KR20190052287A - Composition for preventing and treating a cancer comprising Cnidium officinale Makion - Google Patents
Composition for preventing and treating a cancer comprising Cnidium officinale Makion Download PDFInfo
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- KR20190052287A KR20190052287A KR1020170147840A KR20170147840A KR20190052287A KR 20190052287 A KR20190052287 A KR 20190052287A KR 1020170147840 A KR1020170147840 A KR 1020170147840A KR 20170147840 A KR20170147840 A KR 20170147840A KR 20190052287 A KR20190052287 A KR 20190052287A
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- cancer
- extract
- carcinoma
- makion
- multiple myeloma
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Abstract
Description
본 발명은 천궁 추출물을 포함하는 암의 예방 및 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing and treating cancers, including Cancer oil extract.
2016년에 발표된 중앙암등록본부 자료에 의하면 2014년에 우리나라에서는 217,057건의 암이 발생했는데, 그 중 다발성골수종(C90)은 1,396건으로 전체 암 발생의 0.6%를 차지 하는 질병으로써 발병시 완치가 어려운 질병 중 하나이다. According to data released by the Central Cancer Registry in 2016, 217,057 cancers have occurred in Korea in 2014, among which 1,396 cases of multiple myeloma (C90) account for 0.6% of all cancers. It is one of the diseases.
다발성 골수종은 백혈병, 림프종과 함께 대표적인 혈액종양으로 B림프구의 성숙형태인 형질세포가 증식하는 혈액암이다. 평균 65세 이상의 고령에서 발병하며, 비교적 동양인에서는 낮은 발병율을 보이며, 1980년대 우리나라 발병율은 연간 100명이내로 매우 낮았다. 그러나 급속한 산업화에 따른 공해, 환경호르몬에 노출증가, 고령화로 인해 다발성 골수종 환자는 지속적으로 증가하고 있다. 지난 20년간 다른 암종의 발생률은 5배의 증가에 머물렀으나, 다발성 골수종의 경우, 약 30배 이상의 발생 증가를 보이고 있다. Multiple myeloma is a typical hematologic tumor with leukemia and lymphoma. It is a hematologic malignancy in which plasma cells, a mature form of B lymphocyte, proliferate. The average incidence is 65 years or older, relatively low in Asians, and the incidence rate in Korea is very low in the 1980s. However, due to rapid industrialization, increased exposure to environmental hormones, and aging, the number of patients with multiple myeloma continues to increase. Over the past two decades, the incidence of other carcinomas has increased fivefold, but the incidence of multiple myeloma has increased by more than 30-fold.
형질세포는 B림프구가 항원에 자극을 받아 최종적으로 분화되는 세포로 혈액이나 조직 내에 존재하며, 체내에 침입한 바이러스나 세균 등에 대항해 싸우는 단백질(항체,면역글로불린)을 생산, 저장, 분비하는데 혈액속의 형질세포는 B세포가 외부에서 들어온 침입자(항원)와 싸우기 위해 최종적으로 분화된 세포로써 이 형질세포와 골수에서는 각종 싸이토카인이라는 단백을 분비해 우리 몸에 필요한 항체를 만들게 되는데, 증상으로는 뼈의 용해성 병변, 신부전, 빈혈, 반복되는 감염 등으로 인한 골통증, 어지럼증 등의 여러 가지 임상증상을 나타낸다. 그러나 임상증상이 나타나기 전에 보통 일정기간의 무증상 기간이 선행되며 다발성골수종 환자의 20%는 증상 없이 우연히 발견되기도 한다.Plasma cells are cells in which B lymphocytes are stimulated by antigen and eventually differentiate. They are present in blood or tissues. They produce, store and secrete proteins (antibodies, immunoglobulins) that fight against viruses and bacteria that invade the body. Plasma cells are cells finally differentiated by B cells to fight intruders (antigens) from the outside. In these plasma cells and bone marrow, various proteins called cytokines are secreted to make antibodies for the body. Symptoms include bone solubility Lesions, renal failure, anemia, bone pain due to repeated infections, and dizziness. However, asymptomatic period precedes a certain period before clinical symptoms appear, and 20% of multiple myeloma patients are found incidentally without symptoms.
현재 시행되고 있는 치료법으로는 항암화학요법, 자가조혈모세포이식, 동종조혈모세포이식, 방사선치료 등이 있으나 치료과정에서 정상 세포들이 손상되어 여러 가지 합병증을 초래하기도 한다. 이에 우리는 부작용을 최소화 하고, 상승효과를 기대해 볼수 있는 천연 한방 재료를 이용하여 다발성 골수종 치료제를 개발 하고자 본 연구를 수행하였다. Currently, therapies include chemotherapy, autologous stem cell transplantation, allogeneic stem cell transplantation, and radiation therapy. We have conducted this study to develop a therapeutic agent for multiple myeloma using natural oriental herbal medicine which minimizes side effects and anticipates synergistic effects.
천궁은 쌍떡잎식물 이판화군 산형화목 미나리과에 속하는 다년생 초본식물로 중국이 원산지이며 우리나라에서도 흔히 재배되고 있다. 어린순은 나물로 먹고 뿌리줄기는 건조시켜 약재로 이용하는데, 방향성정유 성분인 ligustilide, cnidilide, senkyunolide, butylphthalide, butylidenephthaliden등을 다량 함유하고 있어서 냄새가 좋다. 특히, 천궁의 주요 성분인 TMP(Tetramethylprazine)가 TXA2와 PGI2의 양을 반영하는 TXB2를 감소시키며, 6-ketpPGF1 증가를 유도하여 혈액순환을 촉진시킨다는 보고가 있다 It is a perennial herbaceous plant belonging to the perennial herbaceous perennial herbaceous family, which is originated from China and is also cultivated in Korea. The young seeds are eaten as herbs and rootstocks are dried and used as medicinal materials. The fragrance is good because it contains a large amount of aromatic essential oils such as ligustilide, cnidilide, senkyunolide, butylphthalide and butylidenephthaliden. In particular, it has been reported that TMP (Tetramethylprazine), a major component of astragalus, decreases TXB2, which reflects the amount of TXA2 and PGI2, and promotes blood circulation by inducing 6-ketpPGF1 increase
또한 TMP는 콜라겐 생성을 저해하여 상처부위에서 콜라겐을로 유발될수 있는 혈액응고에 필요한 Ca2+이동, 혈소판 응집, 혈관수축물질 세로토닌의 증가, 혈관비후를 막아 혈액순환을 개선시킨다는 것이 밝혀져 있다. 실제 임상에서 허혈성 빈혈을 보인 환자를 대상으로 천궁 추물물과 아스피린을 투여한 결과, 90%와 60%로 천궁의 약효가 우수했으며, 이는 뇌혈류의 증가 경련성동맥의 이완, 말초 동맥의 저항 감소, 혈액의 점성 측면에서 아스피린보다 우수한 효능이 있는 것으로 나타났다. 그밖에도 항균, 항산화, 진정작용 항암효과 등이 있다고 알려져 있어 우리는 다발성 골수종에서 천궁에 의한 항암효과를 확인 하고자 연구를 수행하였다. In addition, it has been shown that TMP inhibits collagen production and improves blood circulation by preventing Ca2 + migration, platelet aggregation, increase of serotonin, and vascular hypertrophy, which are required for blood coagulation which can be caused by collagen in wound area. In patients with ischemic anemia, corticosteroids and aspirin were given to 90% and 60% of the patients, respectively. The results showed that the corticosteroid efficacy was superior to that of corticosteroids, because of increased cerebral blood flow, relaxation of the spontaneous artery, The blood viscosity was found to be superior to aspirin in terms of viscosity. In addition, antimicrobial, antioxidant and sedative anticancer effects are known to be effective.
