KR20190039910A - Composition for preventing and treating a cancer comprising carthamus tinctorius - Google Patents
Composition for preventing and treating a cancer comprising carthamus tinctorius Download PDFInfo
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- KR20190039910A KR20190039910A KR1020190040818A KR20190040818A KR20190039910A KR 20190039910 A KR20190039910 A KR 20190039910A KR 1020190040818 A KR1020190040818 A KR 1020190040818A KR 20190040818 A KR20190040818 A KR 20190040818A KR 20190039910 A KR20190039910 A KR 20190039910A
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Abstract
Description
본 발명은 홍화 추출물의 항암 활성에 관한 것으로, 구체적으로는 홍화 추출물의 ER-스트레스 유발 및 ROS 발생으로 인한 암세포의 사멸 효과에 관한 것이다.The present invention relates to the anticancer activity of safflower extract, specifically to the killing effect of cancer cells due to ER-stress induction and ROS development of safflower extract.
인간의 몸을 구성하고 있는 가장 작은 단위를 세포(cell)이라 부르는데 정상적인 세포는 세포 내 조절기능에 의해 분열하며 성장하고 죽어 없어지기도 하며 세포수의 균형을 유지한다. 어떤 원인으로 세포가 손상을 받은 경우, 치료를 받아 정상 세포로 역할을 하거나 회복이 안된 경우 스스로 사멸하게 된다. 그러나 여러 가지 이유로 인해 세포의 유전자에 변화가 일어나면 비정상적으로 세포가 변하여 불완전하게 성숙하고, 세포주기가 조절되지 않아 세포분열을 계속하는데 이를 암(cancer)이라 정의한다. 또한 암은 주의 조직 및 장기에 침입하고 이들을 파괴할 뿐만 아니라 다른 장기로 펴져 갈 수 있는 특징이 있다. 암에 의한 사망률은 국내에서 사망원인 1위로, 매년 그 수가 증가하고 있다. 특정 암의 의학적 치료에는 상당한 진보가 있어 왔지만, 모든 암에 대한 전반적인 5년 생존율은 과거 20년간 약 10% 정도만 개선되었다. 암, 또는 악성종양은 제어되지 않는 방식으로 신속하게 전이 및 성장하기 때문에, 제시간에 이를 검출하고 치료하는 것이 극도로 어렵다. 이 중, 다발성 골수종은 항체를 생성·분비하는 형질세포(plasma cell)의 비정상적인 증식에 의해 전신에 다발성으로 발생하는 혈액암으로 골절과 말초신경변증성 통증·고칼슘혈증을 야기할 뿐만 아니라 면역력저하, 단클론 단백질(Monoclonal protein) 과생산으로 신부전을 일으킨다. 또한, 다발성 골수종은 재발률이 54%로 높은 암으로 노년층에 빈번하게 발생하는데 고령화에 따라 다발성 골수종의 유병률과 사망률이 증가하고 있는 추세이다. 그러나, 다발성 골수종은 암 질환 중 1%를 차지하는 희귀질환이기 때문에 건강보험급여가 보장이 되지 않아 환자의 비용 부담이 크고 뿐만 아니라 항암치료제 중 boterzomib, thalidomide, lenalidomide이 주로 사용되지만 여전히 완치가 불가능하고 항암제에 대한 부작용도 현안으로 남아있다. The smallest unit that makes up the human body is called a cell. Normal cells divide by the intracellular regulating function, grow, die and disappear, and maintain the balance of the cell number. When a cell is damaged for some reason, it is treated and acts as a normal cell or, if it is not recovered, it is killed by itself. However, when the gene of a cell changes for various reasons, the cell is abnormally changed to incompletely mature, and the cell cycle is not regulated so that the cell division is continued, which is defined as cancer. Cancer is also characterized by its ability to invade the tissues and organs of the state and destroy them, as well as spread to other organs. The death rate due to cancer is the number one cause of death in Korea, and the number is increasing every year. Although there has been considerable progress in the medical treatment of certain cancers, the overall 5-year survival rate for all cancers has improved by only about 10% over the past 20 years. Cancer, or malignant tumors rapidly metastasize and grow in an uncontrolled manner, it is extremely difficult to detect and treat them on time. Among these, multiple myeloma is a multiple cancer of the whole body caused by abnormally proliferating plasma cell which produces and secretes antibody. It causes fracture, peripheral neuropathic pain, hypercalcemia, Monoclonal protein and production lead to kidney failure. The incidence of multiple myeloma and the mortality rate are increasing with the aging of multiple myeloma. However, since multiple myeloma is a rare disease that accounts for 1% of cancer diseases, the cost of health insurance is not guaranteed and the cost of patients is high. In addition, boterzomib, thalidomide, and lenalidomide are mainly used as anticancer drugs. However, The side effects of the drug remain a pending issue.
