KR20220134953A - Composition for metastasis inhibition of cancer comprising Ishige okamurae extracts - Google Patents
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- KR20220134953A KR20220134953A KR1020210040274A KR20210040274A KR20220134953A KR 20220134953 A KR20220134953 A KR 20220134953A KR 1020210040274 A KR1020210040274 A KR 1020210040274A KR 20210040274 A KR20210040274 A KR 20210040274A KR 20220134953 A KR20220134953 A KR 20220134953A
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Abstract
Description
본 발명은 패 추출물을 유효성분으로 포함하는 암 전이 억제용 조성물 및 항암 치료 보조용 조성물에 관한 것이다.The present invention relates to a composition for inhibiting cancer metastasis and a composition for adjuvant anti-cancer treatment comprising a shellfish extract as an active ingredient.
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. 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.
그 중 악성 암은 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 암의 진행에 수반되는 현상으로, 악성 암 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.Among them, in most cases, malignant cancer develops in one organ (lung, liver, kidney, stomach, colon, rectum, etc.) and then spreads from the primary organ to other tissues. This is called metastasis. Metastasis is a phenomenon accompanying the progression of malignant cancer. As malignant cancer cells proliferate and acquire new genetic traits necessary for metastasis as the cancer progresses, they infiltrate into blood vessels and lymph glands, circulate through blood and lymph, and then settle in other tissues. After that, it will proliferate.
악성 암의 전이에 대한 치료의 원칙은 암의 종류와 암의 전이 부위에 따라 다르다. 전이에 의한 국소 증상이 심하거나, 전이에 대한 수술적 치료가 악성 암의 자연 경과를 호전시킬 수 있다고 알려진 일부 악성 암의 경우 전이에 대해 치료수술 혹은 방사선치료와 같은 국소 치료 방침을 고려할 수 있다. 일반적으로는 악성 암에서 전이가 일어난 경우 국소적인 치료보다는 항암 화학 요법과 같은 전신적인 치료를 통하여 전이 부위뿐 아니라 원발 부위의 암을 함께 치료하는 것이 도움이 된다. 하지만 림프종과 같은 극소수의 암을 제외하고는 전이가 발생한 악성 암의 경우 완치의 가능성은 대단히 낮다. 전이가 발생한 악성 암에 대한 경과는 다양하며, 원발성 악성 암의 종류와 전반적인 암의 진행 속도에 따라 경과가 결정된다. 어떤 장기에 전이가 되었느냐에 따라 합병증은 다양하게 발생할 수 있다. 예를 들어, 뇌 전이의 경우 두통, 시야감소, 구역, 구토 등의 증상이 발생할 수 있다. 골 전이의 경우 골의 통증이 발생할 수 있으며, 병적 골절이 발생할 수도 있다. 골 전이에 동반하여 고칼슘 혈증으로 의식 혼탁이 발생할 수도 있다. 따라서 검진을 통한 암의 조기 발견 및 원발 암의 유전자 검사는 전이로 인한 사망률 증가를 예방할 수 있는 방법이다. 한편, 일부 암에서 수술적인 치료 후 보조 항암 화학요법 및 방사선 치료를 이용하여 재발 및 전이를 예방할 수 있다고 알려져 있으나 이러한 치료법은 정상세포들에게도 영향을 주어 심각한 부작용을 초래하는 문제가 있다. 따라서 보다 안전하고, 치료 효과가 높은 대체적인 암치료 방법이 요구되고 있으며, 이에 최근에는 안정성이 보장된 식물, 미생물 유래 등 천연자원을 이용한 의약품 연구 및 기능성 식품에 관심이 집중되고 있다.The principle of treatment for metastasis of malignant cancer differs depending on the type of cancer and the site of metastasis of the cancer. In the case of some malignant cancers that have severe local symptoms due to metastasis or that surgical treatment for metastasis can improve the natural course of the malignant cancer, local treatment strategies such as surgery or radiation therapy for metastasis may be considered. In general, when metastasis occurs in malignant cancer, it is helpful to treat the cancer in the primary site as well as the metastasis site through systemic treatment such as chemotherapy rather than local treatment. However, with the exception of very few cancers such as lymphoma, malignant cancers that have metastasized are highly unlikely to be cured. The course of metastatic malignant cancer varies, and the course is determined by the type of primary malignant cancer and the overall rate of cancer progression. Complications can occur in a variety of ways depending on which organ has metastasized. For example, in the case of brain metastasis, symptoms such as headache, blurred vision, nausea, and vomiting may occur. In case of bone metastasis, bone pain may occur and pathological fractures may occur. Concomitant with bone metastasis, hypercalcemia may cause clouding of consciousness. Therefore, early detection of cancer through screening and genetic testing of primary cancer are methods to prevent an increase in mortality due to metastasis. On the other hand, it is known that it is possible to prevent recurrence and metastasis by using adjuvant chemotherapy and radiation therapy after surgical treatment in some cancers, but these treatments have a problem in that they affect normal cells and cause serious side effects. Therefore, there is a need for an alternative cancer treatment method that is safer and has a high therapeutic effect, and in recent years, interest has been focused on drug research and functional foods using natural resources such as plants and microorganisms with guaranteed stability.
현재까지 암 치료를 위해 개발된 약제들은 약제 투여에 따른 전신적인 부작용이 많아 수술이나 방사선 치료에 비해 부작용이 많이 나타나는 단점이 있다. 암 세포를 직접 공격하여 효과를 보는 기존의 화학적 치료법 역시 부작용이 매우 강하고, 폐와 같은 장기로의 전이 등을 막을 수 있는 획기적인 신약은 아직 개발되지 않은 실정이다.Drugs developed so far for cancer treatment have many systemic side effects due to drug administration, which has the disadvantage of showing more side effects than surgery or radiation therapy. Existing chemical treatments that directly attack cancer cells have very strong side effects, and innovative new drugs that can prevent metastasis to organs such as the lungs have not yet been developed.
한편, 프로그램된 세포사멸 수용체-1(Programmed death receptor-ligand 1 , PD-L1)은 암 세포의 면역 회피에 중요한 역할을 하는 것으로 알려져 있는데, 구체적으로 암 세포의 PD-L1은 T 세포의 PD-1과 상호작용하여 T 세포 수용체(T-cell receptor, TCR) 매개성 증식과 사이토카인 생산을 감소시킨다. 그러므로 PD-L1은 암의 정복에 있어서 중요한 타겟이 될 수 있다.On the other hand, programmed death receptor-ligand 1 (PD-L1) is known to play an important role in immune evasion of cancer cells. Specifically, PD-L1 of cancer cells is PD-L1 of T cells. It interacts with 1 to decrease T-cell receptor (TCR)-mediated proliferation and cytokine production. Therefore, PD-L1 can be an important target in the conquering of cancer.