생체의 모든 세포에 존재하는 소포체(Endoplasmic reticulum, ER)는 세포에서 단백질과 콜레스테롤 생산에 관여하는 소기관으로, 세포에서 단백질이 필요한 부위에 단백질을 전달하는 역할을 수행한다. 소포체(ER)에서 단백질들은 번역 후 수식(post-translational modification)과정을 거치게 되며 modification과 folding이 제대로 이루어져야만 이 곳을 통과시킨다. 그러므로 소포체는 분비 또는 막 단백질의 품질관리에 매우 중요한 기관이다. The endoplasmic reticulum (ER), which is present in all cells of living organisms, is an organelle involved in the production of proteins and cholesterol in cells. In the ER, proteins are post-translationally modified, and only through modification and folding they pass through. Therefore, the endoplasmic reticulum is an important organ for quality control of secretion or membrane protein.
ER에서 unfolded protein이 축적되어 나타나는 반응이 unfolded protein response (UPR)인데 이러한 반응이 일어나도록 하는 자극들을 ER stress라고 부른다. 실험적으로는 ER은 산화적환경을 유지하고 있기 때문에 세포에 DTT나 beta-mercaptoethanol과 같은 환원제를 처리하면 UPR가 일어나게 된다. ER stress는 소포체가 처리할 수 있는 능력 이상의 단백질이 소포체 내로 유입되거나 소포체 내 칼슘이 고갈돼 소포체 기능에 장애가 발생하는 상태를 일컫는데, 이는 암의 발달과 유지에 영향을 주기 때문에 중요한 암 치료 타깃으로 생각되고 있다. ER stress가 심해지면 손상된 세포를 제거하기위해 세포사멸 (apoptosis)을 유도한게 되는데 이 과정에서 CHOP/GADD153이 중요한 매계체로 작용한다. 이러한 ER stress의해 유도된 세포사멸 경호 활성은 허혈성 혈관질환에서 활성산소(ROS)와도 연관이 있다고 보고되었다.The unfolded protein response (UPR) is the accumulation of unfolded protein in ER, and the stimuli that cause this reaction are called ER stress. Experimentally, the ER maintains an oxidative environment, so UPR occurs when cells are treated with a reducing agent such as DTT or beta-mercaptoethanol. ER stress refers to a state in which proteins above the ability of the endoplasmic reticulum to treat are introduced into the endoplasmic reticulum or depleted of calcium in the endoplasmic reticulum, resulting in a failure of the endoplasmic reticulum. This is an important cancer treatment target because it affects the development and maintenance of cancer I think. When ER stress is increased, it induces apoptosis in order to remove damaged cells. In this process, CHOP / GADD153 acts as an important all system. These ER stress-induced apoptosis-protective activities were also reported to be associated with reactive oxygen species (ROS) in ischemic vascular disease.
대부분의 생명체는 공기 중의 산소를 호흡하여 산화시켜 얻어지는 에너지를 이용하여 생명을 유지하는데, 이런 산소가 필요한 대사과정에서 불가피하게 세포를 파괴시키는 독성물질들이 부산물로 만들어지는데 이것을 활성산소(reactive oxygen species, ROS)라고 한다. Most living organisms use life-sustaining energy to breathe oxygen in the air. In the process of metabolism that requires oxygen, toxins that inevitably destroy cells are produced as a byproduct, ROS).
이런 ROS는 정상적인 세포내 활성작용 과정에서 생성되며 세포분화, 유전자의 발현, 사이토카인에 분비 등을 포함한 여러 생물학적 과정에 연관되어 있다. 산화적스트레스는 활성산소의 생성과 이를 제거하는 항산화 반응간의 불균형으로 인해 세포내 활성산소가 증가하여 DNA나 단백질, 지질(lipid)과 반응하여 손상시키는 현상으로 이러한 ROS의 항상성을 유지하는 것은 정상세포 뿐만 아니라 암세포성장과 생존에 매우 중요하다.These ROS are produced during normal intracellular activity and are involved in various biological processes including cell differentiation, gene expression, and secretion into cytokines. Oxidative stress is a phenomenon that increases the active oxygen in the cell due to the imbalance between the production of active oxygen and the antioxidative reaction that removes it, and it reacts with DNA, protein, and lipid to damage this homeostasis. It is also important for cancer cell growth and survival.
이에, 본 발명자는 천궁 추출물이 cleaved-PARP 및 CHOP(C/EBP homologous protein)의 발현량을 증가시켜 세포 내의 활성 산소의 생성량을 증가시키고, 이에 따라 소포체(endoplasmic reticulum, ER) 스트레스에 의한 세포사멸을 유도함으로써 다발성 골수암에 대하여 항암 효과가 우수함을 알아내고 본 발명을 완성하였다.Accordingly, the present inventors have found that the extract of Cynomolgus sinensis increases the expression amount of cleaved-PARP and CHOP (C / EBP homologous protein) to increase the production of active oxygen in the cell, and thus, the cell death due to endoplasmic reticulum And thus the present invention has been completed based on the finding that the anticancer effect against multiple myeloma is excellent.
본 발명은 천궁 (Cnidium officinale Makion) 추출물을 유효성분으로 포함하는 암의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.The present invention provides a pharmaceutical composition for preventing or treating cancer comprising an extract of Cnidium officinale Makion as an active ingredient.
본 발명의 다른 목적은 천궁 (Cnidium officinale Makion) 추출물을 포함하는 항암보조제 조성물을 제공하는 것이다.Another object of the present invention is to provide an anticancer adjuvant composition comprising Cnidium officinale Makion extract.
본 발명의 또 다른 목적은 천궁 (Cnidium officinale Makion) 추출물을 포함하는 암의 예방 또는 개선용 건강기능식품 조성물을 제공하는 것이다.It is still another object of the present invention to provide a health functional food composition for preventing or ameliorating cancers containing Cnidium officinale Makion extract.
본 발명의 다른 목적은 천궁 (Cnidium officinale Makion) 추출물을 포함하는 암의 예방 또는 개선용 건강식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a health food composition for preventing or ameliorating cancers containing Cnidium officinale Makion extract.
상기 목적을 달성하기 위하여,In order to achieve the above object,
본 발명은 천궁 (Cnidium officinale Makion) 추출물을 유효성분으로 포함하는 암의 예방 또는 치료용 약학 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating cancer comprising an extract of Cnidium officinale Makion as an active ingredient.
또한, 본 발명은 천궁 (Cnidium officinale Makion) 추출물을 포함하는 항암보조제 조성물을 제공한다.The present invention also provides an anticancer adjuvant composition comprising Cnidium officinale Makion extract.
나아가 본 발명은 천궁 (Cnidium officinale Makion) 추출물을 포함하는 암의 예방 또는 개선용 건강기능식품 조성물을 제공한다.Further, the present invention provides a health functional food composition for preventing or ameliorating cancer comprising Cnidium officinale Makion extract.
또한, 본 발명은 천궁 (Cnidium officinale Makion) 추출물을 포함하는 암의 예방 또는 개선용 건강식품 조성물을 제공한다.In addition, the present invention provides a health food composition for preventing or ameliorating cancer comprising Cnidium officinale Makion extract.
