KR20240018537A - Composition for preventing and treating a pancreatic cancer comprising extracts of Sappan Lignum - Google Patents
Composition for preventing and treating a pancreatic cancer comprising extracts of Sappan Lignum Download PDFInfo
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Abstract
본 발명은 소목(Sappan Lignum) 추출물을 포함하는 췌장암의 예방, 치료 또는 개선용 조성물에 관한 것으로, 본 발명의 소목 추출물은 췌장암 세포에서 소포체-스트레스 반응 및 활성산소 생성을 유발하여 세포사멸을 유도함으로써 암세포의 증식을 억제 및 이의 사멸을 야기하므로, 소목 추출물을 포함하는 조성물을 췌장암 예방, 치료 또는 개선 용도로 이용할 수 있다.The present invention relates to a composition for preventing, treating or improving pancreatic cancer containing an extract of Sappan Lignum. The Sappan Lignum extract of the present invention induces apoptosis by inducing an endoplasmic reticulum-stress response and production of active oxygen in pancreatic cancer cells. Since it inhibits the proliferation of cancer cells and causes their death, a composition containing the extract of Cattle sinensis can be used to prevent, treat, or improve pancreatic cancer.
Description
본 발명은 소목(Sappan Lignum) 추출물을 포함하는 췌장암의 예방, 치료 또는 개선용 조성물에 관한 것이다.The present invention relates to a composition for preventing, treating or improving pancreatic cancer containing an extract of Sappan Lignum.
보건복지부 통계자료에 따르면 췌장암은 2017년 전체 암 발생 중에서 8위를 차지하는 암으로 조기 진단이 어렵고 다른 장기로 전이가 잘 되어 예후가 좋지 않은 암으로 알려져 있다. 또한 5년 생존율이 약 12%정도로 위암, 대장암, 유방암이 각각 76.5%, 75%, 93%인 것에 비해 현저히 낮은 수준이다. 현재 사용되고 있는 젬시타빈(gemcitabine)과 같은 항암제와 방사선치료는 혈관계, 신경계, 혈액계, 피부 등에서 다양한 부작용을 초래할 수 있기 때문에 이를 최소화하고 보다 나은 치료효과를 갖는 새로운 치료제가 필요한 상황이다. According to statistics from the Ministry of Health and Welfare, pancreatic cancer ranks 8th among all cancers in 2017 and is known to be difficult to diagnose early and has a poor prognosis as it easily metastasizes to other organs. Additionally, the 5-year survival rate is approximately 12%, which is significantly lower than the 76.5%, 75%, and 93% for stomach cancer, colon cancer, and breast cancer, respectively. Currently used anticancer drugs such as gemcitabine and radiation therapy can cause various side effects in the vascular system, nervous system, blood system, skin, etc., so new treatments that minimize these and have better treatment effects are needed.
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 이곳을 통과시킨다. 그러므로 소포체는 분비 또는 막 단백질의 품질관리에 매우 중요한 기관이다. The endoplasmic reticulum (ER), which exists in all cells of the living body, is an organelle involved in the production of proteins and cholesterol in cells, and plays a role in delivering proteins to areas in the cell where proteins are needed. In the endoplasmic reticulum (ER), proteins undergo a post-translational modification process, and only when modification and folding are done properly are they allowed to pass through. Therefore, the endoplasmic reticulum is a very important organ for secretion or quality control of membrane proteins.
소포체(endoplasmic reticulum; ER)에서 unfolded protein이 축적되어 나타나는 반응이 unfolded protein response (UPR)인데 이러한 반응이 일어나도록 하는 자극들을 소포체-스트레스(ER stress)라고 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 타겟으로 생각되고 있다. ER stress가 심해지면 손상된 세포를 제거하기 위해 세포사멸 (apoptosis)을 유도하게 되는데 이 과정에서 CHOP(CCAAT/-enhancer-binding protein homologuous protein; C/EBP homologous protein)가 중요한 매개체로 작용한다. 이러한 ER stress의해 유도된 세포사멸 경로 활성은 활성산소(ROS)와도 연관이 있다고 보고되고 있다.The unfolded protein response (UPR) is a reaction that occurs when unfolded proteins accumulate in the endoplasmic reticulum (ER), and the stimuli that cause this reaction are called ER stress. Experimentally, because the ER maintains an oxidative environment, UPR occurs when cells are treated with a reducing agent such as DTT or beta-mercaptoethanol. ER stress refers to a condition in which endoplasmic reticulum function is impaired due to the influx of proteins into the endoplasmic reticulum that exceed the endoplasmic reticulum's ability to process or depletion of calcium in the endoplasmic reticulum. This affects the development and maintenance of cancer, making it an important cancer treatment target. It is being thought. When ER stress becomes severe, apoptosis is induced to remove damaged cells, and CHOP (CCAAT/-enhancer-binding protein homologous protein; C/EBP homologous protein) acts as an important mediator in this process. It has been reported that this ER stress-induced cell death pathway activity is also related to reactive oxygen species (ROS).
한편, 소목(Sappan Lignum)은 콩과에 속한 낙엽 소교목 혹은 관목인 소목(Caesalpinia sappan Linne)의 심재를 건조한 것으로 소방목, 소방, 적목, 홍자 등으로 불리기도 한다. 연중 수시로 채취하여 수피와 변재를 제거하고 중심부분(심재)만 취하여 건조하여 사용한다. 소목의 주요성분으로는 헤마톡실린과 플라보노이드 및 원색소인 브라질린이 함유되어 있으며, 브라질린은 공기중에 산화되어 브라질레인이 된다. 브라질린은 혈압, 칼슘조절과 혈당저하 작용이 알려져 있으며, 지금까지 소목 열수 추출물의 항균 효능에 대하여는 많은 연구가 진행되어 왔으나, 항암에 관해서는 거의 보고된 바가 없다.Meanwhile, Sappan Lignum is the dried heartwood of Caesalpinia sappan Linne, a deciduous tree or shrub belonging to the legume family, and is also called firewood, firewood, redwood, and redwood. It is collected at any time throughout the year, the bark and sapwood are removed, and only the central part (heartwood) is taken, dried, and used. The main components of Somatophyta include hematoxylin, flavonoids, and the primary pigment brasilin, which is oxidized in the air to become brazilein. Brasilin is known to have blood pressure, calcium regulation, and blood sugar lowering effects, and many studies have been conducted on the antibacterial efficacy of Somatophylla hydrothermal extract, but little has been reported regarding its anticancer properties.
이에, 본 발명자들은 췌장암을 예방하고 치료할 수 있는 부작용이 적은 천연물을 찾고자 연구노력하던 중, 췌장암 세포에서 소목이 소포체-스트레스 및 활성사소(ROS)를 유발하여 효과적으로 세포사멸시킬 수 있음을 확인하고 본 발명을 완성하였다.Accordingly, while the present inventors were making research efforts to find a natural product with few side effects that can prevent and treat pancreatic cancer, they confirmed that Somatophyllum can effectively cause cell death by inducing endoplasmic reticulum-stress and activated oxidative oxidation (ROS) in pancreatic cancer cells. The invention was completed.
본 발명의 목적은 췌장암의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.The purpose of the present invention is to provide a pharmaceutical composition for preventing or treating pancreatic cancer.