그러므로 악성 암의 전이를 방지하기 위하여 상기 PD-L1의 발현을 억제할 수 있으며, 부작용을 야기하지 않는 천연물 유래 암 전이 억제제의 개발이 필요하다.Therefore, in order to prevent metastasis of malignant cancer, it is necessary to develop a natural product-derived cancer metastasis inhibitor that can inhibit the expression of PD-L1 and does not cause side effects.
본 발명자들은 암 전이를 억제할 수 있는 천연물에 대하여 연구하던 중, 해양 갈조식물인 패(Ishige okamurae) 추출물이 암 세포의 PD-L1 발현을 우수하게 억제하고, 암 세포의 이동 및 침윤을 억제하는 효과를 보임을 확인하여 본 발명을 완성하였다.While the present inventors were studying natural products capable of inhibiting cancer metastasis, the marine brown algae plant, Ishige okamurae , extracts excellently inhibits PD-L1 expression in cancer cells, and inhibits the migration and invasion of cancer cells. The present invention was completed by confirming that the effect was shown.
따라서 본 발명의 목적은 암 전이 억제용 약학 조성물을 제공하는 것이다.Accordingly, an object of the present invention is to provide a pharmaceutical composition for inhibiting cancer metastasis.
본 발명의 또 다른 목적은 암 전이 예방 또는 개선용 식품 조성물을 제공하는 것이다. Another object of the present invention is to provide a food composition for preventing or improving cancer metastasis.
본 발명의 또 다른 목적은 항암 치료 보조용 약학 조성물을 제공하는 것이다. Another object of the present invention is to provide a pharmaceutical composition for adjuvant anti-cancer treatment.
본 발명의 또 다른 목적은 항암 치료 보조용 식품 조성물을 제공하는 것이다. Another object of the present invention is to provide a food composition for adjuvant anticancer treatment.
상기 목적을 달성하기 위하여, 본 발명은 패(Ishige okamurae) 추출물을 유효성분으로 포함하는 암 전이 억제용 약학 조성물을 제공한다.In order to achieve the above object, the present invention provides a pharmaceutical composition for inhibiting cancer metastasis comprising an extract of Ishige okamurae as an active ingredient.
또한 상기 또 다른 목적을 달성하기 위하여, 본 발명은 패(Ishige okamurae) 추출물을 유효성분으로 포함하는 암 전이 예방 또는 개선용 식품 조성물을 제공한다.In addition, in order to achieve the above another object, the present invention provides a food composition for preventing or improving cancer metastasis comprising an extract of Ishige okamurae as an active ingredient.
또한 상기 또 다른 목적을 달성하기 위하여, 본 발명은 패(Ishige okamurae) 추출물을 유효성분으로 포함하는 항암 보조용 약학 조성물을 제공한다.In addition, in order to achieve the above another object, the present invention provides a pharmaceutical composition for adjuvant anticancer comprising an extract of Ishige okamurae as an active ingredient.
또한 상기 또 다른 목적을 달성하기 위하여, 본 발명은 패(Ishige okamurae) 추출물을 유효성분으로 포함하는 항암 보조용 식품 조성물을 제공한다.In addition, in order to achieve the above another object, the present invention provides a food composition for an anticancer supplement comprising an extract of Ishige okamurae as an active ingredient.
본 발명은 해양 갈조식물 중 패(ishige okamurae) 추출물의 암 전이 억제 활성을 확인한 것으로, 상기 패 추출물은 다양한 암 세포에서 PD-L1 발현 억제 활성을 보이며, 상기 암 세포의 증식에 영향을 미치지 않으면서도 이동 및 침윤 억제 활성을 보이는 바, 이를 암 전이 억제용 조성물 또는 항암 치료 보조용 조성물로써 유용하게 활용할 수 있다.The present invention confirmed the cancer metastasis inhibitory activity of the shellfish ( ishige okamurae ) extract among marine brown algae plants, and the shellfish extract exhibits PD-L1 expression inhibitory activity in various cancer cells, without affecting the proliferation of the cancer cells. Since it exhibits migration and invasion inhibitory activity, it can be usefully used as a composition for inhibiting cancer metastasis or an adjuvant composition for anticancer treatment.
도 1 중 A는 해양 갈조식물 추출물 40종의 PD-L1 발현 억제 효과를 확인한 도이며, 도 1 중 B는 40종 중 선별된 해양 갈조식물 추출물의 PD-L1 억제 활성을 재검증한 도이고, 도 1 중 C는 상기를 통해 선별된 패(ishige okamurae) 추출물의 농도의존적인 효과를 확인한 도이다.
도 2 중 A는 다양한 암에서 패 추출물의 PD-L1 발현 억제 효과를 확인한 도이며, 도 2 중 B는 패 추출물의 암 세포 이동(migration) 억제 활성을 확인한 도이고, 도 2 중 C는 패 추출물의 암 세포 침윤(invasion) 억제 활성을 확인한 도이다.
도 3은 다양한 암에서 패 추출물의 암세포 증식(proliferation)에 미치는 영향을 확인한 도이다.In FIG. 1, A is a diagram confirming the PD-L1 expression inhibitory effect of 40 marine brown algae plant extracts, and FIG. 1 B is a diagram re-verifying the PD-L1 inhibitory activity of marine brown algae plant extracts selected from 40 types, 1C is a diagram confirming the concentration-dependent effect of the extract selected through the above ( ishige okamurae ).
2A is a diagram confirming the PD-L1 expression inhibitory effect of a plaque extract in various cancers, FIG. 2B is a diagram confirming the cancer cell migration inhibitory activity of the shellfish extract, and C in FIG. 2 is a shellfish extract of the cancer cell invasion (invasion) inhibitory activity was confirmed.
3 is a view confirming the effect of plaque extract on cancer cell proliferation (proliferation) in various cancers.
이하, 본 발명에 대해 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 패(Ishige okamurae, I.okamurae) 추출물을 유효성분으로 포함하는 암 전이 억제용 약학 조성물을 제공한다.The present invention provides a pharmaceutical composition for inhibiting cancer metastasis, comprising an extract of Ishige okamurae, I.okamurae as an active ingredient.