현재, 암의 치료를 위해서는 수술 요법, 방사선 치료 요법 및 화학요법 등이 사용되고 있다. 이중에서, 화학요법은 항암제를 이용하여 암을 치료하는 방법을 말한다. 오늘날에는 약 60여종의 다양한 항암제가 사용되고 있으며, 최근 암 발생 및 암 세포의 특성에 관한 지식이 많이 알려짐에 따라, 새로운 항암제 개발에 관한 연구가 활발하게 진행되고 있다. 항암 화학치료에 있어 많은 환자들은 항암제의 부작용에 의하여 고통을 받고 있으며, 특히 항암제의 독성으로 인하여 제한적인 투여가 이루어지고 있다. 임상에서 사용되고 있는 항암물질은 암세포뿐만 아니라 정상세포에도 영향을 미치며 투여회수가 반복되면서 치료에 실패하는 등 부작용 및 항암제 내성과 같은 문제점을 가지고 있다. 암 자체의 다양성 및 발병기전의 다양화로 인해 야기되는 기존항암제의 부작용을 극복할 수 있는 새로운 형태의 항암제 치료물질 연구가 진행되고 있다. Currently, surgery, radiation therapy, and chemotherapy are used to treat cancer. Of these, chemotherapy refers to a method of treating cancer using an anticancer agent. Today, about 60 kinds of various anticancer drugs are used. Recently, as knowledge of cancer development and characteristics of cancer cells is well known, researches on the development of new anticancer drugs are being actively carried out. Many patients in cancer chemotherapy suffer from the side effects of anticancer drugs, especially because of the toxicity of anticancer drugs. The anticancer substances used in clinical use have effects such as side effects and anticancer drug resistance, such as failure to treat the cancer cells as well as normal cells as well as repeated administration. A new type of anticancer drug is being studied to overcome the side effects of existing anticancer drugs caused by the diversity of the cancer itself and the variety of pathogenic mechanisms.
한편, 소포체 스트레스(ER stress)란 생리적 혹은 병리적 환경에 의해 소포체가 처리할 수 있는 능력 이상의 미성숙 단백질이 소포체 내로 유입이 되거나 소포체 내 칼슘이 고갈되어 소포체 기능에 장애가 발생하는 것을 말한다. 구체적으로, ER에서는 오접힘 단백질(misfolding protein), 과발현 단백질들이 ER의 내강에 있는 샤페론 Bip/Grp78(ER transmembrans receptor protein)에 결합하면서 UPR(Unfoded Protein Response) 기전이 개시가 된다. 정상 시에는 활성을 하고 있지 않다가, 오접힘 단백질 및 과발현 단백질과의 결합으로 수용체에서 분리가 되고, 이어서 PERK(protein kinase RNA-like endoplasmic reticulum kinase)가 세포질에서 자가인산화하여 활성화가 되고, 단백질합성을 약화시키기 위해 mRNA의 결합하는 개시인자인 elf2 인자를 음성 조절(negative feedbeck)하여 인산화 조절을 하게 된다. 이러한 과정에서 세포주기의 G1 phase가 억제가 되고, ER 스트레스에서 가장 중요한 CHOP(CCAAT/-enhancer-binding protein homologuous protein)을 발현하게 한다. 이어서 mitochodrial damage에 의해 세포사멸과 관련된 PARP의 절단이 유발되게 한다. 가장 중요한 CHOP은 ROS(reactive oxygen species)를 생성하게 된다. On the other hand, ER stress refers to the infiltration of immature proteins into the endoplasmic reticulum beyond the ability of the endoplasmic reticulum to be treated by a physiological or pathological environment, or depletion of calcium in the endoplasmic reticulum. Specifically, in the ER, the UPR (Unfenced Protein Response) mechanism is initiated while misfolding proteins and overexpressing proteins bind to the chaperone Bip / Grp78 (ER transmembrane receptor protein) located in the lumen of the ER. It is not active at normal time, but is separated from the receptor by binding to the over-folded protein and the over-expressed protein. Then, PERK (protein kinase RNA-like endoplasmic reticulum kinase) is autophosphorylated in the cytoplasm, (Negative feedbeck) of the elf2 factor, the binding initiator of mRNA, to regulate phosphorylation. In this process, the G1 phase of the cell cycle is inhibited and the most important CHOP (CCAAT / -enhancer-binding protein homologous protein) is expressed in ER stress. Followed by mitochondrial damage leading to cleavage of PARP associated with apoptosis. The most important CHOP produces reactive oxygen species (ROS).
세포사멸(apoptosis)을 회피하는 것은 악성 세포의 전형적인 특징이며, 세포사멸에 대한 세포의 저항성은 중요한 임상적 문제가 된다 (Jia et al., 2012; Lopez-Beltran et al., 2007). 이에, 본 발명자들은 암을 예방하고 치료할 수 있는 부작용이 적은 천연물을 찾고자 연구노력하던 중, 한의학개념으로 암이 옹저(癰疽), 적취(積聚)의 개념과 유사하다는 것에 착안하여 천연재료를 이용한 항암제개발연구를 하였으며, 홍화가 ER 스트레스를 유발하고 이로 인해 세포내 ROS를 생성하여 세포사멸을 유도함으로써 다발성골수종에 대해 항암 효과를 나타내는 것을 확인하여 본 발명을 완성하였다.Avoiding apoptosis is a typical feature of malignant cells, and cell resistance to apoptosis is an important clinical problem (Jia et al. , 2012; Lopez-Beltran et al. , 2007). Accordingly, the inventors of the present invention focused on the fact that cancer is similar to the concept of 癰 疽 and cumulative (聚 疽) as the concept of Oriental medicine while trying to find a natural product with a low side effect that can prevent and cure cancer, The present inventors completed the present invention by confirming that safflower induces ER stress, thereby inducing intracellular ROS and inducing apoptosis, thereby exhibiting anticancer effects against multiple myeloma.