본 발명의 다른 목적은 췌장암의 항암 보조제를 제공하는 것이다.Another object of the present invention is to provide an anticancer adjuvant for pancreatic cancer.
본 발명의 또 다른 목적은 췌장암의 예방 또는 개선용 식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a food composition for preventing or improving pancreatic cancer.
본 발명의 또 다른 목적은 췌장암을 예방 또는 치료하는 방법을 제공하는 것이다.Another object of the present invention is to provide a method for preventing or treating pancreatic cancer.
본 발명의 또 다른 목적은 실험관 내에서(in vitro) Caspase-3 절단 및 CHOP의 발현을 증가시키는 방법을 제공하는 것이다.Another object of the present invention is to provide a method for increasing Caspase-3 cleavage and CHOP expression in vitro.
상기 목적을 달성하기 위하여,In order to achieve the above purpose,
본 발명은 소목(Sappan Lignum) 추출물을 유효성분으로 포함하는 췌장암의 예방 또는 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating pancreatic cancer containing Sappan Lignum extract as an active ingredient.
또한, 본 발명은 소목 추출물을 유효성분으로 포함하는 췌장암의 항암 보조제를 제공한다.In addition, the present invention provides an anti-cancer adjuvant for pancreatic cancer containing a Solanum extract as an active ingredient.
나아가, 본 발명은 소목 추출물을 유효성분으로 포함하는 췌장암의 예방 또는 개선용 식품 조성물을 제공한다.Furthermore, the present invention provides a food composition for preventing or ameliorating pancreatic cancer, comprising a Sophylloma extract as an active ingredient.
더 나아가, 본 발명은 약학적으로 유효한 양의 소목 추출물을 이를 필요로 하는 인간을 제외한 개체에 투여하여 췌장암을 예방 또는 치료하는 방법을 제공한다.Furthermore, the present invention provides a method of preventing or treating pancreatic cancer by administering a pharmaceutically effective amount of the extract of Caerella vulgaris to an entity other than a human in need thereof.
더 나아가, 본 발명은 실험관 내에서(in vitro) 소목 추출물을 췌장암 세포에 처리하여 Caspase-3 절단 및 CHOP의 발현을 증가시키는 방법을 제공한다.Furthermore, the present invention provides a method of increasing Caspase-3 cleavage and CHOP expression in vitro by treating pancreatic cancer cells with a Cacarp sinensis extract.
본 발명의 소목(Sappan Lignum) 추출물은 췌장암 세포에서 소포체-스트레스 반응 및 활성산소 생성을 유발하여 세포사멸을 유도함으로써 암세포의 증식을 억제 및 이의 사멸을 야기하므로, 소목 추출물을 포함하는 조성물을 췌장암 예방, 치료 또는 개선 용도로 이용할 수 있다.The Sappan Lignum extract of the present invention induces apoptosis by inducing an endoplasmic reticulum-stress response and production of active oxygen in pancreatic cancer cells, thereby inhibiting the proliferation of cancer cells and causing their death, so a composition containing the Sappan Lignum extract can be used to prevent pancreatic cancer. , can be used for treatment or improvement purposes.
도 1은 소목 추출물 처리에 의한 췌장암 세포주 AsPC-1의 세포 생존율을 확인한 도이다.
도 2는 소목 추출물 처리에 의한 췌장암 세포주 AsPC-1에서의 세포사멸 및 소포체-스트레스 관련 단백질들의 발현 정도를 확인한 도이다.
도 3은 소목 추출물 처리에 의한 췌장암 세포주 AsPc-1의 활성산소 생성을 확인한 도이다.Figure 1 is a diagram confirming the cell survival rate of the pancreatic cancer cell line AsPC-1 by treatment with Solanum extract.
Figure 2 is a diagram confirming the expression level of apoptosis and endoplasmic reticulum-stress-related proteins in the pancreatic cancer cell line AsPC-1 by treatment with Somatophyll extract.
Figure 3 is a diagram confirming the production of reactive oxygen species in the pancreatic cancer cell line AsPc-1 by treatment with Sophylloma extract.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
췌장암의 예방 또는 치료용 약학적 조성물Pharmaceutical composition for preventing or treating pancreatic cancer
본 발명은 소목(Sappan Lignum) 추출물을 유효성분으로 포함하는 췌장암의 예방 또는 치료용 약학적 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for preventing or treating pancreatic cancer containing Sappan Lignum extract as an active ingredient.
본 발명에서, 상기 '소목(Sappan Lignum, 蘇木)'은 콩과(Leguminosae)에 속하는 소목(Caesalpinia sappan Linne)의 심재를 의미하는 것으로, 소목(Caesalpinia sappan Linne)의 수피와 변재를 제거하고 중심부분만 취하여 건조하여 사용하는 것일 수 있다.In the present invention, the 'Sappan Lignum (蘇木)' refers to the heartwood of Caesalpinia sappan Linne belonging to the Leguminosae family. The bark and sapwood of Caesalpinia sappan Linne are removed and the center It may be that only a portion is taken, dried, and used.
본 발명에서 사용되는 용어 "추출물(extract)"은 생약을 적절한 침출액으로 짜내고 침출액을 증발시켜 농축한 제제를 의미하는 것으로, 이에 제한되지는 않으나, 추출 처리에 의해 얻어지는 추출액, 추출액의 희석액 또는 농축액, 추출액을 건조하여 얻어지는 건조물, 이들의 조정제물 또는 정제물일 수 있다. 상기 추출물은 통상의 기술분야에 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" used in the present invention refers to a preparation obtained by squeezing a crude drug into an appropriate leachate and evaporating the leachate to concentrate. It is not limited thereto, but is not limited to, an extract obtained by extraction treatment, a dilution or concentrate of the extract, It may be a dried product obtained by drying the extract, a crude product thereof, or a purified product. The extract can be prepared using general extraction, separation and purification methods known in the art. The extraction method is not limited thereto, but preferably includes boiling water extraction, hot water extraction, cold needle extraction, reflux cooling extraction, or ultrasonic extraction.
본 발명에 있어서, 상기 소목 추출물은 추출용매로 추출하거나 추출용매로 추출하여 제조한 추출물에 분획용매를 가하여 분획함으로써 제조할 수 있다. 상기 추출용매는 이에 제한되지 않으나, 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 탄소수 4의 알코올 또는 이들의 혼합용매를 사용할 수 있으며, 보다 바람직하게는 에탄올을 사용할 수 있다. In the present invention, the bovine wood extract can be prepared by extracting with an extraction solvent or fractionating the extract by adding a fractionating solvent to the extract prepared by extraction with an extraction solvent. The extraction solvent is not limited to this, but water, an organic solvent, or a mixed solvent thereof may be used. The organic solvent may be an alcohol having 1 to 4 carbon atoms, a polar solvent such as ethyl acetate or acetone, hexane, or dichloromethane. A non-polar solvent of methane or a mixed solvent thereof can be used. Additionally, water, alcohol with 1 to 4 carbon atoms, or a mixed solvent thereof can be preferably used, and ethanol can be more preferably used.