본 발명의 발명자들은 암 전이 억제에 효과적인 천연물 유래 물질을 탐색하던 중 상기 패(Ishige okamurae) 추출물이 PD-L1 발현 억제 효과와 더불어 암 세포의 이동 및 침윤 억제 활성을 보이는 것을 확인하여 본 발명을 완성하였다.The inventors of the present invention completed the present invention by confirming that the extract of Ishige okamurae exhibits an inhibitory effect on the expression of PD-L1 as well as an activity of inhibiting the migration and invasion of cancer cells while searching for a natural substance-derived substance effective for inhibiting cancer metastasis. did.
상기 패(Ishige okamurae)는 갈조류로서 패과에 속한다. 중국, 일본, 태국 연안에 분포하며, 우리나라에서는 서해안, 남해안, 제주도 해안가의 바위에 붙어 자생한다. 패는 항염증, 항산화 효과와 더불어 특히 항플라즈민 억제효과가 있다고 보고된 바 있다. 하지만 본 발명과 같이 상기 패가 PD-L1의 발현을 억제하며, 암 전이를 억제할 수 있음은 공지된 바 없다.The shellfish ( Ishige okamurae ) is a brown algae and belongs to the shellfish family. It is distributed along the coast of China, Japan, and Thailand, and in Korea, it grows naturally on rocks along the west coast, south coast, and Jeju Island. In addition to anti-inflammatory and antioxidant effects, plaque has been reported to have an anti-plasmin inhibitory effect. However, as in the present invention, it is not known that the plaque inhibits the expression of PD-L1 and can inhibit cancer metastasis.
상기 패 추출물은 C1 내지 C4의 저급 알코올, 물 및 이들의 혼합물로 이루어진 군에서 선택된 어느 하나의 용매로 추출된 것일 수 있으며, 바람직하게는 에탄올로 추출된 것일 수 있다.The shellfish extract may be extracted with any one solvent selected from the group consisting of C1 to C4 lower alcohols, water, and mixtures thereof, preferably extracted with ethanol.
또한 본 발명의 패 추출물의 제조시 처리, 보관 등의 용이함을 위하여 여과 과정, 농축 및 정제과정, 건조과정, 동결과정 등이 임의로 추가될 수 있다.In addition, in the preparation of the shellfish extract of the present invention, filtration process, concentration and purification process, drying process, freezing process, etc. may be optionally added for ease of processing and storage.
상기 여과 과정은 공지의 여과 방법에 의할 수 있으며 이에 제한되지 않으나, 예를 들어 여과망 또는 마이크로필터를 이용한 여과, 원심분리 및 분액깔때기를 이용할 수 있다. 상기 농축 과정은 공지의 농축 방법에 의할 수 있으며 이에 제한되지는 않으나, 예를 들어 침전농축, 증발농축, 감압농축, 한외여과법, 역삼투법 및 원심분리법을 이용하여 농축할 수 있다.The filtration process may be by a known filtration method, but is not limited thereto, and for example, filtration using a filtration network or microfilter, centrifugation, and a separatory funnel may be used. The concentration process may be by a known concentration method, but is not limited thereto, and may be concentrated using, for example, precipitation concentration, evaporation concentration, reduced pressure concentration, ultrafiltration, reverse osmosis, and centrifugation.
상기 건조 과정은 공지의 건조 방법에 의할 수 있으며 이에 제한되지 아니하나, 예를 들어 동결 건조, 분무 건조 또는 열풍건조 일 수 있다.The drying process may be by a known drying method, but is not limited thereto, and may be, for example, freeze drying, spray drying, or hot air drying.
특히 본 발명의 일 실시예에 따르면, 상기 패 추출물은 다양한 암 종에서 PD-L1 발현을 억제하며 암 세포의 증식에 영향을 미치지 않으면서도 이동 및 침윤 억제 활성을 보인 바, 이를 포함하는 상기 암 전이 억제용 약학 조성물은 상기 효과를 기반으로 하여 다양한 암 세포의 이동을 억제할 수 있다.In particular, according to an embodiment of the present invention, the plaque extract inhibits PD-L1 expression in various cancer types and exhibits migration and invasion inhibitory activity without affecting the proliferation of cancer cells, and the cancer metastasis including the same The inhibitory pharmaceutical composition may inhibit the migration of various cancer cells based on the above effect.
상기 암은 PD-L1 발현 양성을 보이는 암인 것을 특징으로 하며, 바람직하게는 구강암, 침샘암, 유방암 및 전립선암으로 이루어진 군에서 선택된 어느 하나 이상일 수 있으나 이에 제한되는 것은 아니다.The cancer is characterized in that it is a cancer showing a positive PD-L1 expression, and preferably may be any one or more selected from the group consisting of oral cancer, salivary gland cancer, breast cancer and prostate cancer, but is not limited thereto.
본 발명의 약학 조성물은 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 상기 약학 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 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 들 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 본 발명의 패 추출물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 탄산칼슘, 수크로스 또는 락토오스, 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다. The pharmaceutical composition of the present invention may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, and sterile injection solutions according to conventional methods, respectively. . Carriers, excipients and diluents that may be included in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose , methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In the case of formulation, it is prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants that are usually used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations include at least one excipient in the shellfish extract of the present invention, for example, starch, calcium carbonate, sucrose or lactose. , gelatin, etc. are mixed and prepared. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral use include suspensions, solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients, for example, wetting agents, sweeteners, fragrances, preservatives, etc. may be included. . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As a base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like can be used.
본 발명의 약학 조성물의 투여량은 치료받을 대상의 연령, 성별, 체중과, 치료할 특정 질환 또는 병리 상태, 질환 또는 병리 상태의 심각도, 투여경로 및 처방자의 판단에 따라 달라질 것이다. 이러한 인자에 기초한 투여량 결정은 당업자의 수준 내에 있으며, 일반적으로 투여량은 0.01㎎/㎏/일 내지 대략 2000㎎/㎏/일의 범위이다. 더 바람직한 투여량은 0.1㎎/㎏/일 내지 1000㎎/㎏/일이다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다. The dosage of the pharmaceutical composition of the present invention will vary depending on the age, sex, and weight of the subject to be treated, the specific disease or pathological condition to be treated, the severity of the disease or pathological condition, the route of administration, and the judgment of the prescriber. Dosage determination based on these factors is within the level of one of ordinary skill in the art, and dosages generally range from 0.01 mg/kg/day to approximately 2000 mg/kg/day. A more preferred dosage is 0.1 mg/kg/day to 1000 mg/kg/day. Administration may be administered once a day, or may be administered in several divided doses. The above dosage does not limit the scope of the present invention in any way.