본 발명에서는 홍화 추출물이 암세포에 세포 독성을 가지고, 특히, 다발성골수종 세포 내 ROS와 ER 스트레스를 유발하여 세포사멸을 유도하는 것을 확인함으로써, 홍화 추출물을 암의 예방 또는 치료용 조성물, 항암보조제 및 암의 예방 또는 개선용 식품 조성물로 이용하는 것을 목적으로 한다.The present invention confirms that the safflower extract has cytotoxicity to cancer cells and induces cell death by inducing ROS and ER stress in multiple myeloma cells. Thus, it is possible to provide a composition for preventing or treating cancer, As a food composition for preventing or ameliorating osteoporosis.
상기 목적의 달성을 위해, 본 발명은 홍화 추출물을 유효성분으로 포함하는 암의 예방 또는 치료용 약학적 조성물을 제공한다.To achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating cancer comprising an extract of Safflower as an active ingredient.
또한, 본 발명은 홍화 추출물을 유효성분으로 포함하는 항암보조제를 제공한다.The present invention also provides an anticancer adjuvant comprising an extract of safflower as an active ingredient.
아울러, 본 발명은 홍화 추출물을 함유하는 암의 예방 또는 개선용 식품 조성물을 제공한다.In addition, the present invention provides a food composition for preventing or ameliorating cancer containing safflower extract.
본 발명에 따르면, 홍화 추출물이 다발성골수종 세포에 세포 독성을 가지고, 세포 내 ROS를 증가시키며, ER-스트레스 반응을 유발하여 세포사멸을 유도함으로써 암세포를 제거하는 효과가 있다. According to the present invention, the safflower extract has cytotoxic effect on multiple myeloma cells, increases intracellular ROS, induces ER-stress reaction and induces apoptosis, thereby eliminating cancer cells.
도 1은 홍화 추출물 처리에 의한 다발성 골수종 세포주 U937의 세포 생존율을 확인한 도이다.
도 2는 홍화 추출물 처리에 의한 다발성 골수종 세포주 U937에서의 세포사멸 관련 단백질과 ER 스트레스 유발 관련 단백질의 발현 정도를 확인한 도이다.
도 3은 홍화 추출물 처리에 의한 다발성 골수종 세포주 U937에서의 ROS 생성 정도를 확인한 도이다.FIG. 1 is a chart showing the cell survival rate of multiple myeloma cell line U937 by treatment with safflower extract. FIG.
FIG. 2 is a graph showing the expression levels of apoptosis-related proteins and ER stress-related proteins in the multiple myeloma cell line U937 by treatment with safflower extract.
FIG. 3 shows the degree of ROS production in a multiple myeloma cell line U937 by treatment with safflower extract. FIG.
이하, 본 발명의 구현예로 본 발명을 상세히 설명하기로 한다. 다만, 하기 구현예는 본 발명에 대한 예시로 제시되는 것으로, 이에 의해 본 발명이 제한되지는 않으며 본 발명은 후술하는 특허청구범위의 기재 및 그로부터 해석되는 균등 범주 내에서 다양한 변형 및 응용이 가능하다. Hereinafter, the present invention will be described in detail with reference to embodiments of the present invention. It should be understood, however, that the invention is not limited thereto and that various changes and modifications may be made therein without departing from the spirit and scope of the invention as defined by the appended claims and their equivalents. .
일 측면에서, 본 발명은 홍화(Carthamus tinctorius) 추출물을 유효성분으로 포함하는 암의 예방 또는 치료용 약학적 조성물에 관한 것이다.In one aspect, the present invention relates to a pharmaceutical composition for preventing or treating cancer comprising an extract of Carthamus tinctorius as an active ingredient.
일 구현예에서, 상기 추출물은 물, 탄소수 1 내지 탄소수 4의 알코올 또는 이들의 혼합용매로 추출될 수 있으며, 에탄올로 추출되는 것이 더욱 바람직하다.In one embodiment, the extract may be extracted with water, an alcohol having 1 to 4 carbon atoms or a mixed solvent thereof, more preferably ethanol.
본 발명에서 사용되는 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 홍화 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 means a preparation which is obtained by squeezing a herbal medicine with an appropriate leaching solution and concentrating the liquid by evaporating the leaching solution. The extract is not limited thereto, but may be a diluent or concentrate of the extract, A dried product obtained by drying the extract, a controlled preparation thereof, or a purified product thereof. The safflower extract can 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 발명에 있어서, 상기 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 4의 알코올 또는 이들의 혼합용매를 사용할 수 있으며, 보다 바람직하게는 에탄올을 사용할 수 있다. 본 발명의 일 실시예에서는 상기 용매로서 100% 에탄올을 이용하여 추출한 뒤 감압 농축한 홍화 추출물을 제조하였다.In the present invention, the extract may be prepared by extracting with an extraction solvent or extracting with an extraction solvent, followed by fractionation with a fraction solvent. The organic solvent may be an alcohol having 1 to 4 carbon atoms, a polar solvent such as ethyl acetate or acetone, a solvent such as hexane or dichloro, or an organic solvent such as dichloromethane, Methane, 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. In one embodiment of the present invention, the extract was extracted with 100% ethanol as the solvent, and then the reduced extract was concentrated under reduced pressure.