본 발명에 따르면, 천궁 추출물은 cleaved-PARP 및 CHOP(C/EBP homologous protein)의 발현량을 증가시켜 세포 내의 활성 산소의 생성량을 증가시키고, 이에 따라 소포체(endoplasmic reticulum, ER) 스트레스에 의한 세포사멸이 유도됨으로써, 암의 예방 또는 치료에 유용하게 사용될 수 있다.According to the present invention, the extract of Cynomolgus sinensis increases the amount of cleaved-PARP and CHOP (C / EBP homologous protein) expression, thereby increasing the production of reactive oxygen species in the cell. Thus, the endoplasmic reticulum (ER) Can be used to prevent or treat cancer.
도 1a는 천궁 추출물 처리에 의한 다발성 골수종 세포주 U937의 세포 생존율을 확인한 도이다.
도 1b는 천궁 추출물 처리에 의한 다발성 골수종 세포주 U266의 세포 생존율을 확인한 도이다.
도 2a는 천궁 추출물 처리에 의한 다발성 골수종 세포주 U937에서의 세포사멸 관련 단백질과 ER 스트레스 유발 관련 단백질의 발현 정도를 확인한 도이다.
도 2b는 천궁 추출물 처리에 의한 다발성 골수종 세포주 U266에서의 세포사멸 관련 단백질과 ER 스트레스 유발 관련 단백질의 발현 정도를 확인한 도이다.
도 3a는 천궁 추출물 처리에 의한 다발성 골수종 세포주 U937에서의 활성산소 생성을 확인한 도이다.
도 3b는 천궁 추출물 처리에 의한 다발성 골수종 세포주 U266에서의 활성산소 생성을 확인한 도이다.
도 4a는 천궁 추출물 처리에 의한 다발성 골수종 세포주 U937에서의 활성산소 생성과 세포 독성 사이 상관관계를 확인한 도이다.
도 4b는 천궁 추출물 처리에 의한 다발성 골수종 세포주 U266에서의 활성산소 생성과 세포독성 사이 상관관계를 확인한 도이다.
도 5a는 천궁 추출물 처리에 의한 다발성 골수종 세포주 U937서의 활성산소 생성과 소포체 스트레스 유도의 상관관계를 확인한 도이다.
도 5b는 천궁 추출물 처리에 의한 다발성 골수종 세포주 U266서의 활성산소 생성과 소포체 스트레스 유도의 상관관계를 확인한 도이다.FIG. 1A shows the cell survival rate of multiple myeloma cell line U937 by treatment with astragalus extract. FIG.
FIG. 1B shows the cell survival rate of the multiple myeloma cell line U266 by the extract of Astragalus membranaceus.
FIG. 2A shows the expression levels of apoptosis-related proteins and ER stress-related proteins in the multiple myeloma cell line U937 by the treatment with astragalus extract.
FIG. 2B is a graph showing the degree of expression of apoptosis-related protein and ER stress-related protein in U266 cell line by treatment with astragalus extract.
FIG. 3A is a graph showing the production of active oxygen in the multiple myeloma cell line U937 by treatment with the extract of Angelica keiskei koidz.
FIG. 3B is a graph showing the production of active oxygen in the multiple myeloma cell line U266 by the treatment with astragalus extract. FIG.
4A is a graph showing the correlation between the production of active oxygen and the cytotoxicity in the multiple myeloma cell line U937 by the treatment with citron extract.
FIG. 4B is a graph showing the correlation between the production of active oxygen and the cytotoxicity in the multiple myeloma cell line U266 by treatment with the extract of Angelica keiskei koidz.
FIG. 5A is a graph showing the correlation between the production of reactive oxygen species and induction of ER stress in multiple myeloma cell line U937 by the treatment with astragalus extract. FIG.
5B is a graph showing the correlation between the production of reactive oxygen species and induction of endoplasmic reticulum stress in the multiple myeloma cell line U266 by treatment with the extract of T. kai.
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 천궁 (Cnidium officinale Makion) 추출물을 유효성분으로 포함하는 암의 예방 또는 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating cancer comprising an extract of Cnidium officinale Makion as an active ingredient.
본 발명에서 용어, "추출물(extract)"은 생약을 적절한 침출액으로 짜내고 침출액을 증발시켜 농축한 제제를 의미하는 것으로, 이에 제한되지는 않으나, 추출처리에 의해 얻어지는 추출액, 추출액의 희석액 또는 농축액, 추출액을 건조하여 얻어지는 건조물, 이들의 조정제물 또는 정제물일 수 있다. 상기 천궁 추출물은 통상의 기술 분야에 공지된 일반적인 추출방법, 분리 및 정제방법을 이용하여 제조할 수 있다. 상기 추출방법으로는, 이에 제한되지는 않으나, 바람직하게 열탕 추출, 열수 추출, 냉침 추출, 환류 냉각 추출 또는 초음파 추출 등의 방법을 사용할 수 있다.The term " extract " in the present invention means a preparation which is prepared by squeezing a herbal medicine with an appropriate extract solution and evaporating the extract solution. The extract solution obtained by the extraction treatment, the diluent or concentrate of the extract, Or a dried product obtained by drying the above, a controlled preparation thereof or a purified product thereof. The cucurbitaceae extract may be prepared by a common extraction method, separation and purification methods known in the art. The extraction method may be, but not limited to, hot water extraction, hot water extraction, cold extraction, reflux cooling extraction, or ultrasonic extraction.
본 발명에서, 추출용매는 물, 유기용매 또는 이들의 혼합용매 등을 사용할 수 있으며, 상기 유기용매는 탄소수 1 내지 4의 알코올이나, 에틸아세테이트 또는 아세톤 등의 극성용매, 헥산 또는 디크로로메탄의 비극성용매 또는 이들의 혼합용매를 사용할 수 있다. 또한, 바람직하게는 물, 탄소수 1 내지 4의 알코올 또는 이들의 혼합용매를 사용할 수 있으며, 보다 바람직하게는 에탄올을 사용할 수 있다. In the present invention, the extraction solvent may be water, an organic solvent or a mixed solvent thereof. The organic solvent may be an alcohol having 1 to 4 carbon atoms, a polar solvent such as ethyl acetate or acetone, a hexane or a dichloromethane A nonpolar solvent or a mixed solvent thereof may be used. Further, water, an alcohol having 1 to 4 carbon atoms, or a mixed solvent thereof may be preferably used, and more preferably ethanol can be used.
본 발명의 일실시예에 있어서, 상기 용매로서 100% 에탄올을 이용하여 추출한 뒤 감압 농축한 천궁 추출물을 제조하였다.In one embodiment of the present invention, the extract was extracted with 100% ethanol as the solvent, followed by concentration under reduced pressure.