본 발명의 약학 조성물은 쥐, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁내 경막 또는 뇌혈관내 주사에 의해 투여될 수 있다. The pharmaceutical composition of the present invention may be administered to mammals such as mice, livestock, and humans by various routes. All modes of administration can be envisaged, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebrovascular injection.
본 발명에 있어서, 암 전이 억제용 약학 조성물은 유효성분 이외에, 암 전이 억제의 상승, 보강을 위하여 이미 안전성이 검증되고 암 전이 억제 또는 항암 활성을 갖는 것으로 공지된 임의의 화합물이나 천연 추출물을 추가로 포함할 수 있다.In the present invention, in addition to the active ingredient, the pharmaceutical composition for inhibiting cancer metastasis may contain any compound or natural extract that has already been verified for safety and is known to have cancer metastasis inhibition or anticancer activity for the enhancement and reinforcement of cancer metastasis inhibition. may include
더불어 본 발명의 약학 조성물은 암 전이의 억제를 위하여 단독으로, 또는 수술, 방사선 치료, 호르몬 치료, 화학 치료 및 생물학적 반응 조절제를 사용하는 방법들과 병용하여 사용할 수 있다.In addition, the pharmaceutical composition of the present invention can be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers to inhibit cancer metastasis.
또한 본 발명은 패(Ishige okamurae) 추출물을 유효성분으로 포함하는 항암 치료 보조용 약학 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for adjuvant anti-cancer treatment comprising an extract of Ishige okamurae as an active ingredient.
본 명세서에서 사용된 용어, "항암 치료 보조용"은 항암제에 의한 치료와 병행하여 적용 시, 암의 전이 발생 가능성을 방지하여 항암 치료의 효과를 상승적으로 증가시키는 효과를 의미한다.As used herein, the term "anticancer treatment adjuvant" refers to an effect of synergistically increasing the effect of anticancer treatment by preventing the possibility of cancer metastasis when applied in parallel with treatment with an anticancer agent.
따라서 상기 항암 치료 보조용 조성물은 공지된 항암제를 이용한 암 치료에 보조적으로 사용될 수 있으며, 항암 보조제로써 항암제와 함께, 동시에 또는 순차적으로 투여 가능하다.Therefore, the composition for adjuvant anti-cancer treatment may be used as an adjuvant for cancer treatment using a known anti-cancer agent, and may be administered simultaneously or sequentially with the anti-cancer agent as an anti-cancer adjuvant.
또한, 본 발명은 패(Ishige okamurae) 추출물을 유효성분으로 포함하는 암 전이 예방 또는 개선용 식품 조성물을 제공한다.In addition, the present invention provides a food composition for preventing or improving cancer metastasis comprising an extract of Ishige okamurae as an active ingredient.
더불어 본 발명은 패(Ishige okamurae) 추출물을 유효성분으로 포함하는 항암 치료 보조용 식품 조성물을 제공한다.In addition, the present invention provides a food composition for adjuvant anticancer treatment comprising an extract of Ishige okamurae as an active ingredient.
본 발명에 따른 식품 조성물은 기능성 식품(functional food), 영양 보조제(nutritional supplement), 건강식품(health food) 및 식품 첨가제(food additives) 등의 모든 형태를 포함한다. 상기 유형의 식품 조성물은 당업계에 공지된 통상적인 방법에 따라 다양한 형태로 제조할 수 있다.The food composition according to the present invention includes all types of functional foods, nutritional supplements, health foods, and food additives. Food compositions of this type can be prepared in various forms according to conventional methods known in the art.
예를 들면, 건강식품으로는 본 발명의 패 추출물 자체를 과립화, 캡슐화 및 분말화하여 섭취하거나 차, 쥬스 및 드링크의 형태로 제조하여 음용하도록 할 수 있다. 또한, 본 발명의 패 추출물을 암 전이 억제 효과 또는 항암 효과가 있다고 알려진 공지의 물질 또는 활성 성분과 함께 혼합하여 조성물의 형태로 제조할 수 있다.For example, as a health food, the shellfish extract of the present invention may be ingested by granulating, encapsulating and powdering itself, or it may be prepared and consumed in the form of tea, juice or drink. In addition, the shellfish extract of the present invention can be prepared in the form of a composition by mixing it with a known substance or active ingredient known to have cancer metastasis inhibitory effect or anticancer effect.
또한, 기능성 식품으로는 음료(알콜성 음료 포함), 과실 및 그의 가공식품(예: 과일통조림, 병조림, 잼, 마멀레이드 등), 어류, 육류 및 그 가공식품(예: 햄, 소시지콘비이프 등), 빵류 및 면류(예: 우동, 메밀국수, 라면,스파게티, 마카로니 등), 과즙, 각종 드링크, 쿠키, 엿, 유제품(예: 버터, 치이즈 등), 식용식물유지, 마아가린, 식물성 단백질, 레토르트 식품, 냉동식품, 각종 조미료(예: 된장, 간장, 소스 등) 등에 본 발명의 패 추출물을 첨가하여 제조할 수 있다.In addition, functional foods include beverages (including alcoholic beverages), fruits and their processed foods (eg, canned fruit, bottled, jam, marmalade, etc.), fish, meat and their processed foods (eg, ham, sausage corn beef, etc.) , Breads and noodles (eg udon noodles, noodles, ramen, spaghetti, macaroni, etc.), fruit juice, various drinks, cookies, syrup, dairy products (eg butter, cheese, etc.), edible vegetable oils and fats, margarine, vegetable protein, retort It can be prepared by adding the shellfish extract of the present invention to food, frozen food, various seasonings (eg, soybean paste, soy sauce, sauce, etc.).
본 발명의 식품 조성물 중 상기 본 발명의 패 추출물의 바람직한 함유량으로는 이에 한정되지 않지만 예를 들어 최종적으로 제조된 식품 중 0.01 내지 80 중량%일 수 있으며, 바람직하게는 최종적으로 제조된 식품 중 0.01 내지 50 중량%일 수 있다.The preferred content of the shellfish extract of the present invention in the food composition of the present invention is not limited thereto, but may be, for example, 0.01 to 80% by weight of the finally prepared food, preferably 0.01 to 80% by weight of the finally prepared food. 50% by weight.