일 구현예에서, 상기 암은 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 구성된 군으로부터 선택되는 어느 하나일 수 있으며, 다발성 골수종(multiple myeloma)인 것이 더욱 바람직하다.In one embodiment, the cancer is selected from the group consisting of: colorectal cancer, breast cancer, cervical cancer, cervical cancer, ovarian cancer, prostate cancer, brain tumor, head and neck carcinoma, melanoma, myeloma, leukemia, lymphoma, stomach cancer, pancreatic cancer, Renal cell carcinoma, kidney cell carcinoma, renal pelvic carcinoma, bone cancer, skin cancer, head cancer, endometrial carcinoma, endometrial carcinoma, vulvar carcinoma, Hodgkin's disease, bladder cancer, kidney cancer, Cancer of the central nervous system (CNS), primary CNS lymphoma, spinal cord tumor, cervical cancer, endometrial carcinoma, endometrial carcinoma, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, Brain giant glioma, and pituitary adenoma. It is more preferable that the myeloma is multiple myeloma.
일 구현예에서, 홍화 추출물이 10 내지 200㎍/ml의 농도로 포함될 수 있으며, 예를 들어, 10 내지 150㎍/ml, 10 내지 100㎍/ml, 50 내지 200㎍/ml, 100 내지 200㎍/ml 또는 50 내지 100㎍/ml의 농도로 포함될 수 있다.In one embodiment, the safflower extract may be included at a concentration of 10-200 μg / ml, for example 10-150 μg / ml, 10-100 μg / ml, 50-200 μg / ml, / ml or 50 to 100 [mu] g / ml.
일 구현예에서, 암의 예방 또는 치료는 암세포의 소포체(endoplasmic reticulum, ER) 스트레스로 인한 세포사멸과 ROS 증가에 의해 달성될 수 있다.In one embodiment, the prevention or treatment of cancer can be accomplished by increasing cell death and ROS due to endoplasmic reticulum (ER) stress.
본 발명의 일 실시예에서는 홍화 추출물 처리에 의한 다발성 골수종 세포의 사멸이 증가하는 것을 확인하였으며, 이와 같은 항암 활성 기작을 확인하기 위하여 ER 스트레스에서 가장 중요한 CHOP의 발현과 이로 인한 ROS 및 세포사멸 관련 PARP의 절단을 확인한 결과, CHOP 발현이 증가하고 PARP의 절단이 증가하였으며, 골수종 내의 ROS가 증가하는 것을 확인하고(도 2), 세포사멸 기작이 ER-스트레스에 의해 유발되는 것임을 ROS의 발현 증가를 통해 확인함으로써(도 3), 본 발명의 홍화 추출물이 ER-스트레스와 ROS를 유발하고 이를 통해 세포사멸을 유도해 항암 활성을 나타내는 것임을 유추할 수 있다.In one embodiment of the present invention, it was confirmed that the death of multiple myeloma cells by the treatment with safflower extract was increased. To confirm this anticancer activity mechanism, expression of CHOP most important in ER stress and ROS and apoptosis related PARP (Fig. 2). The expression of CHOP was increased, the cleavage of PARP was increased, and the ROS in the myeloma was increased (Fig. 2) (FIG. 3), it can be deduced that the safflower extract of the present invention induces ER-stress and ROS and induces apoptosis through this, thereby exhibiting anticancer activity.
본 발명에서 사용되는 용어, "ER-스트레스"는 암이 생존하는 기전에서 hypoxia, inflammation, angiogenesis를 억제할 수 있어서 항상성을 회복할 수 있는 기전으로서, 항암제가 타켓해야 할 하는 새로운 기전으로 주목받고 있다. ER-스트레스에서 pro-survival UPR(unfolded protein response)로 가서 손상된 세포를 복구하거나, 복구가 될 가능성이 없을 경우에는 pro-apoptotic ERAD(ER-assoicated degradtion)로 제거하게 된다. ERAD(ER-assoicated degradtion) 기전에서 가장 중요한 인자들인 CHOP (C/EBP homology protein)-GADD34 과 cPARP 발현을 확인하였다. CHOP (C/EBP homology protein)-GADD34은 anti-cancer로 하는 항암제에서 관심을 가지는 주요인자이다. CHOP은 cell death program를 유도하는데 oxidation으로 인한 apoptosis protein synthesis을 하게 하는데 조절을 하는 주요인자이다.The term " ER-stress " used in the present invention can be used to inhibit hypoxia, inflammation, and angiogenesis in a cancer survival mechanism, and is a new mechanism for anticancer drugs . ER-stress leads to pro-survival UPR (unfolded protein response), repairing damaged cells, or removing pro-apoptotic ERAD (ER-assoicated degradation) if there is no possibility of repair. The most important factors in the ER-assoicated degradation (ERAD) mechanism were CHOP (C / EBP homology protein) -GADD34 and cPARP expression. CHOP (C / EBP homology protein) -GADD34 is a major factor of interest in anticancer drugs that are anti-cancer. CHOP induces cell death programs and is a major factor in controlling apoptosis protein synthesis induced by oxidation.
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. As used herein, the term " apoptosis " is also referred to as apoptosis or apoptosis, and is a kind of programmed cell death (PCD), which is characterized by abnormal cells, damaged cells, aged It is a mechanism that allows cells to maintain their overall physical health by killing themselves and killing themselves.
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.The term " prevention " in the present invention means all the actions of inhibiting or delaying the development, spread and recurrence of cancer by administration of the pharmaceutical composition according to the present invention, and " treatment " Suspicion of cancer and all the behaviors that alleviate or ameliorate symptoms of the onset individuals.