본 발명에서, 상기 암은 다발성 골수종, 대장암, 유방암, 자궁암, 자궁경부암, 난소암, 전립선암, 뇌종양, 두경부암종, 흑색종, 골수종, 백혈병, 림프종, 위암, 폐암, 췌장암, 비소세포성폐암, 간암, 식도암, 소장암, 항문부근암, 나팔관암종, 자궁내막암종, 질암종, 음문암종, 호지킨병, 방광암, 신장암, 수뇨관암, 신장세포암종, 신장골반암종, 골암, 피부암, 두부암, 경부암, 피부흑색종, 안구내흑색종, 내분비선암, 갑상선암, 부갑상선암, 부신암, 연조직육종, 요도암, 음경암, 중추신경계(central nervous system; CNS) 종양, 1차 CNS 림프종, 척수종양, 뇌간신경교종, 뇌하수체선종 등이 있으며, 다발성 골수종(multiple myeloma)인 것이 바람직하다.In the present invention, the cancer is selected from the group consisting of multiple myeloma, colorectal cancer, breast cancer, cervical cancer, cervical cancer, ovarian cancer, prostate cancer, brain tumor, head and neck carcinoma, melanoma, myeloma, leukemia, lymphoma, gastric cancer, lung cancer, Ovarian cancer, kidney cancer, renal cell carcinoma, renal pelvic carcinoma, bone cancer, skin cancer, tofu, ovarian cancer, endometrial carcinoma, endometrial carcinoma, vulvar carcinoma, vulvar carcinoma, Cancer of the central nervous system (CNS), primary CNS lymphoma, spinal cord tumor, cervical cancer, endometrial carcinoma, thyroid cancer, pituitary adenocarcinoma, soft tissue sarcoma, Tumor, brainstem glioma, pituitary adenoma, and multiple myeloma are preferable.
본 발명의 일실시예에 있어서, 암의 예방 또는 치료는 암세포의 소포체(endoplasmic reticulum, ER) 스트레스로 인한 세포사멸에 의해 달성될 수 있다.In one embodiment of the present invention, the prevention or treatment of cancer can be accomplished by apoptosis due to endoplasmic reticulum (ER) stress.
본 발명의 일 실시예에 있어서, 천궁 추출물 처리에 의한 다발성 골수종 세포의 사멸이 증가하는 것을 확인하였으며, 이와 같은 항암 활성 기작을 확인하기 위하여 세포사멸 관련 단백질들과 ER-스트레스 관련 세포사멸 유발 단백질들의 발현 변화를 확인한 결과, 천궁 추출물 처리에 의해 세포사멸 관련 Pro-PARP 및 procaspase-3이 감소하고 Bax 발현이 증가함을 확인함으로써 본 발명의 천궁 추출물이 ER-스트레스를 유발하고 이를 통해 세포사멸을 유도해 항암 활성을 나타내는 것임을 확인하였다.In one embodiment of the present invention, it was confirmed that the death of multiple myeloma cells by the extract of Astragalus membranaceus was increased, and in order to confirm the anticancer activity mechanism, the apoptosis-related proteins and ER-stress related apoptosis- As a result of confirming expression changes, it was confirmed that pro-PARP and procaspase-3 related to apoptosis were decreased by Bombyx mori extract treatment and Bax expression was increased. Thus, the extract of Bombyx mori of the present invention induced ER-stress, Indicating that it exhibited anti-cancer activity.
본 발명에서의 용어, "apoptosis"는 세포자멸사라고도 하며, 일종의 계획된 세포 죽음(programmed cell death; PCD)으로서, 우리 몸 안에 입력되어 있는 생체 프로그램에 의해 비정상 세포, 손상된 세포, 노화된 세포가 스스로 자살해 사멸함으로써 전체적인 신체 건강을 유지하도록 하는 메커니즘이다. The term " apoptosis " in the present invention, also called apoptosis, is a kind of programmed cell death (PCD) in which abnormal cells, damaged cells, It is a mechanism to maintain overall physical health by decay.
본 발명의 천궁 추출물은 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 extract of the present invention may be administered orally or parenterally in various dosage forms during clinical administration. In the case of formulation, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, .
경구투여를 위한 고형 제제에는 정제, 환자, 산제, 과립제, 캡슐제, 트로키제 등이 포함되며, 이러한 고형 제제는 하나 이상의 본 발명의 천궁 추출물에 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 formulations for oral administration include tablets, patients, powders, granules, capsules, troches, and the like, which may contain one or more excipients such as starch, calcium carbonate, Sucrose, lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate talc are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions or syrups. Various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like are included in addition to commonly used simple diluents such as water and liquid paraffin. .
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 sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. Examples of the non-aqueous solvent and suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. As a base for suppositories, witepsol, macrogol, tween 61, cacao paper, laurin, glycerol, gelatin and the like can be used.
또한, 본 발명의 천궁 추출물의 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.The effective dose of the extract of the present invention for the human body may vary depending on the patient's age, body weight, sex, dosage form, health condition and disease severity, and is generally about 0.001-100 mg / kg / Preferably 0.01 to 35 mg / kg / day. It is generally from 0.07 to 7000 mg / day, preferably from 0.7 to 2500 mg / day, based on an adult patient weighing 70 kg, and may be administered once a day It may be divided into several doses.
항암보조제 조성물Anticancer adjuvant composition
본 발명은 천궁 추출물을 유효성분으로 포함하는 항암보조제를 제공한다.The present invention provides an anticancer adjuvant comprising an extract of Angelica keiskei koidz. As an active ingredient.
본 발명의 용어, "항암보조제"는 항암제의 항암효과를 증대시키고, 항암제의 부작용을 억제하거나 개선시키 위하여 사용될 수 있으며, 항암제와 병용하여 환자에게 투여될 수 있다. The term " anticancer adjuvant " of the present invention can be used to increase the anticancer effect of an anticancer agent, to suppress or improve side effects of the anticancer agent, and to administer it to a patient in combination with an anticancer agent.
건강기능성식품 및 건강식품 조성물Health functional food and health food composition
본 발명의 천궁 추출물을 건강기능식품 및 건강식품으로 사용하는 경우, 식품의 종류에는 특별한 제한은 없다. 본 발명의 천궁 추출물을 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 건강식품을 모두 포함한다.When the extract of the present invention is used as a health functional food and a health food, the kind of the food is not particularly limited. Examples of the food to which the extract of the present invention can be added include a dairy product including a drink, meat, sausage, bread, biscuit, rice cake, chocolate, candy, snack, confectionery, pizza, ramen, Various soups, beverages, alcoholic beverages and vitamin complexes, dairy products and dairy products, and includes health functional foods and health foods in a conventional sense.
본 발명에 따른 천궁 추출물을 함유하는 건강기능식품 및 건강식품 조성물은 식품에 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 천궁 추출물의 혼합량은 그의 사용 목적(예방 또는 개선용)에 따라 적합하게 결정될 수 있다. 일반적으로, 건강기능식품 및 건강식품 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 천궁 추출물은 상기 범위 이상의 양으로도 사용될 수 있다.The health functional food and the health food composition containing the extract of cinnabar according to the present invention can be added directly to the food or can be used together with other food or food ingredients and suitably used according to a conventional method. The amount of the cucurbitaceae extract to be mixed can be suitably determined according to its use purpose (for prevention or improvement). Generally, the amount of the composition in the health functional food and the health food may be 0.1 to 90 parts by weight of the total food weight. However, in the case of long-term intake for the purpose of health maintenance or health control, the amount may be less than the above range, and there is no problem in terms of safety.
본 발명의 건강기능식품 및 건강식품 조성물은 지시된 비율로 필수 성분으로서 본 발명 천궁 추출물을 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 foods and health food compositions of the present invention are not particularly limited to the ingredients other than those containing the extract of the present invention as an essential ingredient in the indicated ratios and may include various flavors or natural carbohydrates ≪ / RTI > 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 dextrin, cyclodextrin and the like, and sugar alcohols such as xylitol, sorbitol, and erythritol. Natural flavors (tau martin, stevia extracts (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavors (saccharin, aspartame, etc.) can be advantageously used as flavors other than those described above . The ratio of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 parts of the health functional food and health food composition of the present invention.