본 발명의 일실시예에서는 상기 용매로서 100% 에탄올을 이용하여 추출한 뒤 감압 농축하여 소목 추출물을 제조하였다. 이때, 소목 분말 중량 기준 8 내지 12배 부피에 해당하는 양의 100% 에탄올을 혼합하여 2시간 이상, 바람직하게는 2 내지 10시간 추출하는 것일 수 있으나, 이에 제한되지는 않는다.In one embodiment of the present invention, the extract was prepared by extracting using 100% ethanol as the solvent and then concentrating under reduced pressure. At this time, 100% ethanol in an amount equivalent to 8 to 12 times the volume based on the weight of the wood powder may be mixed and extracted for 2 hours or more, preferably 2 to 10 hours, but is not limited to this.
일 구현예에서, 상기 암은 췌장암, 대장암, 유방암, 자궁암, 자궁경부암, 난소암, 전립선암, 뇌종양, 두경부암종, 흑색종, 골수종, 백혈병, 림프종, 위암, 폐암, 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 구성된 군으로부터 선택되는 어느 하나일 수 있으며, 췌장암인 것이 더욱 바람직하다.In one embodiment, the cancer is pancreatic cancer, colon cancer, breast cancer, uterine cancer, cervical cancer, ovarian cancer, prostate cancer, brain tumor, head and neck carcinoma, melanoma, myeloma, leukemia, lymphoma, stomach cancer, lung cancer, non-small cell lung cancer, and liver cancer. , esophageal cancer, small intestine cancer, perianal cancer, fallopian tube carcinoma, endometrial carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, bladder cancer, kidney cancer, ureteral cancer, renal cell carcinoma, renal pelvic carcinoma, bone cancer, skin cancer, head cancer, Cervical cancer, cutaneous melanoma, intraocular melanoma, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, central nervous system (CNS) tumor, primary CNS lymphoma, spinal tumor, It may be any one selected from the group consisting of brainstem glioma and pituitary adenoma, and pancreatic cancer is more preferable.
일 구현예에서, 상기 췌장암의 예방 또는 치료는 암세포의 소포체(endoplasmic reticulum, ER) 스트레스로 인한 세포사멸과 활성산소(reactive oxygen species, ROS) 증가에 의해 달성될 수 있다.In one embodiment, the prevention or treatment of pancreatic cancer can be achieved by apoptosis and an increase in reactive oxygen species (ROS) due to endoplasmic reticulum (ER) stress in cancer cells.
본 발명에서 사용되는 용어, "세포사멸"은 아폽토시스 또는 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" used in the present invention is also called apoptosis or apoptosis, and is a type of programmed cell death (PCD), which refers to abnormal cells, damaged cells, and aged cells caused by biological programs entered into our bodies. It is a mechanism by which cells commit suicide to maintain overall body health.
본 발명의 일실시예에 따르면, 상기 추출물은 췌장암의 소포체(endoplasmic reticulum, ER) 스트레스로 인한 세포사멸을 유도하는 것일 수 있다. According to one embodiment of the present invention, the extract may induce cell death due to endoplasmic reticulum (ER) stress in pancreatic cancer.
본 발명의 일실시예에 따르면, 상기 추출물은 Caspase-3 절단을 증가시키고, CHOP(C/EBP homologous protein) 발현을 증가시킴으로서 세포사멸과 소포체-스트레스를 증가시키는 것일 수 있다.According to one embodiment of the present invention, the extract may increase apoptosis and endoplasmic reticulum-stress by increasing Caspase-3 cleavage and CHOP (C/EBP homologous protein) expression.
본 발명의 일실시예에 따르면, 상기 추출물은 활성 산소(reactive oxygen species, ROS)의 생성량을 증가시키는 것일 수 있다.According to one embodiment of the present invention, the extract may increase the production of reactive oxygen species (ROS).
본 발명의 일실시예에 따르면, 상기 조성물은 췌장암 세포의 생존율을 억제 또는 감소시키는 것일 수 있다.According to one embodiment of the present invention, the composition may inhibit or reduce the survival rate of pancreatic cancer cells.
본 발명의 일실시예에서는 본 발명의 소목 추출물이 췌장암 세포주인 AsPC-1 세포에서 소포체-스트레스 관련 CHOP 발현을 증가시키고, ROS 및 세포사멸 관련 Caspase-3의 절단을 증가시키는 것을 확인하였고, 이에 따라 상기 AsPC-1 세포의 소포체-스트레스 및 ROS를 증가시킴으로써 세포사멸을 효과적으로 유도할 수 있음을 확인하였다(실험예 1 내지 3 참조).In one embodiment of the present invention, it was confirmed that the extract of the present invention increases endoplasmic reticulum-stress-related CHOP expression and cleavage of ROS and apoptosis-related Caspase-3 in AsPC-1 cells, a pancreatic cancer cell line. Accordingly, It was confirmed that apoptosis can be effectively induced by increasing endoplasmic reticulum stress and ROS of the AsPC-1 cells (see Experimental Examples 1 to 3).
본 발명에서, 용어 "예방"이란 본 발명에 따른 약학적 조성물의 투여에 의해 암의 발생, 확산 및 재발을 억제 또는 지연시키는 모든 행위를 의미하고, "치료"란 상기 약학적 조성물의 투여에 의해 암의 의심 및 발병 개체의 증상이 호전되거나 이롭게 변경하는 모든 행위를 의미한다.In the present invention, the term "prevention" refers to all actions that inhibit or delay the occurrence, spread, and recurrence of cancer by administration of the pharmaceutical composition according to the present invention, and "treatment" refers to all actions that inhibit or delay the occurrence, spread, and recurrence of cancer by administration of the pharmaceutical composition according to the present invention. It refers to all actions that improve or beneficially change the symptoms of an individual suspected of having cancer or developing cancer.
본 발명에서 사용되는 용어 "치료"란 본 발명의 소목을 포함하는 조성물의 투여로 암세포의 사멸 또는 암의 증세를 호전시키거나 이롭게 변경하는 모든 방법들을 의미한다. 본 발명이 속하는 기술분야에서 통상의 지식을 가진 자라면, 대한의학협회 등에서 제시된 자료를 참조하여 본원의 조성물이 효과가 있는 질환의 정확한 기준을 알고, 개선, 향상 및 치료된 정도를 판단할 수 있을 것이다.The term "treatment" used in the present invention refers to all methods of improving or beneficially changing the death of cancer cells or symptoms of cancer by administering a composition containing the plant of the present invention. Anyone with ordinary knowledge in the technical field to which the present invention pertains can refer to the data presented by the Korean Medical Association, etc. to know the exact criteria for diseases for which our composition is effective and to determine the degree of improvement, improvement, and treatment. will be.