또한, 본 발명의 패 추출물을 식품 첨가제의 형태로 사용하기 위해서는 분말 또는 농축액 형태로 제조하여 사용할 수 있다.In addition, in order to use the shellfish extract of the present invention in the form of a food additive, it may be prepared and used in the form of a powder or a concentrate.
상술한 본 발명의 내용은 상호 모순되지 않는 한, 서로 동일하게 적용되며, 당해 기술분야의 통상의 기술자가 적절한 변경을 가해 실시하는 것 또한 본 발명의 범주에 포함된다.The above-described contents of the present invention are applied equally to each other unless contradictory to each other, and those skilled in the art to implement with appropriate changes are also included in the scope of the present invention.
이하 본 발명을 실시예를 통해 상세하게 설명하나 본 발명의 범위가 하기 실시예로만 한정되는 것은 아니다. Hereinafter, the present invention will be described in detail through examples, but the scope of the present invention is not limited only to the following examples.
실시예 1. 암 세포 배양Example 1. Cancer cell culture
구강암 세포의 일종으로 구강편평암세포주(HN22, HSC-2, HSC-3), 침샘암 세포의 일종으로 점액표피양세포주(YD-15M), 유방암세포주(MDA-MB-231) 및 전립선암세포주(DU145)를 실험에 사용하였다. HN22 세포주는 단국대학교, HSC-2와 HSC-3 세포주는 훗카이도 대학에서 제공받았으며, YD-15M세포주는 한국세포주은행에서 직접 분양받았다. 또한, MDA-MB-231 세포주는 ATCC (American Type Culture Collection)에서 구매하였고, DU145 세포주는 한국생명공학연구원에서 분양받았다. HN22, HSC-2, HSC-3, MDA-MB-231 세포주는 Dulbecco's Modified Eagle Medium/Nutrient Mixture F-12 (1:1) 배지에 배양하였으며, YD-15M, DU145 세포주는 Rosewell Park Memorial Institute 1640 배지에 배양하였다. 실험에 사용한 각 배지에 1% 페니실린(penicillin)/스트렙토마이신(streptomycin)과 10% FBS(Fetal Bovine Serum)를 첨가하였고, 세포배양기를 사용하여 5% CO2와 37℃의 배양 조건을 유지해주었다.Oral squamous cancer cell line (HN22, HSC-2, HSC-3) as a type of oral cancer cell line, mucinous epidermoid cell line (YD-15M) as a type of salivary gland cancer cell line, breast cancer cell line (MDA-MB-231) and prostate cancer cell line (DU145) was used in the experiment. The HN22 cell line was provided by Dankook University, the HSC-2 and HSC-3 cell lines were provided by the University of Hokkaido, and the YD-15M cell line was purchased directly from the Korea Cell Line Bank. In addition, the MDA-MB-231 cell line was purchased from ATCC (American Type Culture Collection), and the DU145 cell line was purchased from the Korea Research Institute of Bioscience and Biotechnology. The HN22, HSC-2, HSC-3, and MDA-MB-231 cell lines were cultured in Dulbecco's Modified Eagle Medium/Nutrient Mixture F-12 (1:1) medium, and the YD-15M and DU145 cell lines were cultured in Rosewell Park Memorial Institute 1640 medium. incubated in 1% penicillin/streptomycin and 10% FBS (Fetal Bovine Serum) were added to each medium used in the experiment, and culture conditions of 5% CO 2 and 37° C. were maintained using a cell incubator.
실시예 2. 해양 갈조식물 추출물 준비Example 2. Preparation of marine brown algae extract
암 세포의 PD-L1 발현 억제 효능을 가지는 천연 추출물을 도출하기 위해, 해양 갈조식물 자원 기탁 등록보존기관에서 하기 표 1의 갈조식물을 분양받았다.In order to derive a natural extract having the effect of inhibiting PD-L1 expression in cancer cells, the brown algae plants shown in Table 1 below were distributed from the marine brown algae resource deposit and preservation institution.
실험에 사용된 갈조류는 세척 및 건조한 후, 믹서로 갈아 분말화하였다. 이를 80% 에탄올로 추출한 후 농축하고 동결건조하였다. The brown algae used in the experiment were washed and dried, and then ground into a powder with a mixer. This was extracted with 80% ethanol, concentrated and lyophilized.
실시예 3. 해양 갈조식물 추출물의 PD-L1 발현 억제 효과 확인Example 3. Confirmation of PD-L1 expression inhibition effect of marine brown algae plant extract
구강편평암세포(HN22 cells)에 상기 실시예 2를 통해 수득한 40개의 해양 갈조식물 추출물을 처리한 후 PD-L1 발현의 감소 여부를 평가하였다. Oral squamous cancer cells (HN22 cells) were treated with the 40 marine brown algae extracts obtained in Example 2, and then the decrease in PD-L1 expression was evaluated.