본 발명에서 사용되는 용어, "치료"란 본 발명의 홍화을 포함하는 조성물의 투여로 암세포의 사멸 또는 암의 증세를 호전시키거나 이롭게 변경하는 모든 행위를 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.As used herein, the term " treatment " means any action that improves or alleviates the death or cancer of a cancer cell by administration of a composition comprising safflower of the present invention. Those skilled in the art will be able to ascertain the precise criteria of the disease for which the composition of the present invention is effective by referring to the data presented by the Korean Medical Association, will be.
본 발명에서 유효성분과 결합하여 사용된 "치료학적으로 유효한 양"이란 용어는 대상 질환을 예방 또는 치료하는데 유효한 홍화 추출물의 약학적으로 허용가능한 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 Hardman and Limbird, eds., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th ed.(2001), Pergamon Press; 및 E.W. Martin ed., Remington's Pharmaceutical Sciences, 18th ed.(1990), Mack Publishing Co.에 기술되어있다.The term " therapeutically effective amount " used in combination with the active ingredient in the present invention means the amount of a pharmaceutically acceptable salt of safflower extract effective for preventing or treating a target disease, The amount can vary depending on a number of factors, such as the mode of administration, the site of administration, the condition of the patient, and the like. Therefore, when used in the human body, the dosage should be determined in consideration of safety and efficacy. It is also possible to estimate the amount used in humans from the effective amount determined through animal experiments. Such considerations in determining the effective amount are described, for example, in Hardman and Limbird, eds., Goodman and Gilman ' s Pharmacological Basis of Therapeutics, 10th ed. (2001), Pergamon Press; And E.W. Martin ed., Remington ' s Pharmaceutical Sciences, 18th ed. (1990), Mack Publishing Co.
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, 부작용없이 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 herein, the term " pharmaceutically effective amount " means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment and not causing side effects, Factors well known in the art and other medical disciplines including health status, type of cancer, severity, activity of the drug, sensitivity to the drug, method of administration, time of administration, route of administration and rate of release, duration of treatment, ≪ / RTI > The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiply. Taking all of the above factors into consideration, it is important to administer an amount that can achieve the maximum effect in a minimal amount without side effects, which can be easily determined by those skilled in the art.
본 발명의 약학 조성물은 생물학적 제제에 통상적으로 사용되는 담체, 희석제, 부형제 또는 둘 이상의 이들의 조합을 포함할 수 있다. 본 발명에서 사용되는 용어, "약학적으로 허용가능한"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 성분 이상을 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 등과 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 compositions of the present invention may include carriers, diluents, excipients, or a combination of two or more thereof commonly used in biological formulations. As used herein, the term " pharmaceutically acceptable " means that the composition is free of toxicity to cells or humans exposed to the composition. The carrier is not particularly limited as long as the composition is suitable for in vivo delivery, for example, Merck Index, 13th ed., Merck & Inc. A buffered saline solution, a buffer solution, a dextrose solution, a maltodextrin solution, glycerol, ethanol, and one or more of these components may be mixed and used, and if necessary, an antioxidant, a buffer, Conventional additives may be added. In addition, diluents, dispersants, surfactants, binders, and lubricants may be additionally added to formulate into main dosage forms such as aqueous solutions, suspensions, emulsions, etc., pills, capsules, granules or tablets. Further, it can be suitably formulated according to each disease or ingredient, using the method disclosed in Remington's Pharmaceutical Science (Mack Publishing Company, Easton PA, 18th, 1990) in a suitable manner in the art.
본 발명의 약학 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 comprise a pharmaceutically acceptable additive, wherein the pharmaceutically acceptable additives include starch, gelatinized starch, microcrystalline cellulose, lactose, povidone, colloidal silicon dioxide, calcium hydrogen phosphate, Wherein the starch is selected from the group consisting of lactose, mannitol, sugar, arabic gum, pregelatinized starch, cornstarch, powdered cellulose, hydroxypropyl cellulose, opaques, sodium starch glycolate, carnauba wax, synthetic aluminum silicate, stearic acid, magnesium stearate, Calcium, white sugar, dextrose, sorbitol and talc may be used. The pharmaceutically acceptable additive according to the present invention is preferably included in the composition in an amount of 0.1 part by weight to 90 parts by weight, but is not limited thereto.
본 발명의 약학 조성물은 유효성분으로서 홍화 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 comprise a known anti-cancer agent other than safflower extract as an active ingredient, and may be used in combination with other treatments known 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 therapies, immunotherapy, and the like.
본 발명의 약학 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 may be included in the pharmaceutical compositions of the present invention include DNA alkylating agents such as mechloethamine, chlorambucil, phenylalanine, mustard, cyclophosphamide, cyclophosphamide, ifosfamide, carmustine (BCNU), lomustine (CCNU), streptozotocin, busulfan, thiotepa, cisplatin ) And carboplatin; The anticancer antibiotics include dactinomycin (actinomycin D), doxorubicin (adriamycin), daunorubicin, idarubicin, mitoxantrone, Plicamycin, mitomycin C, and bleomycin; And plant alkaloids such as vincristine, vinblastine, paclitaxel, docetaxel, etoposide, teniposide, topotecan, And iridotecan, but are not limited thereto.