본 발명에서 유효성분과 결합하여 사용된 "치료학적으로 유효한 양"이란 용어는 대상 질환을 예방 또는 치료하는데 유효한 소목 추출물의 약학적으로 허용 가능한 염의 양을 의미하며, 본 발명의 조성물의 치료적으로 유효한 양은 여러 요소, 예를 들면 투여방법, 목적부위, 환자의 상태 등에 따라 달라질 수 있다. 따라서, 인체에 사용 시 투여량은 안전성 및 효율성을 함께 고려하여 적정량으로 결정되어야 한다. 동물실험을 통해 결정한 유효량으로부터 인간에 사용되는 양을 추정하는 것도 가능하다. 유효한 양의 결정시 고려할 이러한 사항은, 예를 들면 Effect of Sanguis Draconis on Perforator Flap Survival in Rats, Yang Zhang et al., Molecules, 2016)에 기술되어있다.The term "therapeutically effective amount" used in combination with the active ingredient in the present invention refers to the amount of a pharmaceutically acceptable salt of the extract of Caerella nigra effective in preventing or treating the target disease, and the therapeutically effective amount of the composition of the present invention. The amount may vary depending on several factors, such as administration method, target site, and patient condition. Therefore, when used in the human body, the dosage must be determined as appropriate by considering both safety and efficiency. It is also possible to estimate the amount used in humans from the effective amount determined through animal testing. These considerations when determining the effective dose are described, for example, in Effect of Sanguis Draconis on Perforator Flap Survival in Rats, Yang Zhang et al., Molecules, 2016).
본 발명의 약학조성물은 약학적으로 유효한 양으로 투여한다. 본 발명에서 사용되는 용어, "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분하며 부작용을 일으키지 않을 정도의 양을 의미하며, 유효용량 수준은 환자의 건강상태, 암의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 방법, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고, 종래의 치료제와 순차적으로 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여, 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. As used in the present invention, the term "pharmaceutically effective amount" refers to an amount that is sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment and does not cause side effects, and the effective dose level is determined by the patient's Factors including health status, type and severity of cancer, activity of drug, sensitivity to drug, method of administration, time of administration, route of administration and excretion rate, duration of treatment, drugs combined or used simultaneously, and other factors well known in the field of medicine. It can be decided depending on The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. Considering all of the above factors, it is important to administer an amount that can achieve maximum effect with the minimum amount without side effects, and this can be easily determined by a person skilled in the art.
본 발명의 약학조성물은 생물학적 제제에 통상적으로 사용되는 담체, 희석제, 부형제 또는 둘 이상의 이들의 조합을 포함할 수 있다. 본 발명에서 사용되는 용어, "약학적으로 허용 가능한"이란 상기 조성물에 노출되는 세포나 인간에게 독성이 없는 특성을 나타내는 것을 의미한다. 상기 담체는 조성물을 생체 내 전달에 적합한 것이면 특별히 제한되지 않으며, 예를 들면, Merck Index, 13th ed., Merck & Co. Inc. 에 기재된 화합물, 식염수, 멸균수, 링거액, 완충 식염수, 덱스트로스 용액, 말토 덱스트린 용액, 글리세롤, 에탄올 및 이들 성분 중 1 성분이상을 혼합하여 이용할 수 있으며, 필요에 따라 항산화제, 완충액, 정균제 등 다른 통상의 첨가제를 첨가할 수 있다. 또한, 희석제, 분산제, 계면활성제, 결합제 및 윤활제를 부가적으로 첨가하여 수용액, 현탁액, 유탁액 등 과 같은 주이용 제형, 환약, 캡슐, 과립 또는 정제로 제제화할 수 있다. 더 나아가 당 분야의 적정한 방법으로 또는 Remington's Pharmaceutical Science(Mack Publishing Company, Easton PA, 18th, 1990)에 개시되어 있는 방법을 이용하여 각 질환에 따라 또는 성분에 따라 바람직하게 제제화할 수 있다.The pharmaceutical composition of the present invention may contain a carrier, diluent, excipient, or a combination of two or more commonly used in biological products. As used in the present invention, the term “pharmaceutically acceptable” means that the composition exhibits non-toxic properties to cells or humans exposed to the composition. The carrier is not particularly limited as long as it is suitable for in vivo delivery of the composition, for example, Merck Index, 13th ed., Merck & Co. Inc. The compounds described in, saline solution, sterilized water, Ringer's solution, buffered saline solution, dextrose solution, maltodextrin solution, glycerol, ethanol, and one or more of these ingredients can be mixed and used, and if necessary, other ingredients such as antioxidants, buffers, and bacteriostatic agents. Normal additives can be added. In addition, diluents, dispersants, surfactants, binders, and lubricants can be additionally added to formulate dosage forms such as aqueous solutions, suspensions, emulsions, etc., into pills, capsules, granules, or tablets. Furthermore, it can be preferably formulated according to each disease or ingredient using an appropriate method in the art or a method disclosed in Remington's Pharmaceutical Science (Mack Publishing Company, Easton PA, 18th, 1990).
본 발명의 약학적 조성물은 약학적으로 허용 가능한 첨가제를 더 포함할 수 있으며, 이때 약학적으로 허용 가능한 첨가제로는 전분, 젤라틴화 전분, 미결정셀룰로오스, 유당, 포비돈, 콜로이달실리콘디옥사이드, 인산수소칼슘, 락토스, 만니톨, 엿, 아라비아고무, 전호화전분, 옥수수전분, 분말셀룰로오스, 히드록시프로필셀룰로오스, 오파드라이, 전분글리콜산나트륨, 카르나우바 납, 합성규산알루미늄, 스테아린산, 스테아린산마그네슘, 스테아린산알루미늄, 스테아린산칼슘, 백당, 덱스트로스, 소르비톨 및 탈크 등이 사용될 수 있다. 본 발명에 따른 약학적으로 허용 가능한 첨가제는 상기 조성물에 대해 0.1 중량부 내지 90 중량부 포함되는 것이 바람직하나, 이에 한정되는 것은 아니다.The pharmaceutical composition of the present invention may further include pharmaceutically acceptable additives, wherein the pharmaceutically acceptable additives include starch, gelatinized starch, microcrystalline cellulose, lactose, povidone, colloidal silicon dioxide, and calcium hydrogen phosphate. , lactose, mannitol, taffy, gum arabic, pregelatinized starch, corn starch, powdered cellulose, hydroxypropyl cellulose, Opadry, sodium starch glycolate, lead carnauba, synthetic aluminum silicate, stearic acid, magnesium stearate, aluminum stearate, Calcium stearate, white sugar, dextrose, sorbitol, and talc may be used. The pharmaceutically acceptable additive according to the present invention is preferably contained in an amount of 0.1 to 90 parts by weight based on the composition, but is not limited thereto.
본 발명의 약학적 조성물은 유효성분으로서 소목 추출물 이외에 공지된 항암제를 추가로 포함할 수 있고, 이들 질환의 치료를 위해 공지된 다른 치료와 병용될 수 있다. 다른 치료에는 화학요법, 방사선치료, 호르몬 치료, 골수 이식, 줄기-세포 대체치료, 다른 생물학적 치료, 면역치료 등이 포함되지만, 이에 한정되는 것은 아니다.The pharmaceutical composition of the present invention may further contain a known anticancer agent in addition to the Cadensis extract as an active ingredient, and may be used in combination with other known treatments for the treatment of these diseases. Other treatments include, but are not limited to, chemotherapy, radiation therapy, hormone therapy, bone marrow transplantation, stem-cell replacement therapy, other biological treatments, and immunotherapy.
