by weight of lapachol; a pharmaceutical composition for inhibiting cancer metastasis.
상기 암은 뇌종양, 양성성상세포종, 악성성상세포종, 뇌하수체 선종, 뇌수막종, 뇌림프종, 핍지교종, 두개내인종, 상의세포종, 뇌간종양, 두경부 종양, 후두암, 구인두암, 비강암, 부비동암, 비인두암, 침샘암, 하인두암, 갑상선암, 흉부종양, 소세포성 폐암, 비소세포성 폐암, 흉선암, 종격동 종양, 식도암, 유방암, 남성유방암, 복부종양, 위암, 간암, 담낭암, 담도암, 췌장암, 소장암, 대장암, 항문암, 방광암, 신장암, 남성생식기종양, 음경암, 요도암, 전립선암, 여성생식기종양, 자궁경부암, 자궁내막암, 난소암, 자궁육종, 질암, 여성 외부생식기암, 여성요도암, 피부암, 골수종, 백혈병 및 악성림프종으로 이루어진 군으로부터 선택된 1종인 것을 특징으로 하는 암 전이 억제용 약학적 조성물.According to claim 1,
The cancer is brain tumor, benign astrocytoma, astrocytoma, pituitary adenoma, meningioma, cerebral lymphoma, oligodendroglioma, intracranial tumor, ependymoma, brain stem tumor, head and neck tumor, laryngeal cancer, oropharyngeal cancer, nasal cancer, sinus cancer, nasopharyngeal cancer, Salivary gland cancer, hypopharyngeal cancer, thyroid cancer, chest tumor, small cell lung cancer, non-small cell lung cancer, thymus cancer, mediastinum tumor, esophageal cancer, breast cancer, male breast cancer, abdominal tumor, stomach cancer, liver cancer, gallbladder cancer, biliary tract cancer, pancreatic cancer, small intestine cancer, large intestine Cancer, anal cancer, bladder cancer, kidney cancer, male genital tumor, penile cancer, urethral cancer, prostate cancer, female genital tumor, cervical cancer, endometrial cancer, ovarian cancer, uterine sarcoma, vaginal cancer, female external genital cancer, female urethral cancer , a pharmaceutical composition for inhibiting cancer metastasis, characterized in that it is one selected from the group consisting of skin cancer, myeloma, leukemia and malignant lymphoma.
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