일 측면에서, 본 발명은 홍화 추출물을 이를 필요로 하는 개체에게 투여하는 단계를 포함하는, 암을 예방 또는 치료하는 방법에 관한 것이다.In one aspect, the invention relates to a method of preventing or treating cancer, comprising administering the safflower extract 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. 본 발명의 약학적 조성물은 기존의 치료제와 병행하여 투여될 수 있다.The term " individual " used in the present invention means a monkey, a horse, a sheep, a pig, a chicken, a turkey, a quail, a cat, a dog, a mouse, a rat, a rabbit Refers to all animals including guinea pigs, and the diseases can be effectively prevented or treated by administering the pharmaceutical composition of the present invention to an individual. The pharmaceutical composition of the present invention can be administered in parallel with existing therapeutic agents.
본 발명에서 사용되는 용어, "투여"란 임의의 적절한 방법으로 환자에게 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 다양하다. 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 포함된다. 본 발명의 약학적 조성물은 활성 물질이 표적 세포로 이동할 수 있는 임의의 장치에 의해 투여될 수도 있다. 바람직한 투여방식 및 제제는 정맥 주사제, 피하 주사제, 피내주사제, 근육 주사제, 점적 주사제 등이다. 주사제는 생리식염액, 링겔액 등의 수성 용제, 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, 미생물 발육을 저지하기 위한 보존제 (예, 질산페닐수은, 치메로살, 염화벤잘코늄, 페놀, 크레솔, 벤질알코올 등) 등의 약학적 담체를 포함할 수 있다.As used herein, the term " administering " means providing a given material to a patient in any suitable manner and may be administered orally, parenterally (e.g., intravenously, subcutaneously, intraperitoneally or topically The dosage ranges vary depending on the patient's body weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and severity of the disease. Examples of the liquid preparation for oral administration of the composition of the present invention include suspensions, solutions, emulsions, syrups, and the like. In addition to water and liquid paraffin which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, Etc. may be included together. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. The pharmaceutical composition of the present invention may be administered by any device capable of moving the active substance to the target cell. The preferred modes of administration and formulations are intravenous, subcutaneous, intradermal, intramuscular, and drip injections. The injectable solution may be a non-aqueous solvent such as an aqueous solvent such as a physiological saline solution or a ring gel solution, a vegetable oil, a higher fatty acid ester (e.g., oleic acid), an alcohol (e.g., ethanol, benzyl alcohol, propylene glycol, glycerin, etc.) (For example, ascorbic acid, sodium hydrogen sulfite, sodium pyrophosphate, BHA, tocopherol, EDTA and the like), an emulsifier, a buffer for pH control, a microbial growth inhibitor And a pharmaceutical carrier such as a preservative (e.g., mercury nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.).
일 측면에서, 본 발명은 홍화(Carthamus tinctorius) 추출물을 유효성분으로 포함하는 항암보조제에 관한 것이다.In one aspect, the present invention relates to an anticancer adjuvant comprising an extract of Carthamus tinctorius as an active ingredient.
일 측면에서, 본 발명은 홍화(Carthamus tinctorius) 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 carfam ( Carthamus tinctorius ) extract.
본 발명의 조성물을 식품 조성물로 사용하는 경우, 상기 홍화 추출물을 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용할 수 있고, 통상의 방법에 따라 적절하게 사용할 수 있다. 상기 조성물은 유효성분 이외에 식품학적으로 허용가능한 식품보조첨가제를 포함할 수 있으며, 유효성분의 혼합량은 사용 목적(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 safflower extract can be used as it is or can be used together with other food or food ingredients, and can be appropriately used according to a conventional method. The composition may contain a food-acceptable food-aid additive in addition to the active ingredient, and the amount of the active ingredient to be mixed may be suitably determined according to the intended 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.As used herein, the term " food supplementary additive " refers to a component that can be added to foods in a supplementary manner, and is appropriately selected and used by those skilled in the art as added to produce health functional foods of each formulation. Examples of food-aid additives include flavors such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, colorants and fillers, pectic acid and its salts, alginic acid and its salts, organic acids, , a pH adjusting agent, a stabilizer, a preservative, a glycerin, an alcohol, and a carbonating agent used in a carbonated drink. However, the types of the food auxiliary additives of the present invention are not limited by these 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 생리학적 작용 등과 같은 보건용도에 유용한 효과를 얻는 것을 의미한다. 본 발명의 건강기능식품은 통상의 기술분야에서 통상적으로 사용되는 방법에 의하여 제조가능하며, 상기 제조시에는 통상의 기술분야에서 통상적으로 첨가하는 원료 및 성분을 첨가하여 제조할 수 있다. 또한 상기 건강기능식품의 제형 또한 건강기능식품으로 인정되는 제형이면 제한없이 제조될 수 있다. 본 발명의 식품용 조성물은 다양한 형태의 제형으로 제조될 수 있으며, 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용 등이 없는 장점이 있고, 휴대성이 뛰어나, 본 발명의 건강기능식품은 항암제의 효과를 증진시키기 위한 보조제로 섭취가 가능하다.A health functional food may be included in the food composition of the present invention. The term " health functional food " as used in the present invention refers to a food prepared and processed in the form of tablets, capsules, powders, granules, liquids and rings using raw materials and components having useful functions in the human body. Here, 'functional' refers to the structure and function of the human body to obtain nutritional effects and obtain useful effects for health use such as physiological action. The health functional food of the present invention can be prepared by a method commonly used in the art, and can be prepared by adding raw materials and components which are usually added in the conventional technical fields. In addition, the formulations of the above health functional foods may also be manufactured without limitations as long as they are acceptable as health functional foods. The composition for food of the present invention can be manufactured in various forms, and unlike general pharmaceuticals, it has the advantage that there is no side effect that may occur when a drug is used for a long period of time, and is excellent in portability, Can be ingested as an adjuvant to enhance the effectiveness of anticancer drugs.