본 발명의 약학적 조성물에 포함될 수 있는 항암제의 예시에는 DNA 알킬화제(DNA alkylating agents)로 메클로에타민(mechloethamine), 클로람부칠(chlorambucil), 페닐알라닌(phenylalanine), 무스타드(mustard), 사이클로포스파미드(cyclophosphamide), 이포스파미드(ifosfamide), 카르무스틴(carmustine: BCNU), 로무스틴(lomustine: CCNU), 스트렙토조토신(streptozotocin), 부술판(busulfan), 티오테파(thiotepa), 시스플라틴(cisplatin) 및 카보플라틴(carboplatin); 항암 항생제(anti-cancer antibiotics)로 닥티노마이신(dactinomycin: actinomycin D), 독소루비신(doxorubicin: adriamycin), 다우노루비신(daunorubicin), 이다루비신(idarubicin), 미토크산트론(mitoxantrone), 플리카마이신(plicamycin), 마이토마이신 C(mitomycin C) 및 블레오마이신(bleomycin); 및 식물 알카로이드(plant alkaloids)로 빈크리스틴(vincristine), 빈블라스틴(vinblastine), 파클리탁셀(paclitaxel), 도세탁셀(docetaxel), 에토포시드(etoposide), 테니포시드(teniposide), 토포테칸(topotecan) 및 이리도테칸(iridotecan) 등이 포함되지만, 이에 한정되는 것은 아니다.Examples of anticancer agents that can be included in the pharmaceutical composition of the present invention include DNA alkylating agents such as mechloethamine, chlorambucil, phenylalanine, mustard, and cyclophospha. Cyclophosphamide, ifosfamide, carmustine (BCNU), lomustine (CCNU), streptozotocin, busulfan, thiotepa, cisplatin ( cisplatin) and carboplatin; Anti-cancer antibiotics include dactinomycin (actinomycin D), doxorubicin (adriamycin), daunorubicin, idarubicin, mitoxantrone, and plicama. plicamycin, mitomycin C, and bleomycin; and plant alkaloids such as vincristine, vinblastine, paclitaxel, docetaxel, etoposide, teniposide, and topotecan. and iridotecan, but are not limited thereto.
췌장암을 예방 또는 치료하는 방법How to Prevent or Treat Pancreatic Cancer
일 측면에서, 본 발명은 소목 추출물을 필요로 하는 개체에게 투여하는 단계를 포함하는, 췌장암을 예방 또는 치료하는 방법에 관한 것이다. In one aspect, the present invention relates to a method of preventing or treating pancreatic cancer, comprising administering an extract of Cattle sinensis to a subject in need thereof.
본 발명에서 사용되는 용어, "개체"란, 상기 암이 발병하였거나 발병할 수 있는 인간을 포함한 원숭이, 소, 말, 양, 돼지, 닭, 칠면조, 메추라기, 고양이, 개, 마우스, 쥐, 토끼 또는 기니아 피그를 포함한 모든 동물을 의미하고, 본 발명의 약학적 조성물을 개체에게 투여함으로써 상기 질환들을 효과적으로 예방 또는 치료할 수 있다.As used in the present invention, the term "individual" refers to a monkey, cow, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, or This refers to all animals, including guinea pigs, and the above diseases can be effectively prevented or treated by administering the pharmaceutical composition of the present invention to the subject.
일 측면에서, 본 발명은 약학적으로 유효한 양의 소목 추출물을 이를 필요로 하는 인간을 제외한 개체에 투여하여 췌장암을 예방 또는 치료하는 방법에 관한 것이다.In one aspect, the present invention relates to a method of preventing or treating pancreatic cancer by administering a pharmaceutically effective amount of a P. arborvitae extract to an entity other than a human in need thereof.
또한, 본 발명은 약학적으로 유효한 양의 소목 추출물을 인간을 제외한 개체에 투여하여 췌장암 세포의 생존율을 감소시키는 방법을 제공한다.In addition, the present invention provides a method of reducing the survival rate of pancreatic cancer cells by administering a pharmaceutically effective amount of a Cacarp sinensis extract to subjects other than humans.
본 발명의 약학적 조성물은 기존의 치료제와 병행하여 투여될 수 있다.The pharmaceutical composition of the present invention can be administered in combination with existing therapeutic agents.
본 발명에서 사용되는 용어, "투여"란, 임의의 적절한 방법으로 환자(또는 개체)에게 소정의 물질을 제공하는 것을 의미하며, 목적하는 방법에 따라 비 경구 투여(예를 들어 정맥 내, 피하, 복강 내 또는 국소에 주사 제형으로 적용)하거나 경구 투여할 수 있으며, 투여량은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설률 및 질환의 중증도 등에 따라 그 범위가 다양. 본 발명의 조성물의 경구 투여를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데, 통상적으로 사용되는 단순 희석제인 물, 액체 파라핀 이외에 다양한 부형제, 예컨대 습윤제, 감미제, 방향제, 보존제 등이 함께 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성 용제, 현탁제, 유제, 동결건조 제제, 좌제 등이 포함됨. 본 발명의 약학적 조성물은 활성물질이 표적 세포로 이동할 수 있는 임의의 장치에 의해 투여될 수도 있다. 바람직한 투여방식 및 제제는 정맥주사제, 피하 주사제, 피내주사제, 근육 주사제, 점적 주사제 등이 있다. 주사제는 생리식염액, 링겔액 등의 수성용제, 식물유, 고급 지방산 에스테르(예, 올레인산에칠 등), 알코올 류(예, 에탄올, 벤질알코올, 프로필렌글리콜, 글리세린 등) 등의 비수성 용제 등을 이용하여 제조할 수 있고, 변질 방지를 위한 안정화제(예, 아스코르빈산, 아황산수소나트륨, 피로아황산나트륨, BHA, 토코페롤, EDTA 등), 유화제, pH 조절을 위한 완충제, 미생물발육을 저지하기 위한 보존제 (예, 질산페닐수은, 치메로살, 염화벤잘코늄, 페놀, 크레솔, 벤질알코올 등) 등의 약학적 담체를 포함할 수 있다.As used in the present invention, the term "administration" means providing a predetermined substance to a patient (or individual) by any appropriate method, and is administered parenterally (e.g., intravenously, subcutaneously, etc.) according to the desired method. It can be applied intraperitoneally or locally as an injection formulation) or orally, and the dosage range varies depending on the patient's weight, age, gender, health status, diet, administration time, administration method, excretion rate, and severity of the disease. . Liquid preparations for oral administration of the composition of the present invention include suspensions, oral solutions, emulsions, syrups, etc., and in addition to the commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives are used. etc. may be included together. Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, etc. The pharmaceutical composition of the present invention may be administered by any device capable of transporting the active agent to target cells. Preferred administration methods and formulations include intravenous injection, subcutaneous injection, intradermal injection, intramuscular injection, and drip injection. Injections include aqueous solvents such as physiological saline solution and Ringer's solution, non-aqueous solvents such as vegetable oil, higher fatty acid esters (e.g., ethyl oleate, etc.), and alcohols (e.g., ethanol, benzyl alcohol, propylene glycol, glycerin, etc.). It can be manufactured using stabilizers to prevent deterioration (e.g., ascorbic acid, sodium bisulfite, sodium pyrosulfite, BHA, tocopherol, EDTA, etc.), emulsifiers, buffers for pH adjustment, and agents to prevent microbial growth. It may contain pharmaceutical carriers such as preservatives (e.g., phenylmercuric nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.).