상기 외에 본 발명의 천궁 추출물을 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 health functional food and the health food composition containing the extract of the present invention may be used in various flavoring agents such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, coloring agents, ), Pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloid thickening agents, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated drinks and the like. In addition, the health functional food and health food composition of the present invention may contain natural fruit juice and pulp for the production of fruit juice drinks and vegetable drinks.
이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 그렇게 중요하진 않지만 본 발명의 천궁 추출물을 함유하는 건강기능식품 및 건강식품 조성물 100 중량부 당 0.1 내지 약 20 중량부의 범위에서 선택되는 것이 일반적이다.These components may be used independently or in combination. Although the ratio of such additives is not so important, it is generally selected in the range of 0.1 to about 20 parts by weight per 100 parts by weight of the health functional food and health food composition containing the cucurbitaceae extract of the present invention.
이하, 본 발명을 하기의 실시예에 의하여 더욱 상세히 설명한다. 단, 하기의 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기의 실시예에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are illustrative of the present invention, and the present invention is not limited by the following examples.
<실시예 1> 천궁 (≪ Example 1 > Cnidium officinale MakionCnidium officinale Makion )) 추출물 제조 Extract preparation
천궁 추출물을 제조하기 위해, 100% 에탄올 1L에 천궁 1kg을 삼각 플라스크에 넣고 상온에서 96시간 추출한 뒤 거름종이로 약재를 걸러주어 천궁 에탄올 추출액을 제조하였다. 상기 천궁 에탄올 추출액을 100ml씩 50℃에서 3시간 동안 감압 농축한 후, -80℃에서 4 내지 10Pa 압력으로 6시간동안 동결 건조 시킨 후 다시 -80℃에서 얼려 주고 다시 동결 건조를 시키는 작업을 3회 반복 하여 천궁 에탄올 추출물을 제조하였다. 이후 약 수저를 이용하여 동결 건조시킨 천궁 추출물을 긁어 낸 후 무게를 재서 수득률을 계산 하였더. DMSO(dimethyl sulfoxide)1ml에 천궁 추출물을 400mg으로 녹여 400mg/ml의 농도로 Stock 을 만든 후 1.5ml 튜브에 넣어 -20℃에 보관 하여 사용하였다.In order to prepare cucurbitaceae extract, 1 kg of cucumber was added to 1 L of 100% ethanol in an Erlenmeyer flask, and the mixture was extracted at room temperature for 96 hours. The ethanol extract of celadon shell was concentrated under reduced pressure at 50 ° C for 3 hours at 50 ° C, lyophilized at -80 ° C under 4 to 10 Pa pressure for 6 hours, frozen at -80 ° C again, The ethanol extract of Angelica gigas was prepared repeatedly. After the freeze-dried cucurbit extract was scraped off by using a spoon, the weight was determined and the yield was calculated. DMSO (dimethyl sulfoxide) was dissolved in 400mg of celgol extract to make a stock at a concentration of 400mg / ml, and the mixture was stored at -20 ° C in a 1.5ml tube.
<실험예1> 천궁 추출물의 다발성 골수종에 대한 세포 독성 확인<Experimental Example 1> Cytotoxicity test for multiple myeloma of cynomolgus monkey extract
상기 실시예 1에서 제조한 천궁 추출물의 다발성 골수종에 대한 항암 활성을 확인하기 위하여, 다발성 골수종 세포주인 U937 세포주 (한국세포주은행)와 U266 세포주 (ATCC) 50㎕를 96웰-플레이트에 2×104세포/웰이 되도록 분주한 뒤, 10% inactivated fetal bovine serum (FBS) 및 1% penicillin-streptomycin 을 첨가한 RPMI 배지에서, 37℃의 5% CO2 인큐베이터 (MCO-15AC, Sanyo, Osaka, Japan)로 배양하였다. The embodiments, multiple myeloma cell line, U937 cells (Korea Cell Line Bank) and the U266 cell line (ATCC) the 50㎕ 96 wells to confirm that the anti-cancer activity against multiple myeloma in a Cnidium extract prepared in Example 1 to the plate 2 × 10 4 After cells were divided into cells / well, in RPMI medium supplemented with 10% inactivated fetal bovine serum (FBS) and 1% penicillin-streptomycin, And cultured in a 5% CO 2 incubator (MCO-15AC, Sanyo, Osaka, Japan) at 37 ° C.
배양한 세포주 U937와 U266에 상기 실시예 1에서 제조한 천궁 추출물을 0, 25, 50, 100 및 200㎍/ml의 농도로 각각 50㎕씩 처리한 뒤, 24시간 동안 인큐베이션 하였다. 인큐베이션 한 세포에 EZ-Cytox 시약 (DoGen)을 암상태에서 10㎕ 처리하고 30분 내지 4시간 동안 인큐베이션한 뒤, 마이크로플레이트 리더기 (Bio-rad Model 680)를 이용하여 흡광도 450nm파장대에서 세포 생존율을 확인하였다. 도 1a 및 도 1b에 천궁 추출물 처리에 의한 다발성 골수종 세포주 U937과 U266의 세포 생존율을 확인한 결과를 나타내었다.Each of the cultured cell lines U937 and U266 was treated with 50 μl each of the extracts prepared in Example 1 at concentrations of 0, 25, 50, 100 and 200 μg / ml, followed by incubation for 24 hours. The incubated cells were treated with 10 μl of EZ-Cytox reagent (DoGen) in the dark and incubated for 30 minutes to 4 hours. Cell viability was confirmed at a wavelength of 450 nm in absorbance using a microplate reader (Bio-rad Model 680) Respectively. FIGS. 1A and 1B show cell viability of multiple myeloma cell lines U937 and U266 by treatment with cucumber extracts.
상기 도 1a 및 도 1b에 나타낸 바와 같이, 천궁 추출물의 농도 의존적으로 다발성 골수종에 독성을 나타냈고, 100㎍/ml 이후부터는 농도에 큰 차이 없이 다발성 골수종을 사멸시키는 것을 알 수 있었다.As shown in FIG. 1A and FIG. 1B, the extracts showed toxicity to multiple myeloma in a concentration-dependent manner, and the multiple myeloma was killed without significant difference in concentration after 100 μg / ml.
<실험예2> 천궁 추출물에 의한 다발성 골수종의 세포사멸 및 소포체 스트레스 유발 효과 확인 <Experimental Example 2> Confirmation of apoptosis and endothelial stress-induced effects of multiple myeloma cells by extracts
상기 실시예 1에서 제조한 천궁 추출물이 다발성 골수종에서의 세포사멸에 미치는 영향을 확인하기 위해, 세포사멸 진행시 절단되는 것으로 알려진 PARP(Poly ADP ribose polymerase)와 DNA 손상을 유도하고 ER 스트레스를 유발 마커로 이용되는 CHOP(C/EBP homologous protein) 및 P-ATF4 (Activating transcription factor 4), P-PERK (protein kinase R (PKR)-like endoplasmic reticulum kinase) 의 발현 정도를 웨스턴 블롯 분석으로 확인하였다. In order to examine the effect of the extracts of cucumbers prepared in Example 1 on apoptosis in multiple myeloma, PARP (Poly ADP ribose polymerase), which is known to be cleaved during apoptosis, induces DNA damage and induces ER stress The expression levels of CHOP (C / EBP homologous protein), P-ATF4 (activating transcription factor 4) and P-PERK (PKR) -like endoplasmic reticulum kinase) were analyzed by Western blot analysis.