또한, 본 발명의 조성물이 사용될 수 있는 건강식품의 종류에는 제한이 없다. 아울러 본 발명의 홍화 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.There is no limitation on the kind of health food to which the composition of the present invention can be used. In addition, the composition comprising the safflower extract of the present invention as an active ingredient can be prepared by mixing other suitable auxiliary ingredients that can be contained in health functional foods with known additives according to the choice of a person skilled in the art. Examples of foods that can be added include dairy products, such as meat, sausage, bread, chocolates, candies, snacks, confectionery, pizza, ramen, other noodles, gums, ice cream, various soups, drinks, tea, Vitamin complex, and the like, and can be prepared by adding to the juice, tea, jelly, and juice prepared from the extract of the present invention as a main component.
본 발명의 홍화 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 safflower extract of the present invention is a raw material of natural plant, it can be used as a pharmaceutical composition or a food composition and can be safely used in a pharmaceutical composition and a health functional food safely because it has less side effects than a general synthetic compound.
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 with reference to the following examples. However, the following examples are only for the purpose of illustrating the present invention, and thus the present invention is not limited thereto.
실시예 1. 홍화(Example 1. Safflower ( Carthamus tinctoriusCarthamus tinctorius ) 추출물 제조) Preparation of extract
100% 에탄올로 홍화을 추출한 뒤 감압농축하여 홍화 에탄올 추출물을 제조하였다.Safflower was extracted with 100% ethanol and concentrated under reduced pressure to prepare a safflower ethanol extract.
실험예 1. 홍화 추출물의 다발성 골수종에 대한 세포 독성 확인EXPERIMENTAL EXAMPLE 1. Cytotoxicity of Extract of Safflower on Multiple Myeloma
상기 실시예 1에서 제조한 홍화 추출물의 다발성 골수종에 대한 항암 활성을 확인하기 위하여, 다발성 골수종 세포주인 U937 세포주 (한국세포주은행) 50㎕를 96웰-플레이트에 2×104 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 세포주 U937에 상기 실시예 1에서 제조한 홍화 추출물을 0, 50, 100, 150 및 200㎍/ml의 농도로 각각 50㎕씩 처리한 뒤, 하루 동안 인큐베이션 하였다. 암상태에서 인큐베이션한 세포에 EZ-Cytox 시약 (DoGen)을 10㎕ 처리하고 30분 내지 4시간 동안 인큐베이션한 뒤, 마이크로플레이트 리더기 (Bio-rad Model 680) 흡광도 450nm에서 세포 생존율을 확인하였다.To confirm the anticancer activity against the multiple myeloma of the safflower extract prepared in Example 1, 50 쨉 l of a U937 cell line (Korean Cell Line Bank), which is a multiple myeloma cell line, was dispensed into a 96 well plate at a rate of 2 x 10 4 cells / In RPMI medium supplemented with 10% inactivated fetal bovine serum and 1% penicillin-streptomycin, And cultured in a 5% CO 2 incubator (MCO-15AC, Sanyo, Osaka, Japan) at 37 ° C. The cultured cell line U937 was treated with 50 .mu.l of the safflower extract prepared in Example 1 at the concentrations of 0, 50, 100, 150 and 200 .mu.g / ml, respectively, followed by incubation for one day. Cells incubated in the dark state were treated with 10 [mu] l of EZ-Cytox reagent (DoGen) and incubated for 30 minutes to 4 hours, and cell viability was confirmed at 450 nm absorbance of the microplate reader (Bio-rad Model 680).
그 결과, 홍화 추출물의 농도 의존적으로 다발성 골수종에 독성을 나타냈고, 100㎍/ml 이후부터는 농도에 큰 차이 없이 다발성 골수종을 사멸시키는 것을 알 수 있었다 (도 1).As a result, it was found that toxicities were observed in multiple myeloma depending on the concentration of safflower extract, and that multiple myeloma was killed without significant difference in concentration after 100 μg / ml (FIG. 1).