HN22 세포를 6-웰 플레이트에 1.2 ×105 cells/ml의 조건으로 2ml 씩 분주하였고, 50%의 세포 밀집도를 형성하였을 때, 20μg/ml의 40개 해양 갈조식물 추출물과 대조군으로 0.2% DMSO(dimethyl sulfoxide)를 24시간 동안 처리하였다. 이후 특정 단백질의 양을 웨스턴 블롯(Western blot)을 통해 확인하였다. 먼저 DMSO(dimethyl sulfoxide)와 40개의 해양 갈조식물 추출물을 처리한 HN22 세포주를 PBS를 통해 2차례 세척하고, 0.5ml의 0.5% 트립신(trypsin)으로 처리한 후 세포 배양기에서 10분동안 반응시켜 세포 부착을 억제하였다. 각 웰에 2ml의 PBS(phosphate buffer saline)를 첨가하여 부유한 세포를 수거하고 원심분리기를 통해 세포를 상층액과 분리하였다. 70μl의 RIPA 버퍼(Radioimmunoprecipitation assay buffer)를 첨가한 후 볼텍스 및 원심분리기를 이용하여 단백질을 추출하였다. BCA 단백질 분석(Bicinchoninic Acid Protein Assay) 정량법을 통해 단백질의 농도를 측정하였다. 각 샘플의 동일한 단백질(30μg)을 SDS 폴리아크릴아마이드젤(polyacrylamide gel) 전기영동법을 이용하여 100V의 전류로 2시간 10분동안 분자량에 따라 분리하였다. SDS 폴리아크릴아마이드젤에 분리된 단백질을 PVDF 멤브레인(Polyvinylidene fluoride membrane)에 흡착시켰다. 항체의 불특정 결합을 감소시키기 위해서 단백질이 흡착된 PVDF 멤브레인을 5% 탈지유(skim milk)에 침지하여 상온에서 1시간 반응시킨 후, PD-L1(Cell Signaling Technology, #13684)과 정량 대조군인 β-액틴(β-actin(Santa Cruz Biotechnology, sc-47778)) 항체를 TBS-T 버퍼에 적정량(PD-L1: 1:2000; β-actin: 1:3000)으로 희석하여 4℃에서 하루 동안 반응시켰다. 그 후 1차 항체의 호스트에 맞는 겨자무과산화효소(horseradish peroxidase)가 결합된 2차 항체와 반응시킨 후에 웨스턴 블롯 루미놀 시약(Western Blotting Luminol Reagent(sc-2048))과 X-레이 필름(X-ray film)을 이용하여 형광을 검출하였다.2ml of HN22 cells were aliquoted into a 6-well plate under the condition of 1.2 × 10 5 cells/ml, and when a cell density of 50% was formed, 20 μg/ml of 40 marine brown algae extracts and 0.2% DMSO as a control ( dimethyl sulfoxide) was treated for 24 hours. Thereafter, the amount of a specific protein was confirmed through Western blot. First, the HN22 cell line treated with DMSO (dimethyl sulfoxide) and 40 marine brown algae extracts was washed twice with PBS, treated with 0.5 ml of 0.5% trypsin, and reacted in a cell incubator for 10 minutes to attach cells. was suppressed. Suspended cells were collected by adding 2ml of phosphate buffer saline (PBS) to each well, and the cells were separated from the supernatant by centrifugation. After adding 70 μl of RIPA buffer (Radioimmunoprecipitation assay buffer), the protein was extracted using a vortex and centrifuge. The concentration of the protein was measured through the BCA protein assay (Bicchoninic Acid Protein Assay) quantification method. The same protein (30 μg) of each sample was separated according to molecular weight for 2 hours and 10 minutes at a current of 100 V using SDS polyacrylamide gel electrophoresis. The protein separated on the SDS polyacrylamide gel was adsorbed onto a PVDF membrane (Polyvinylidene fluoride membrane). In order to reduce the unspecific binding of the antibody, the PVDF membrane to which the protein is adsorbed is immersed in 5% skim milk and reacted at room temperature for 1 hour, then PD-L1 (Cell Signaling Technology, #13684) and the quantitative control β- Actin (β-actin (Santa Cruz Biotechnology, sc-47778)) antibody was diluted to an appropriate amount (PD-L1: 1:2000; β-actin: 1:3000) in TBS-T buffer and reacted at 4°C for one day. . Then, after reacting with a secondary antibody bound to horseradish peroxidase suitable for the host of the primary antibody, Western Blotting Luminol Reagent (sc-2048) and X-ray film (X- ray film) was used to detect fluorescence.
그 결과 도 1 중 A와 같이, 3번 (구멍쇠미역(agarum clathratum), TC 9124) 17번 (청각(codium fragile), TC 15429), 26번 (꼬시래기(gracilaria vermiculophylla), TC7763), 29번 (헛뿌리엉킨실(derbesia rhizophora), TC9099) 및 34번 (패(ishige okamurae), TC9238) 추출물이 PD-L1 발현을 효과적으로 감소시키는 것을 확인하였다.As a result, as shown in A in FIG. 1, No. 3 ( agarum clathratum , TC 9124) No. 17 ( codium fragile , TC 15429), No. 26 ( gracilaria vermiculophylla ), TC7763), No. 29 It was confirmed that extracts ( derbesia rhizophora , TC9099) and 34 ( ishige okamurae , TC9238) effectively reduce PD-L1 expression.
상기에서 확인한 바를 기반으로, 선별된 4 종의 해양 갈조식물 추출물을 구강편평암세포(HN22 cells)에 처리하여 각 추출물의 PD-L1 발현 억제 활성을 재검증하였다. 그 결과 도 1 중 B와 같이, 상기 4 종의 추출물 중 패 추출물이 암세포의 PD-L1의 발현을 가장 우수하게 감소시킴을 확인하였다. 더불어 상기 패 추출물을 0, 10, 20 또는 40 μg/ml의 농도로 처리하여, 농도에 따른 PD-L1 발현 억제 활성을 확인하였다. 그 결과 도 1 중 C와 같이, 패 추출물은 PD-L1의 발현에 있어서 농도의존적인 억제 효과를 보임을 확인하였다.Based on the confirmation above, the selected four kinds of marine brown algae plant extracts were treated with oral squamous cancer cells (HN22 cells) to re-verify the PD-L1 expression inhibitory activity of each extract. As a result, as shown in B of FIG. 1 , it was confirmed that the shellfish extract among the four extracts reduced the expression of PD-L1 in cancer cells most excellently. In addition, the plaque extract was treated at a concentration of 0, 10, 20 or 40 μg/ml to confirm the PD-L1 expression inhibitory activity according to the concentration. As a result, as shown in C in FIG. 1 , it was confirmed that the shellfish extract showed a concentration-dependent inhibitory effect on the expression of PD-L1.
실시예 4. 다양한 암 종에서의 패 추출물의 효과 확인Example 4. Confirmation of the effect of plaque extract in various carcinomas
상기 실시예 3에서 확인한 패 추출물의 효과를 바탕으로 구강편평암세포를 포함한 다양한 암 종에서 패 추출물에 의한 PD-L1 발현 억제 효과를 확인하였다.Based on the effect of the plaque extract confirmed in Example 3, the effect of inhibiting PD-L1 expression by the plaque extract in various carcinomas including oral squamous cancer cells was confirmed.
이를 위하여 구강편평암세포주(HN22, HSC-2, HSC-3 cells), 점액표피양세포주(YD-15M), 유방암세포주(MDA-MB-231) 및 전립선암세포주(DU145)에 40 μg/ml의 패 추출물을 24시간 동안 처리한 후, 상기 실시예 3과 동일한 방법으로 PD-L1 발현을 확인하였다. 그 결과 도 2 중 A와 같이, 패 추출물은 HN22, HSC-2, HSC-3, YD-15M, MDA-MB-231 및 DU145 세포 모두에서 PD-L1 억제 활성을 보였다. For this purpose, 40 μg/ml of oral squamous cancer cell lines (HN22, HSC-2, HSC-3 cells), mucinous epithelial cell line (YD-15M), breast cancer cell line (MDA-MB-231) and prostate cancer cell line (DU145) After treatment with the plaque extract of 24 hours, PD-L1 expression was confirmed in the same manner as in Example 3. As a result, as shown in FIG. 2A, the shell extract showed PD-L1 inhibitory activity in all of HN22, HSC-2, HSC-3, YD-15M, MDA-MB-231 and DU145 cells.