췌장암의 항암보조제Anticancer supplement for pancreatic cancer
일 측면에서, 본 발명은 소목 추출물을 유효성분으로 포함하는 췌장암의 항암보조제에 관한 것이다.In one aspect, the present invention relates to an anti-cancer adjuvant for pancreatic cancer containing an extract of Cattle sinensis as an active ingredient.
본 발명의 소목 추출물은 화학적 항암 약물(항암제) 등과 함께 투여함으로써, 암세포의 사멸 효과를 통해 종래의 항암제의 암치료 효과를 증가시킬 수 있다. 병용 투여는 상기 항암제와 동시에 또는 순차적으로 이루어질 수 있다.By administering the Sophylloma extract of the present invention together with chemical anticancer drugs (anticancer agents), the cancer treatment effect of conventional anticancer drugs can be increased through the killing effect of cancer cells. Concurrent administration may be performed simultaneously or sequentially with the anticancer agent.
췌장암의 예방 또는 개선용 식품 조성물Food composition for preventing or improving pancreatic cancer
일 측면에서, 본 발명은 소목 추출물을 함유하는 암의 예방 또는 개선용 식품 조성물에 관한 것이다.In one aspect, the present invention relates to a food composition for preventing or ameliorating cancer containing an extract of Cattle sinensis.
본 발명의 조성물을 식품 조성물로 사용하는 경우, 상기 소목 추출물을 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용할 수 있고, 통상의 방법에 따라 적절하게 사용할 수 있다. 상기 조성물은 유효성분 이외에 식품학적으로 허용 가능한 식품보조첨가제를 포함할 수 있으며, 유효성분의 혼합량은 사용목적(예방, 건강 또는 치료적 처치)에 따라 적합하게 결정될 수 있다.When the composition of the present invention is used as a food composition, the above-mentioned Cattle extract can be added as is or used together with other foods or food ingredients, and can be used appropriately according to conventional methods. In addition to the active ingredients, the composition may contain food additives that are foodologically acceptable, and the mixing amount of the active ingredients can be appropriately determined depending on the purpose of use (prevention, health, or therapeutic treatment).
본 발명에서 사용되는 용어 "식품보조첨가제"란 식품에 보조적으로 첨가될 수 있는 구성요소를 의미하며, 각 제형의 건강기능식품을 제조하는데 첨가되는 것으로서 당업자가 적절히 선택하여 사용할 수 있다. 식품보조첨가제의 예로는 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 충진제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산음료에 사용되는 탄산화제 등이 포함되지만, 상기 예들에 의해 본 발명의 식품보조첨가제의 종류가 제한되는 것은 아니다.The term "food supplement" used in the present invention refers to a component that can be added as an auxiliary food additive, and can be appropriately selected and used by a person skilled in the art as it is added to manufacture each type of health functional food. Examples of food supplements include various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavors, colorants and fillers, pectic acid and its salts, alginic acid and its salts, organic acids, and protective colloidal thickeners. , pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc., but the types of food supplements of the present invention are not limited to the above examples.
본 발명의 식품 조성물에는 건강기능식품이 포함될 수 있다. 본 발명에서 사용되는 용어 "건강기능식품"이란 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 정제, 캅셀, 분말, 과립, 액상 및 환 등의 형태로 제조 및 가공한 식품을 말한다. 여기서 '기능성'이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적작용 등과 같은 보건용도에 유용한 효과를 얻는 것을 의미한다. 본 발명의 건강기능식품은 통상의 기술분야에서 통상적으로 사용되는 방법에 의하여 제조가 능하며, 상기 제조 시에는 통상의 기술분야에서 통상적으로 첨가하는 원료 및 성분을 첨가하여 제조할 수 있다. 또한 상기 건강기능식품의 제형 또한 건강기능식품으로 인정되는 제형이면 제한 없이 제조될 수 있다. 본 발명의 식품용 조성물은 다양한 형태의 제형으로 제조될 수 있으며, 일반약품과는 달리 식품을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용 등이 없는 장점이 있고, 휴대성이 뛰어나, 본 발명의 건강기능식품은 항암제의 효과를 증진 시키기 위한 보조제로 섭취가 가능하다.The food composition of the present invention may include health functional foods. The term “health functional food” used in the present invention refers to food manufactured and processed in the form of tablets, capsules, powders, granules, liquids, and pills using raw materials or ingredients with functional properties useful to the human body. Here, ‘functionality’ means controlling nutrients for the structure and function of the human body or obtaining useful effects for health purposes such as physiological effects. The health functional food of the present invention can be manufactured by methods commonly used in the field of technology, and can be manufactured by adding raw materials and components commonly added in the field of technology. Additionally, the formulation of the health functional food can also be manufactured without limitation as long as it is a formulation recognized as a health functional food. The food composition of the present invention can be manufactured in various types of formulations, and unlike general drugs, it is made from food as a raw material and has the advantage of not having side effects that may occur when taking the drug for a long period of time, and is excellent in portability, so the present invention Health functional foods can be consumed as supplements to enhance the effectiveness of anticancer drugs.
또한, 본 발명의 조성물이 사용될 수 있는 건강식품의 종류에는 제한이 없다. 아울러 본 발명의 소목 추출물을 활성성분으로 포함하는 조성물은 당업자의 선택에 따라 건강기능식품에 함유될 수 있는 적절한 기타 보조 성분과 공지의 첨가제를 혼합하여 제조할 수 있다. 첨가할 수 있는 식품의 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림 류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등이 있으며, 본 발명에 따른 추출물을 주성분으로 하여 제조한 즙, 차, 젤리 및 주스 등에 첨가하여 제조할 수 있다.Additionally, there is no limitation to the types of health foods in which the composition of the present invention can be used. In addition, the composition containing the Sophylloma extract of the present invention as an active ingredient can be prepared by mixing known additives with other appropriate auxiliary ingredients that may be contained in health functional foods according to the selection of a person skilled in the art. Examples of foods that can be added include meat, sausages, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, and There are vitamin complexes, etc., and they can be manufactured by adding them to juices, teas, jellies, juices, etc. prepared using the extract according to the present invention as a main ingredient.
실험관 내에서 Caspase-3 절단 및 CHOP의 발현을 증가시키는 방법How to increase Caspase-3 cleavage and expression of CHOP in vitro
일 측면에서, 본 발명은 실험관 내에서(in vitro) 소목 추출물을 췌장암 세포에 처리하여 Caspase-3 절단 및 CHOP의 발현을 증가시키는 방법을 제공한다.In one aspect, the present invention provides a method of increasing Caspase-3 cleavage and CHOP expression in vitro by treating pancreatic cancer cells with a Cacarp sinensis extract.
본 발명의 소목 추출물은 시험관(in vitro)내에서 췌장암 세포주에 처리시 Caspase-3 절단 증가, GADD153/CHOP의 발현을 증가시켜 췌장암 세포의 소포체 스트레스 유발을 통한 세포사멸을 유도할 수 있다.When treated with a pancreatic cancer cell line in vitro, the extract of the Cacarp sinensis of the present invention can increase the cleavage of Caspase-3 and the expression of GADD153/CHOP, thereby inducing apoptosis through endoplasmic reticulum stress in pancreatic cancer cells.