다발성 골수종 세포주인 U937와 U266 세포주에 상기 실시예 1에서 제조한 천궁 추출물을 0, 40 및 80㎍/ml로 각각 처리하고 24시간 동안 37℃의 5% CO2 인큐베이터로 인큐베이션 한 후 세포를 수집하여 PBS로 워싱하고, 세포 파쇄 버퍼 RIPA (20mM Tris-HCL (pH 7.5), 150mM NaCl, 1mM NaEDTA, 1mM EGTA, 1% NP-40, 1% sodium pyrpphophate, 1mM beta-glycerophosphate, 1mM Na3VO4 및 1㎍/ml leupeptin (Cell signaling))를 첨가하여 30분간 4℃에서 세포를 파쇄하였다. U937 and U266 cell lines, which are multiple myeloma cell lines, were treated with 0, 40 and 80 / / ml of the extracts prepared in Example 1, respectively, and incubated in a 5% CO 2 incubator at 37 캜 for 24 hours. Cells were collected washing with PBS, and cell disruption buffer RIPA (20mM Tris-HCL (pH 7.5), 150mM NaCl, 1mM NaEDTA, 1mM EGTA, 1% NP-40, 1% sodium pyrpphophate, 1mM beta-glycerophosphate, 1mM Na 3 VO 4 , and 1 [mu] g / ml leupeptin (Cell signaling)) was added and cells were disrupted at 4 [deg.] C for 30 minutes.
세포 파쇄물을 15,520×g에서 20분간 원심 분리하여 세포막 성분 등을 제거한 후, RC DC™ Protein Assay Kit II(protein assay kit) (Bio-rad, USA)를 사용하여 단백질을 정량하여 시료별 (천궁 추출물 0, 40 및 80㎍/ml 처리군들)로 동일한 단백질의 양이 포함되도록 조절하였다. Cell lysates were centrifuged at 15,520 × g for 20 minutes to remove cell membrane components and the proteins were quantified using RC DC ™ Protein Assay Kit II (Bio-Rad, USA) 0, 40 and 80 [mu] g / ml treated groups).
준비된 단백질 시료에 5×로딩 다이를 넣고 5분 동안 95℃로 가열하여 단백질을 변성시켰다. 그 후, 8~10% SDS-PAGE 젤에 시료를 로딩하여 90 내지 100V로 1시간 30분 내지 3시간 동안 전기영동을 수행하였으며, 젤 위에서 분리된 단백질들을 200mA~300mA로 1시간 내지 4시간 동안 멤브레인으로 트랜스퍼하였다. 단백질이 트랜스퍼된 멤브레인을 5% 스킴 밀크가 포함된 TBST (tris buffered saline, pH 7.5) 용액으로 상온에서 2시간 동안 블로킹한 뒤 1차 항체 항-PARP 및 항-CHOP, 항-인산화 PERK, 항인산화-ATF4 를 각각 1:500으로 희석하여 블로킹한 멤브레인과 4℃에서 1시간 내지 오버나잇으로 반응시켰다. Proteins were denatured by adding 5x loading dies to the prepared protein samples and heating to 95 ° C for 5 minutes. Thereafter, the sample was loaded on an 8 to 10% SDS-PAGE gel and electrophoresed at 90 to 100 V for 1 hour and 30 minutes to 3 hours. Proteins separated from the gel were incubated at 200 mA to 300 mA for 1 hour to 4 hours And transferred to the membrane. Protein-transferred membranes were blocked with TBST (tris buffered saline, pH 7.5) solution containing 5% skim milk at room temperature for 2 hours and then incubated with primary antibodies anti-PARP and anti-CHOP, anti-phosphorylation PERK, -ATF4 were each diluted 1: 500 and reacted with the blocked membrane at 4 ° C for 1 hour to overnight.
멤브레인을 TBST로 3회 워싱한 뒤 horseradish peroxidase가 결합된 항-rabbit IgG를 1:1,000으로 희석하여 상온에서 멤브레인과 1시간 동안 반응시킨 다음 TBST로 3회 워싱하였다. 워싱한 멤브레인을 chemiluminescent reagent와 1 내지 3분 동안 반응시키고 필름에 감광하여 단백질 밴드를 가시화하였다. 도 2a 및 도 2b에 천궁 추출물 처리에 의한 다발성 골수종 세포주 U937과 U266에서의 세포사멸 관련 단백질과 ER 스트레스 유발 관련 단백질의 발현 정도를 확인하였다.The membranes were washed three times with TBST, and anti-rabbit IgG conjugated with horseradish peroxidase was diluted to 1: 1,000, reacted with the membrane at room temperature for 1 hour, and then washed three times with TBST. The washed membrane was reacted with a chemiluminescent reagent for 1 to 3 minutes and exposed to a film to visualize the protein band. FIGS. 2A and 2B show the expression levels of apoptosis-related proteins and ER stress-related proteins in the U937 and U266 multiple myeloma cell lines, respectively, by treatment with astragalus extract.
상기 도 2a 및 도 2b에 나타낸 바와 같이, 천궁 추출물의 농도에 의존적으로 PARP의 절단이 증가하고, CHOP 및 P-ATF4, P-PERK 의 발현이 증가하였다. 따라서 천궁 추출물이 다발성 골수종에서 소포체 스트레스를 증가 시키므로써 세포사멸을 농도 의존적으로 유발하는 것을 알 수 있었다.As shown in FIG. 2A and FIG. 2B, the cleavage of PARP was increased and the expression of CHOP and P-ATF4 and P-PERK were increased depending on the concentration of cecum extract. Therefore, it was found that the extracts of T. monocytogenes increase the stress of the endoplasmic reticulum in multiple myeloma, leading to apoptosis in a concentration dependent manner.
<실험예 3> 다발성 골수종에서의 천궁 추출물의 활성산소 생성 확인<Experimental Example 3> Determination of active oxygen production of cynomolgus sinensis extracts in multiple myeloma
상기 실시예 1에서 제조한 천궁 추출물이 다발성 골수종에 미치는 영향을 확인하기 위하여, 다발성 골수종 세포주인 U937 세포주와 U266 세포주를 6well에 1.5×105 세포/웰 로 분주한 뒤 활성산소 억제제인 NAC (N-Acetyl-L-cysteine)를 5mM농도로 1시간 전처리 후 상기 실시예 1에서 제조한 천궁 추출물 80㎍/ml농도로 처리하고 24시간 동안 37℃의 5% CO2 인큐베이션 한 후 세포를 수집하였다. In order to examine the effect of the extract on the myeloma produced in Example 1 on the multiple myeloma, U937 cell line and U266 cell line were divided into 6 wells and 1.5 × 10 5 cells / well, and NAC (N -Acetyl-L-cysteine) was pretreated at a concentration of 5 mM for 1 hour, treated with the extract of Cucurbitaceae extract prepared in Example 1 at a concentration of 80 μg / ml, incubated at 37 ° C in 5% CO 2 for 24 hours and then collected.