한편, 최근 연구결과를 통해 암 세포는 PD-L1 발현 증가를 통해 전이 및 성장을 포함한 암의 특성을 획득한다고 보고된 바 있다. 그러므로 패 추출물의 암 세포 PD-L1 발현 억제 효과가 암 세포의 전이능을 조절하는지 확인하기 위해 상처 회복 분석(wound-healing assay)을 통한 암 세포의 이동(migration) 능력 및 트랜스-웰 침윤 분석(Trans-well invasion assay)을 통하여 침입 능력을 확인하였다. Meanwhile, it has been reported that cancer cells acquire cancer characteristics including metastasis and growth through an increase in PD-L1 expression through recent research results. Therefore, in order to confirm whether the cancer cell PD-L1 expression inhibitory effect of the plaque extract regulates the metastatic ability of cancer cells, cancer cell migration ability and trans-well invasion assay through wound-healing assay ( Trans-well invasion assay) was used to confirm the ability to invade.
상기 상처 회복 분석은 다음과 같이 수행하였다. 패 추출물에 의해 PD-L1의 발현이 억제되었던 HN22, HSC-2, HSC-3, YD-15M, MDA-MB-231 및 DU145 세포를 PBS로 세척한 후, 0.5% 트립신을 이용하여 부착된 세포를 떼어내고 원심분리를 이용해 상층액을 제거하였다. 수득한 세포를 배양액을 이용하여 부유시켜준 후 세포수를 측정하였다. 상기 실험을 진행하기 위해 6-웰 플레이트를 사용하였으며, 각 세포주의 크기와 분화 주기에 따라 2 - 4 x 105 cells/ml의 범위로 희석하고 2ml 씩 분주하여 세포배양기에서 배양을 하였다. 약 18시간 정도 후에 세포 밀집도가 90% 정도 도달하였을 때, 10μg/ml의 미토마이신 C(mitomycin C)가 희석된 무혈청(serum free) 배양액을 4시간 처리하여 세포의 성장을 억제했다. 이후, 10μl 피펫 팁을 이용하여 세포로 덮힌 웰 중앙을 같은 간격으로 긁어냈다. 떨어져 나간 세포가 다시 플레이트에 붙는 것을 방지하기 위해 PBS를 이용하여 3회 세척을 하였고, 40 μg/ml의 패 추출물 또는 대조군으로 0.2% DMSO가 희석된 세포배양액을 처리한 후 3~4시간 간격으로 세포의 이동을 확인하였다. 처리한 시점의 간격과 간격이 좁아진 시점을 현미경을 사용해 촬영하였으며, 회복 분석 정도는 Image J software를 통해 시작 시점의 간격의 넓이에서 종료 시점의 간격 넓이의 차를 통해 나타내었다.The wound healing assay was performed as follows. HN22, HSC-2, HSC-3, YD-15M, MDA-MB-231 and DU145 cells in which PD-L1 expression was suppressed by the plaque extract were washed with PBS and then adhered using 0.5% trypsin was removed and the supernatant was removed by centrifugation. After the obtained cells were suspended using a culture medium, the number of cells was measured. For the above experiment, a 6-well plate was used, diluted to a range of 2 - 4
침윤 분석은 트렌스 웰을 통해 다음과 같이 수행하였다. 8.0 μm PET Falcon 트렌스웰 상부에 매트리젤 매트릭스(matrigel matrix)와 무혈청 배양액이 1:15 비율로 섞인 혼합물을 100μl 넣어 코팅하였다. 이를 24웰 플레이트에 얹은 후에 세포배양기에서 8시간동안 보관한 후, 코팅된 매트리젤 매트릭스를 제외한 잔여물은 제거하였다. 트렌스웰의 상부와 24웰에 무혈청 배양액을 첨가한 후, 2시간 동안 세포배양기에서 재수화시켰다. 암세포주들을 트립신과 원심분리기를 통해 수득한 후, 적당량의 무혈청 배양액을 이용하여 세포수를 측정하였다. 각 세포의 침윤 능력에 따라 1.5 x 105 내지 3 x 105 cells/well로 트렌스 웰 상부에 첨가하였고, 하부에는 10% FBS가 포함된 배양액 750 μl를 첨가해 화학주성을 형성시켜 주었다. 마지막으로 트렌스 웰 상부의 세포가 포함된 배양액에 40 μg/ml의 패 추출물 또는 대조군으로 0.2% DMSO가 희석된 세포배양액을 처리하였다. 24시간동안 세포배양기에서 배양한 후, 기질을 뚫고 침윤한 세포를 크리스탈 바이올렛(crystal violet)을 이용하여 염색하였다. 그런 후 현미경을 통해 DMSO와 패 추출물 처리 실험군의 침윤 세포 수의 차이를 확인해 침윤 영향을 검증하였다.Infiltration assays were performed through trans wells as follows. On top of the 8.0 μm PET Falcon transwell, 100 μl of a mixture of matrigel matrix and serum-free culture medium in a ratio of 1:15 was put and coated. After placing it on a 24-well plate, it was stored for 8 hours in a cell incubator, and the remainder except for the coated Matrigel matrix was removed. After adding a serum-free culture medium to the upper part of the transwell and 24 wells, it was rehydrated in a cell incubator for 2 hours. After the cancer cell lines were obtained through trypsin and centrifugation, the number of cells was measured using an appropriate amount of serum-free culture medium. According to the infiltration capacity of each cell, 1.5 x 10 5 to 3 x 10 5 cells/well were added to the top of the trans-well, and 750 μl of a culture solution containing 10% FBS was added to the bottom to form chemotaxis. Finally, the culture medium containing the cells at the top of the trans well was treated with a cell culture solution diluted with 40 μg/ml of shell extract or 0.2% DMSO as a control. After culturing in a cell incubator for 24 hours, the cells that penetrated the substrate and infiltrated were stained with crystal violet. Then, the effect of invasion was verified by checking the difference in the number of infiltrating cells in the DMSO and plaque extract-treated experimental groups through a microscope.