상기 췌장암 세포주는 다발성 골수종 또는 백혈병 세포주인 U937 또는 THP-1 세포주인 것일 수 있다.The pancreatic cancer cell line may be the U937 or THP-1 cell line, which is a multiple myeloma or leukemia cell line.
본 발명의 소목 추출물은 천연 식물을 원료로 하므로 약학적 조성물 또는 식품 조성물로 사용할 경우에도 일반적인 합성 화합물에 비하여 부작용이 덜할 수 있으므로, 안전하게 약학적 조성물 및 건강기능식품에 포함되어 유용하게 사용될 수 있다.Since the extract of the wood of the present invention is made from natural plants, it may have fewer side effects than common synthetic compounds even when used in pharmaceutical compositions or food compositions, so it can be safely included in pharmaceutical compositions and health functional foods and usefully used.
하기의 실시예를 통하여 본 발명을 보다 상세하게 설명한다. 그러나 하기 실시예는 본 발명의 내용을 구체화하기 위한 것일 뿐 이에 의해 본 발명이 한정되는 것은 아니다.The present invention will be described in more detail through the following examples. However, the following examples are only for illustrating the content of the present invention and are not intended to limit the present invention.
<실시예 1> 소목 추출물의 제조<Example 1> Preparation of Cattlewood extract
100% 에탄올로 소목을 추출한 뒤 감압 농축하여 소목 에탄올 추출물을 제조하였다.The ethanol extract of the wood was extracted with 100% ethanol and then concentrated under reduced pressure.
구체적으로, 소목을 약원 한약방에서 구입하여, 소목 분말 200g을 기준으로 100% 에탄올 2000mL를 혼합하여 3시간 동안 용매 추출을 진행하였다. 추출액을 여과한 다음 감압 농축하여 소목 에탄올 추출물을 제조하였다.Specifically, Somok was purchased from an herbal medicine store, 2000 mL of 100% ethanol was mixed with 200 g of Somok powder, and solvent extraction was performed for 3 hours. The extract was filtered and then concentrated under reduced pressure to prepare an ethanol extract of Somatophyllum.
<실험예 1> 소목 추출물의 췌장암에 대한 세포 사멸 효과 확인<Experimental Example 1> Confirmation of cell death effect of Somatophyll extract on pancreatic cancer
상기 실시예 1에서 제조한 소목 추출물의 췌장암에 대한 항암 활성을 확인하기 위해, 췌장암 세포주 AsPC-1 세포에 본 발명의 소목 추출물을 처리하고 세포 독성을 확인하였다.In order to confirm the anti-cancer activity of the extract prepared in Example 1 against pancreatic cancer, the pancreatic cancer cell line AsPC-1 cells were treated with the extract of the extract of the present invention and cytotoxicity was confirmed.
구체적으로, 췌장암 세포주인 AsPC-1 세포주 (한국세포주은행) 100㎕를 96웰-플레이트에 1×104 세포/웰이 되도록 분주한 뒤, 10% inactivated fetal bovine serum 및 1% penicillin-streptomycin을 첨가한 RPMI 배지에서, 37℃의 5% CO2 인큐베이터 (MCO-15AC, Sanyo, Osaka, Japan)로 배양하였다. 배양한 96웰-플레이드에서 배지만 걷어내고 상기 실시 예 1에서 제조한 소목 추출물을 0, 25, 50, 100 및 200㎍/ml의 농도로 각각 100㎕씩 처리한 뒤, 24시간 동안 인큐베이션 하였다. 인큐베이션 한 세포에 EZ-Cytox 시약 (DoGen)을 10㎕ 처리하고 30분 내지 4시간 동안 인큐베이션하였다. 인큐베이션 한 뒤 마이크로플레이트 리더기 (Bio-rad Model 680)를 이용하여 450nm 파장대에서 흡광도를 측정함으로써 세포 생존율을 확인하였다. Specifically, 100㎕ of AsPC-1 cell line (Korea Cell Line Bank), a pancreatic cancer cell line, was dispensed into a 96-well plate to make 1× 104 cells/well, and then 10% inactivated fetal bovine serum and 1% penicillin-streptomycin were added. In one RPMI medium, Cultured in a 5% CO 2 incubator (MCO-15AC, Sanyo, Osaka, Japan) at 37°C. Only the medium was removed from the cultured 96-well plate, and 100 ㎕ of the Somatophylla extract prepared in Example 1 was treated at concentrations of 0, 25, 50, 100, and 200 ㎍/ml, and then incubated for 24 hours. The incubated cells were treated with 10 μl of EZ-Cytox reagent (DoGen) and incubated for 30 minutes to 4 hours. After incubation, cell viability was confirmed by measuring absorbance in the 450 nm wavelength range using a microplate reader (Bio-rad Model 680).
그 결과, 도 1에 나타낸 바와 같이, 소목 추출물은 농도 의존적으로 췌장암 세포에서 독성을 나타내었다.As a result, as shown in FIG. 1, the extract of Siberian sinensis showed toxicity to pancreatic cancer cells in a concentration-dependent manner.
<실험예 2> 소목 추출물에 의한 췌장암 세포주의 세포사멸 및 소포체스트레스 유발 효과 확인<Experimental Example 2> Confirmation of apoptosis and endoplasmic reticulum stress-inducing effects on pancreatic cancer cell lines by Somatophyll extract
상기 실시 예 1에서 제조한 소목 추출물이 췌장암 세포주의 세포사멸에 미치는 영향을 확인하기 위해, 세포사멸 진행시 절단되는 것으로 알려진 Caspase-3와 DNA 손상을 유도하고 ER 스트레스를 유발하여 세포사멸의 마커로 이용되는 CHOP(C/EBP homologous protein)의 발현 정도를 웨스턴 블롯 분석으로 확인하였다.In order to determine the effect of the Somaum extract prepared in Example 1 on apoptosis of pancreatic cancer cell lines, Caspase-3, which is known to be cleaved during apoptosis, induces DNA damage and induces ER stress as a marker of apoptosis. The expression level of CHOP (C/EBP homologous protein) used was confirmed by Western blot analysis.