DCFDA Cellular Reactive Oxygen Species Detection Assay kit (abcam)를 20μM로 처리하여 37℃에서 암상태로 30분 동안 인큐베이션하고 이 후, kit에 포함된 1X 버퍼로 조심스럽게 워싱 후 10% FBS가 포함된 1X 버퍼로 각각의 처리군들의 세포들을 수집 후 96웰-플레이트에 1×105 세포/웰로 분주하고, 마이크로플레이트 리더기를 이용하여 485/535nm에서 흡광도를 측정하였다. 도 3a 및 도 3b에 천궁 추출물 처리에 의한 다발성 골수종 세포주 U937과 U266에서의 활성산소 생성을 확인한 결과를 나타내었다.DCFDA Cellular Reactive Oxygen Species Detection Assay kit (abcam) was treated with 20 μM and incubated at 37 ° C for 30 min in the dark. The cells were then carefully washed with 1X buffer included in the kit and incubated in 1X buffer containing 10% FBS after collection of each of the cells of the group treated with 96 well - 1 × 10 5 cells / well in the plate and dispense, using a microplate reader, the absorbance was measured at 485 / 535nm. FIGS. 3A and 3B show the results of the production of active oxygen in U937 and U266 of the multiple myeloma cell lines by treatment with cucumber extracts.
상기 도 3a 및 도 3b에 나타낸 바와 같이, 천궁 80㎍/ml농도로 처리한 군에서는 활성산소가 증가 한 반면, 활성산소 억제제 처리시엔 활성산소가 감소 되었음을 확인 할 수 있었다.As shown in FIG. 3A and FIG. 3B, it was confirmed that active oxygen was increased in the group treated with 80 μg / ml of astragalus, whereas active oxygen was decreased in the treatment with the active oxygen inhibitor.
<실험예 4> 다발성 골수종에서 천궁 추출물 처리에 의한 활성산소 생성과 세포 독성 사이 상관관계 확인 <Experimental Example 4> Correlation between the production of active oxygen and the cytotoxicity by the treatment with the extract of Chenopodium ambrosioides in multiple myeloma
상기 실시예 1에서 제조한 천궁 추출물이 다발성 골수종에서 활성산소에 따른 세포사멸에 미치는 영향을 확인하기 위하여, 다발성 골수종 세포주인 U937 세포주와 U266 세포주 50㎕를 96웰-플레이트에 2×104 세포/웰이 되도록 분주한 뒤, ROS 억제제인 NAC (N-Acetyl-L-cysteine)를 5mM농도로 1시간 전처리 후 상기 실시예 1에서 제조한 천궁 추출물 50㎕을 80㎍/ml농도로 처리한 뒤, 24시간 동안 인큐베이션 하였다. 암 상태에서 인큐베이션 한 세포에 EZ-Cytox 시약 (DoGen)을 10㎕ 처리하고 30분 내지 2시간 동안 인큐베이션한 뒤, 마이크로플레이트 리더기 (Bio-rad Model 680) 흡광도 450nm에서 세포 생존율을 확인하였다. 도 4a 및 도 4b에 천궁 추출물 처리에 의한 다발성 골수종 세포주 U937과 U266에서의 활성산소 생성과 세포 독성 사이의 상관관계를 나타내었다.In order to examine the effect of the extract of Echinosophora koreensis prepared in Example 1 on the apoptosis according to reactive oxygen species in multiple myeloma, U937 cell line and 50 μl U266 cell line, which are multiple myeloma cell lines, were cultured in 96 well plate at 2 × 10 4 cells / (N-acetyl-L-cysteine), which is an ROS inhibitor, was pretreated at a concentration of 5 mM for 1 hour, treated with 50 μl of the extract of Cacao extract prepared in Example 1 at a concentration of 80 μg / ml, And incubated for 24 hours. Cells incubated in the dark state were treated with 10 [mu] l of EZ-Cytox reagent (DoGen) and incubated for 30 minutes to 2 hours, and cell viability was confirmed at 450 nm absorbance of the microplate reader (Bio-rad Model 680). FIGS. 4A and 4B show the correlation between active oxygen production and cytotoxicity in the multiple myeloma cell lines U937 and U266 by treatment with cucumber extracts.
상기 도 4a 및 도 4b에서 나타낸 바와 같이, 천궁 80㎍/ml 처리시 세포 생존율이 감소된 반면, ROS 억제제인 NAC 처리시 세포 생존율이 증가 된 것을 확인 할 수 있었다. 따라서, 천궁은 활성산소를 증가시킴으로써 세포사멸을 유도 한다는 것을 알 수 있었다.As shown in FIGS. 4A and 4B, the cell survival rate was decreased during treatment with 80 μg / ml of astragalus, whereas the cell survival rate was increased during treatment with NOS, an ROS inhibitor. Therefore, it was found that the astrocytoma induces apoptosis by increasing reactive oxygen species.
<실험예 5> 다발성 골수종에서 천궁 추출물의 활성산소 생성과 소포체 스트레스 유도의 상관관계 확인<Experimental Example 5> Correlation between the production of oxygen radicals and induction of endoplasmic reticulum stress in astrocytes of multiple myeloma
상기 실시예 1에서 제조한 천궁 추출물이 다발성 골수종에서 활성산소 생성과 소포체스트레스 유도 의 상관관계 확인해 보았다. 다발성 골수종 세포주인 U937와 U266 세포주에 ROS 억제제인 NAC (N-Acetyl-L-cysteine)를 5mM농도로 1시간 전처리 후 상기 실시 예 1에서 제조한 천궁 추출물 80㎕/ml농도로 처리하고, 24시간 동안 37℃의 5% CO2 인큐베이터로 인큐베이션 한 후 세포를 수집하여 PBS로 워싱하고, 세포 파쇄 버퍼 RIPA (20mM Tris-HCL (pH 7.5), 150mM NaCl, 1mM NaEDTA, 1mM EGTA, 1% NP-40, 1% sodium pyrpphophate, 1mM beta-glycerophosphate, 1mM Na3VO4 및 1㎍/ml leupeptin (Cell signaling))를 첨가하여 30분간 4℃에서 세포를 파쇄하였다. The correlation between the production of reactive oxygen species and the induction of ER stress in the multiple myeloma was investigated. NAC (N-Acetyl-L-cysteine), which is an ROS inhibitor, was pre-treated for 1 hour at a concentration of 5 mM, and then treated with UC37 extract and U266 cell line, which are cell lines of multiple myeloma, Incubated with a 5% CO 2 incubator at 37 ° C, the cells were collected, washed with PBS, and resuspended in a cell disruption buffer RIPA (20 mM Tris-HCl (pH 7.5), 150 mM NaCl, 1 mM NaEDTA, 1 mM EGTA, 1% , 1% sodium pyrpphophate, 1 mM beta-glycerophosphate, 1 mM Na 3 VO 4, and 1 [mu] g / ml leupeptin (Cell signaling)) was added and cells were disrupted at 4 [deg.] C for 30 minutes.
세포 파쇄물을 15,520×g에서 20분간 원심 분리하여 세포막 성분 등을 제거한 후, RC DC™ Protein Assay Kit II(protein assay kit) (Bio-rad, USA)를 사용하여 단백질을 정량하여 시료별로 동일한 단백질의 양이 포함되도록 조절하였다. 준비된 단백질 시료에 5×로딩 다이를 넣고 5분 동안 95℃로 가열하여 단백질을 변성시켰다. The cell lysates were centrifuged at 15,520 × g for 20 minutes to remove cell membrane components and the proteins were quantified using RC DC ™ Protein Assay Kit II (Bio-Rad, USA) . Proteins were denatured by adding 5x loading dies to the prepared protein samples and heating to 95 ° C for 5 minutes.