그 결과 도 2 중 B와 같이, 패 추출물을 처리한 실험군의 경우, 모든 암 세포의 이동 능력이 현저히 억제된 것을 확인하였다. 더불어 도 2 중 C와 같이 암 세포의 침윤 능력 또한 패 추출물의 처리에 의하여 현저히 억제된 것을 확인하였다. As a result, as shown in B of FIG. 2 , in the case of the experimental group treated with the shellfish extract, it was confirmed that the migration ability of all cancer cells was significantly inhibited. In addition, as shown in FIG. 2C , it was confirmed that the infiltration ability of cancer cells was also significantly inhibited by the treatment of the plaque extract.
실시예 5. 암세포 증식에 대한 패 추출물의 효과 확인Example 5. Confirmation of effect of plaque extract on cancer cell proliferation
패 추출물이 암세포 증식에 영향을 주는지 확인하기 위해, 세포 성장 분석(cell proliferation assay)를 실시하였다.To determine whether the plaque extract affects cancer cell proliferation, a cell proliferation assay was performed.
세포 성장 분석은 다음과 같이 수행하였다. 96웰 세포 배양 플레이트에 각 세포주의 크기와 분화 주기에 따라 8000 내지 12000 cells/well의 범위로 세포를 배양하였고, well 당 200μl의 세포 배양액에 적정량의 세포가 포함되도록 하였다. 현미경으로 확인하여 50%의 밀집도를 형성하였을 때, 패 추출물이 희석된 배양액을 세포배양액과 동일한 양으로 첨가하였고, 증가된 희석배수를 고려하여 80 μg/ml의 패 추출물로 희석하였다. 추출물 처리 시간을 기준으로, 40 μg/ml의 패 추출물 처리한 세포와 처리하지 않은 세포의 0시간과 24시간 시점의 세포의 양을 측정하였다. 살아있는 세포를 측정하는 테트라졸리움 환원 분석(Tetrazolium Reduction Assays)의 일종인 MTS(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) 분석을 통해 진행하였다. 측정하고자 하는 웰에 20 μl의 MTS 시약을 첨가한 후 빛에 반응하지 않도록 호일로 감싸고 세포배양기에서 세포타입에 따라 1시간 또는 2시간 동안 반응시켰다. 이 후 흡광도를 분석하였으며, 세포의 양과 흡광도의 값을 비례하여 세포 증식률 변화를 측정하였다. Cell growth assays were performed as follows. Cells were cultured in a range of 8000 to 12000 cells/well according to the size and differentiation cycle of each cell line in a 96-well cell culture plate, and an appropriate amount of cells was included in 200 μl of cell culture solution per well. When the density of 50% was confirmed under a microscope, the diluted culture solution of the shellfish extract was added in the same amount as the cell culture solution, and the shell extract was diluted with 80 μg/ml of the shellfish extract in consideration of the increased dilution factor. Based on the extract treatment time, the amount of cells at 0 hours and 24 hours in cells treated with 40 μg/ml shellfish extract and cells not treated was measured. MTS(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H, a type of Tetrazolium Reduction Assays that measure living cells -tetrazolium) was analyzed. After adding 20 μl of MTS reagent to the well to be measured, it was wrapped with foil so as not to react to light, and reacted for 1 hour or 2 hours depending on the cell type in a cell incubator. After that, the absorbance was analyzed, and the change in the cell proliferation rate was measured in proportion to the amount of cells and the value of the absorbance.
그 결과 도 3과 같이, 패 추출물을 24시간 동안 처리하였을 때 대부분의 암세포주에서 증식의 변화를 찾을 수 없었다. 전립선 암세포에 있어서는 증식률 10% 감소를 보였으나, 앞선 전이 또는 침윤억제에 비해 미비한 효과임을 확인하였다. As a result, as shown in FIG. 3, no change in proliferation was found in most cancer cell lines when the shellfish extract was treated for 24 hours. In prostate cancer cells, the proliferation rate was reduced by 10%, but it was confirmed that the effect was insignificant compared to the previous metastasis or invasion inhibition.
종합적으로 본 발명은 해양 갈조식물 중 패(ishige okamurae) 추출물의 암 전이 억제 활성을 확인한 것으로, 상기 패 추출물은 구강편평암세포, 점액표피양세포주, 유방암세포 및 전립선암세포에서 PD-L1 발현 억제 활성을 보이며, 상기 암 세포의 증식에 영향을 미치지 않으면서 이동 및 침윤 억제 활성을 보이는 바, 이를 암 전이 억제용 조성물로써 암 치료에 유용하게 활용할 수 있다.Overall, the present invention confirmed the cancer metastasis inhibitory activity of the shellfish ( ishige okamurae ) extract among marine brown algae plants, and the shellfish extract inhibited PD-L1 expression in oral squamous cancer cells, mucinous epithelial cell lines, breast cancer cells and prostate cancer cells. and shows migration and invasion inhibitory activity without affecting the proliferation of cancer cells, which can be usefully used for cancer treatment as a composition for inhibiting cancer metastasis.
Claims (8)
A pharmaceutical composition for inhibiting cancer metastasis comprising an extract of Ishige okamurae as an active ingredient.
상기 추출물은 에탄올 추출물인 것을 특징으로 하는, 암 전이 억제용 약학 조성물.
The method of claim 1,
The extract is an ethanol extract, characterized in that, a pharmaceutical composition for inhibiting cancer metastasis.
상기 조성물은 암 세포의 PD-L1 발현을 억제하여 이동을 억제하는 것을 특징으로 하는, 암 전이 억제용 약학 조성물.
The method of claim 1,
The composition inhibits the expression of PD-L1 in cancer cells, characterized in that to inhibit migration, a pharmaceutical composition for inhibiting cancer metastasis.
상기 암은 PD-L1 발현 양성을 보이는 암인 것을 특징으로 하는, 암 전이 억제용 약학 조성물.
The method of claim 1,
The cancer is characterized in that the cancer showing a positive PD-L1 expression, a pharmaceutical composition for inhibiting cancer metastasis.
상기 암은 구강암, 침샘암, 유방암 및 전립선암으로 이루어진 군에서 선택된 어느 하나 이상인 것을 특징으로 하는, 암 전이 억제용 약학 조성물.
5. The method of claim 4,
The cancer is a pharmaceutical composition for inhibiting cancer metastasis, characterized in that at least one selected from the group consisting of oral cancer, salivary gland cancer, breast cancer and prostate cancer.
A food composition for preventing or improving cancer metastasis, comprising an Ishige okamurae extract as an active ingredient.
A pharmaceutical composition for adjuvant anticancer treatment comprising an extract of Ishige okamurae as an active ingredient.
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