구체적으로, 췌장암 세포주인 AsPC-1 세포주에 상기 실시 예 1에서 제조한 소목 추출물을 0, 20 및 40 ㎍/ml로 각각 처리하고 24시간 동안 37℃의 5% CO2 인큐베이터로 인큐베이션 후, 세포를 수집하여 PBS로 워싱하고, 세포 파쇄 버퍼 CETI Lysis Buffer with Inhibitor(TransLab, Korea)를 첨가하여 30분간 4℃에서 세포를 파쇄하였다. 세포파쇄물을 13,000 RPM에서 10분간 원심 분리하여 세포막 성분 등을 제거한 후, RC DC™ Protein Assay Kit II(protein assay kit) (Bio-rad, USA)를 사용하여 단백질을 정량하여 시료별 (소목 추출물 0, 20 및 40 ㎍/ml 처리군들)로 동일한 단백질의 양이 포함되도록 조절하였다. 준비된 단백질 시료에 5×로딩 다이를 넣고 5분 동안 95℃로 가열하여 단백질을 변성시켰다. 그 후, 10~12% SDS-PAGE 젤에 시료를 로딩하여 100V로 1시간 20분 내지 1시간 40분 동안 전기영동을 수행하였으며, 젤 위에서 분리된 단백질들을 200mA~300mA로 1시간 내지 2시간 동안 멤브레인으로 트랜스퍼하였다. 단백질이 트랜스퍼된 멤브레인을 5% 탈지유가 포함된 TBST (tris buffered saline, pH 7.5) 용액으로 상온에서 1시간 동안 블로킹한 뒤 1차 항체 항-Caspase-3 및 항-CHOP를 각각 1:1,000으로 희석하여 블로킹한 멤브레인과 4℃에서 오버나잇으로 반응시켰다. 멤브레인을 TBST로 3회 워싱한뒤 horseradish peroxidase가 결합된 항-rabbit, mouse IgG를 각각 1:3,000, 1:1,000 으로 희석하여 상온에서 멤브레인과 2시간 동안 반응시킨 다음 TBST로 3회 워싱하였다. 워싱한 멤브레인을 chemiluminescent reagent와 1 내지 3분 동안 반응시키고 필름 및 LAS를 통해 단백질 밴드를 가시화하였다.Specifically, the AsPC-1 cell line, a pancreatic cancer cell line, was treated with 0, 20, and 40 μg/ml of the Sophylloma extract prepared in Example 1, respectively, and incubated in a 5% CO 2 incubator at 37°C for 24 hours, and then the cells were Collected, washed with PBS, cell disruption buffer CETI Lysis Buffer with Inhibitor (TransLab, Korea) was added, and cells were disrupted at 4°C for 30 minutes. After centrifuging the cell lysate at 13,000 RPM for 10 minutes to remove cell membrane components, proteins were quantified using RC DC™ Protein Assay Kit II (protein assay kit) (Bio-rad, USA) and analyzed for each sample (Sammon extract 0). , 20 and 40 μg/ml treatment groups) were adjusted to contain the same amount of protein. A 5×loading die was placed in the prepared protein sample and heated to 95°C for 5 minutes to denature the protein. Afterwards, the sample was loaded onto a 10-12% SDS-PAGE gel and electrophoresis was performed at 100V for 1 hour 20 minutes to 1 hour 40 minutes, and the proteins separated on the gel were electrophoresed at 200mA~300mA for 1 hour to 2 hours. Transferred to the membrane. The protein-transferred membrane was blocked with TBST (tris buffered saline, pH 7.5) containing 5% skim milk for 1 hour at room temperature, and then the primary antibodies anti-Caspase-3 and anti-CHOP were diluted 1:1,000, respectively. It was reacted with the blocked membrane overnight at 4°C. After washing the membrane three times with TBST, horseradish peroxidase-conjugated anti-rabbit and mouse IgG were diluted 1:3,000 and 1:1,000, respectively, reacted with the membrane at room temperature for 2 hours, and then washed three times with TBST. The washed membrane was reacted with chemiluminescent reagent for 1 to 3 minutes, and the protein band was visualized through film and LAS.
그 결과, 도 2에 나타낸 바와 같이, 소목 추출물에 의해 농도 의존적으로 Caspase-3의 절단이 증가하고, CHOP의 발현이 증가함으로써, 소목 추출물이 췌장암 세포주의 ER-스트레스와 세포 사멸을 효과적으로 유발할 수 있음을 확인하였다.As a result, as shown in Figure 2, the cleavage of Caspase-3 is increased in a concentration-dependent manner and the expression of CHOP is increased by the Sojak extract, thereby effectively causing ER-stress and cell death in pancreatic cancer cell lines. was confirmed.
<실험예 3> 췌장암 세포주에서 소목 추출물의 활성산소 유발 효과 확인<Experimental Example 3> Confirmation of reactive oxygen species-inducing effect of Somatophyll extract in pancreatic cancer cell lines
상기 실시예 1에서 제조한 소목 추출물이 췌장암 세포주에서 활성산소(ROS) 생성에 미치는 영향을 확인하기 위하여, 췌장암 세포주인 AsPC-1 100 ㎕를 96웰-플레이트에 1×105 세포/웰이 되도록 분주한 뒤, 37℃의 5% CO2 인큐베이터에 오버나잇하였다. 오버나잇 후 배지를 걷어내고 각 웰에 25 μM의 DCFDA 100 μl 분주한 뒤 45분간 인큐베이터에서 반응시켰다. DCFDA를 걷어내고 상기 실시예 1에서 제조한 소목 추출물을 0, 20 및 40 ㎍/ml의 농도로 각각 100 ㎕씩 처리한 뒤, 6시간 동안 인큐베이션 하였다. In order to confirm the effect of the S. arborvitae extract prepared in Example 1 on the production of reactive oxygen species (ROS) in the pancreatic cancer cell line, 100 ㎕ of AsPC-1, a pancreatic cancer cell line, was cultured in a 96-well plate at 1 × 10 5 cells/well. After dispensing, the mixture was kept overnight in a 5% CO 2 incubator at 37°C. After overnight, the medium was removed, and 100 μl of 25 μM DCFDA was dispensed into each well and incubated in an incubator for 45 minutes. DCFDA was removed, and 100 ㎕ of the Cattlewood extract prepared in Example 1 was treated at concentrations of 0, 20, and 40 ㎍/ml, respectively, and incubated for 6 hours.
그 결과, 도 3에 나타난 바와 같이, 20 및 40 ㎍/ml의 소목 추출물 처리 시 활성산소가 증가되는 것을 확인하였다.As a result, as shown in FIG. 3, it was confirmed that active oxygen increased when treated with 20 and 40 ㎍/ml of Cattlewood extract.
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 특허 청구범위에 나타나 있으며, 그와 동등한 범위 내에 있는 모든 차이점은 본 발명에 포함된 것으로 해석되어야 할 것이다.So far, the present invention has been examined focusing on its preferred embodiments. A person skilled in the art to which the present invention pertains will understand that the present invention may be implemented in a modified form without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments should be considered from an illustrative rather than a restrictive perspective. The scope of the present invention is indicated in the claims rather than the foregoing description, and all differences within the equivalent scope should be construed as being included in the present invention.
Claims (6)
상기 추출물은 물, 탄소수 1 내지 탄소수 4의 알코올 또는 이들의 혼합용매로 추출한 것인 방법.According to paragraph 1,
A method in which the extract is extracted with water, an alcohol having 1 to 4 carbon atoms, or a mixed solvent thereof.
상기 추출물은 에탄올로 추출한 것인 방법.According to paragraph 2,
A method wherein the extract is extracted with ethanol.
상기 추출물은 소목 및 에탄올을 1 : 10의 중량비로 혼합하여 추출한 것인, 방법.According to paragraph 2,
The method wherein the extract is extracted by mixing wood and ethanol at a weight ratio of 1:10.
상기 추출물은 췌장암 세포의 소포체(endoplasmic reticulum, ER) 스트레스로 인한 세포사멸을 유도하는 것인, 방법.According to paragraph 1,
The method of claim 1, wherein the extract induces apoptosis due to endoplasmic reticulum (ER) stress in pancreatic cancer cells.
상기 추출물은 췌장암 세포의 활성산소(reactive oxygen species, ROS) 생성량을 증가시키는 것인, 방법.According to paragraph 1,
The method of claim 1, wherein the extract increases the amount of reactive oxygen species (ROS) production in pancreatic cancer cells.
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