그 후, 8~10% SDS-PAGE 젤에 시료를 로딩하여 90 내지 100V로 1시간 30분 내지 3시간 동안 전기영동을 수행하였으며, 젤 위에서 분리된 단백질들을 200mA~300mA로 1시간 내지 4시간 동안 멤브레인으로 트랜스퍼하였다. 단백질이 트랜스퍼된 멤브레인을 5% 스킴 밀크가 포함된 TBST (tris buffered saline, pH 7.5) 용액으로 상온에서 1시간 동안 블로킹한 뒤 1차 항체 항-CHOP를 각각 1:500으로 희석하여 블로킹한 멤브레인을 4℃에서 오버나잇으로 반응시켰다. Thereafter, the sample was loaded on an 8 to 10% SDS-PAGE gel and electrophoresed at 90 to 100 V for 1 hour and 30 minutes to 3 hours. Proteins separated from the gel were incubated at 200 mA to 300 mA for 1 hour to 4 hours And transferred to the membrane. Protein-transferred membranes were blocked with TBST (tris buffered saline, pH 7.5) solution containing 5% skim milk for 1 hour at room temperature, and then blocked with a 1: 500 dilution of primary antibody anti-CHOP And reacted at 4 ° C overnight.
멤브레인을 TBST로 3회 워싱한 뒤 horseradish peroxidase가 결합된 항-rabbit IgG를 1:1,000으로 희석하여 상온에서 멤브레인과 2시간 동안 반응시킨 다음 TBST로 3회 워싱 하였다. 워싱한 멤브레인을 chemiluminescent reagent와 1 내지 3분 동안 반응시키고 필름에 감광하여 단백질 밴드를 가시화하였다. 도 5a 및 도 5b에 천궁 추출물 처리에 의한 다발성 골수종 세포주 U937과 U266에서의 활성산소 생성과 소포체 스트레스 유도의 상관관계를 나타내었다.The membranes were washed three times with TBST, and anti-rabbit IgG conjugated with horseradish peroxidase was diluted to 1: 1,000, reacted with the membrane at room temperature for 2 hours, and then washed three times with TBST. The washed membrane was reacted with a chemiluminescent reagent for 1 to 3 minutes and exposed to a film to visualize the protein band. FIGS. 5A and 5B show the correlation between the production of reactive oxygen species and induction of endoplasmic reticulum stress in U937 and U266 by multiple myeloma cell lines.
상기 도 5a 및 도 5b에서 나타낸 바와 같이, 천궁 추출물을 80㎍/ml 농도처리한 군은 CHOP 발현이 증가한 반면, 활성산소 억제제인 NAC를 5mM농도로 처리한군은 CHOP이 감소 되었음을 확인 할 수 있었다. 따라서, 천궁은 다발성 골수종세포에서 활성산소를 증가시킴으로써 소포체 스트레스를 유도 한다는 것을 확인 할 수 있었다. As shown in FIGS. 5A and 5B, CHOP expression was increased in the group treated with 80 μg / ml of the extract of Cynomolgus sinensis, whereas CHOP was decreased in the group treated with 5 mM of NAC as an active oxygen inhibitor. Therefore, it was confirmed that astrocytes induce ER stress by increasing reactive oxygen species in multiple myeloma cells.
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 특히 청구범위에 나타나 있으며, 그와 동등한 범위내에 있는 모든 차이점은 본 발명에 포함된 것으로 해석되어야 할 것이다.The present invention has been described with reference to the preferred embodiments. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the disclosed embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is indicated by the appended claims rather than by the foregoing description, and all differences within the scope of equivalents thereof should be construed as being included in the present invention.
Claims (11)
A pharmaceutical composition for preventing or treating cancer comprising an extract of Cnidium officinale Makion as an active ingredient.
상기 추출물은 물, 탄소수 1 내지 4의 알코올 또는 이들의 혼합 용매로 추출한 것을 특징으로 하는 조성물.
The method according to claim 1,
Wherein the extract is extracted with water, an alcohol having 1 to 4 carbon atoms or a mixed solvent thereof.
상기 추출물은 탄소수 1 내지 4의 알코올로 추출한 것을 특징으로 하는 조성물.
3. The method of claim 2,
Wherein the extract is extracted with an alcohol having 1 to 4 carbon atoms.
상기 추출물은 에탄올로 추출한 것을 특징으로 하는 조성물.
The method of claim 3,
Wherein the extract is extracted with ethanol.
상기 추출물은 암세포의 소포체(endoplasmic reticulum, ER) 스트레스로 인한 세포사멸을 유도하는 것을 특징으로 하는 조성물.
The method according to claim 1,
Wherein said extract induces apoptosis due to endoplasmic reticulum (ER) stress of cancer cells.
상기 추출물은 활성 산소(reactive oxygen species, ROS)의 생성량을 증가시키는 것을 특징으로 하는 조성물.
The method according to claim 1,
Wherein the extract increases the amount of reactive oxygen species (ROS) produced.
상기 암은 다발성 골수종, 대장암, 유방암, 자궁암, 자궁경부암, 난소암, 전립선암, 뇌종양, 두경부암종, 흑색종, 골수종, 백혈병, 림프종, 위암, 폐암, 췌장암, 비소세포성폐암, 간암, 식도암, 소장암, 항문부근암, 나팔관암종, 자궁내막암종, 질암종, 음문암종, 호지킨병, 방광암, 신장암, 수뇨관암, 신장세포암종, 신장골반암종, 골암, 피부암, 두부암, 경부암, 피부흑색종, 안구내흑색종, 내분비선암, 갑상선암, 부갑상선암, 부신암, 연조직육종, 요도암, 음경암, 중추신경계(central nervous system; CNS) 종양, 1차 CNS 림프종, 척수종양, 뇌간신경교종 및 뇌하수체선종으로 이루어진 그룹에서 선택되는 어느 하나인 것을 특징으로 하는 조성물.
The method according to claim 1,
Wherein the cancer is selected from the group consisting of multiple myeloma, colorectal cancer, breast cancer, uterine cancer, cervical cancer, ovarian cancer, prostate cancer, brain tumor, head and neck carcinoma, melanoma, myeloma, leukemia, lymphoma, gastric cancer, pancreatic cancer, Renal cancer, renal cell carcinoma, renal pelvic carcinoma, bone cancer, skin cancer, head cancer, head and neck cancer, endometrial carcinoma, endometrial carcinoma, endometrial carcinoma, vulvar carcinoma, Hodgkin's disease, bladder cancer, Cancer of the central nervous system (CNS), primary CNS lymphoma, spinal cord tumor, brainstem neuron, neuroendocrine carcinoma, soft tissue sarcoma, urothelial carcinoma, Glioma, and pituitary adenoma. ≪ RTI ID = 0.0 > 21. < / RTI >
상기 암은 다발성 골수종(multiple myeloma)인 암의 예방 또는 치료용 약학적 조성물.
The method according to claim 1,
Wherein said cancer is a multiple myeloma.
An anti-cancer adjuvant composition comprising Cnidium officinale Makion extract.
A health functional food composition for preventing or ameliorating cancer, which comprises an extract of Cnidium officinale Makion .
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