실험예 2. 홍화 추출물에 의한 다발성 골수종의 세포사멸 유발 효과 확인 Experimental Example 2. Determination of cell death-inducing effect of multiple myeloma by safflower extract
상기 실시예 1에서 제조한 홍화 추출물이 다발성 골수종에서의 세포사멸에 미치는 영향을 확인하기 위해, 세포사멸 진행시 절단되는 것으로 알려진 PARP(Poly ADP ribose polymerase)와 DNA 손상을 유도하고 ER 스트레스를 유발하여 세포사멸의 마커로 이용되는 CHOP(C/EBP homologous protein)의 발현 정도를 웨스턴 블롯 분석으로 확인하였다. 구체적으로, 다발성 골수종 세포주인 U937 세포주에 상기 실시예 1에서 제조한 홍화 추출물을 0, 50 및 100㎍/ml로 각각 처리하고 24시간 동안 37℃의 5% CO2 인큐베이터로 인큐베이션하였다. 그 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 세포파쇄하였다. 세포파쇄물을 15,520×g에서 20분간 원심분리하여 세포막 성분 등을 제거한 후, RC DC™ Protein Assay Kit II(protein assay kit) (Bio-rad, USA)를 사용하여 단백질을 정량하여 시료별 (홍화 추출물 0, 50 및 100㎍/ml 처리군들)로 동일한 단백질의 양이 포함되도록 조절하였다. 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 (Cell signaling) 및 항-CHOP (Cell signaling)를 각각 1:500으로 희석하여 블로킹한 멤브레인과 4℃에서 1시간 내지 오버나잇으로 반응시켰다. 멤브레인을 TBST로 3회 세정한 뒤 horseradish peroxidase가 결합된 항-rabbit IgG를 1:2,000으로 희석하여 상온에서 멤브레인과 1시간 동안 반응시킨 다음 TBST로 3회 세정하였다. 세정한 멤브레인을 chemiluminescent reagent와 1 내지 3분 동안 반응시키고 필름에 감광하여 단백질 밴드를 가시화하였다.In order to examine the effect of the safflower extract 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 level of CHOP (C / EBP homologous protein) used as a marker of apoptosis was confirmed by Western blot analysis. Specifically, the safflower extract prepared in Example 1 was treated at 0, 50, and 100 / / ml, respectively, in a U937 cell line, which is a multiple myeloma cell line, and incubated in a 5% CO 2 incubator at 37 캜 for 24 hours. Cells were then harvested, washed with PBS and resuspended in cell-disrupted buffer RIPA (20 mM Tris-HCl (pH 7.5), 150 mM NaCl, 1 mM NaEDTA, 1 mM EGTA, 1% NP-40, 1% sodium pyrpphophate, 1 mM beta-glycerophosphate , 1 mM Na 3 VO 4 and 1 [mu] g / ml leupeptin (Cell signaling)) was added thereto and the cells were disrupted at 4 [deg.] C for 30 minutes. Cell lysates were centrifuged at 15,520 × g for 20 min to remove cell membrane components and the proteins were quantified using RC DC ™ Protein Assay Kit II (Bio-Rad, USA) 0, 50 and 100 [mu] g / ml treated groups). 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 for 2 hours at room temperature, followed by primary antibody anti-PARP (Cell signaling) and anti-CHOP (Cell signaling) Were each diluted 1: 500 and reacted with the blocked membrane at 4 ° C for 1 hour to overnight. The membranes were washed three times with TBST, and anti-rabbit IgG conjugated with horseradish peroxidase was diluted 1: 2,000, reacted with membrane at room temperature for 1 hour, and washed three times with TBST. The washed membrane was reacted with a chemiluminescent reagent for 1 to 3 minutes and photographed on a film to visualize the protein band.
그 결과, 홍화 추출물의 농도에 의존적으로 PARP의 절단이 증가하고, CHOP의 발현이 증가하여 세포사멸과 ER-스트레스가 홍화 추출물에 의해 향상되는 것을 알 수 있어, 홍화 추출물이 다발성 골수종의 세포 사멸을 농도의존적으로 유발하는 것을 알 수 있었다 (도 2).As a result, it was found that PARP cleavage was increased depending on the concentration of safflower extract, CHOP expression was increased, and cell death and ER-stress were improved by safflower extract. Dependent manner (FIG. 2).
실험예 3. 다발성 골수종에서의 홍화 추출물의 활성산소 유발 효과 확인 Experimental Example 3: Determination of reactive oxygen species effect of safflower extract in multiple myeloma
상기 실시예 1에서 제조한 홍화 추출물이 다발성 골수종에 미치는 영향을 확인하기 위하여, 다발성 골수종 세포주인 U937 세포주 4×105개를 PBS로 세정한 뒤, DCFDA Cellular Reactive Oxygen Species Detection Assay kit (abcam)를 20mM 처리하여 37℃에서 암상태로 30분 동안 인큐베이션하고, 다시 PBS로 세정하였다. 이 후, 2×104개의 세포 (50㎕)를 96월-플레이트에 분주하고, 상기 실시예 1에서 제조한 홍화 추출물 50㎕을 0, 50 및 100㎍/ml로 각각 처리한 뒤, 6시간 동안 암상태에서 인큐베이션하였다. 그 후, 마이크로플레이트 리더기를 이용하여 485/535nm에서 흡광도를 측정하였다. To examine the effect of the safflower extract prepared in Example 1 on multiple myeloma, 4 × 10 5 U937 cell lines, multiple myeloma cell lines, were washed with PBS, and then DCFDA Cellular Reactive Oxygen Species Detection Assay kit (abcam) 20 mM, incubated at 37 캜 for 30 minutes in a dark state, and then washed again with PBS. Subsequently, 2 x 10 4 cells (50 μl) were dispensed into 96-well plates, and 50 μl of the safflower extract prepared in Example 1 was treated at 0, 50, and 100 μg / ml, Lt; / RTI > After that, the absorbance was measured at 485/535 nm using a microplate reader.
그 결과, 홍화를 50㎍/ml 또는 100㎍/ml 처리시 다발성 골수종 세포에서 ROS 생성을 증가시키는 것을 알 수 있었다 (도 3). As a result, it was found that treatment with safflower at 50 / / ml or 100 / / ml increased ROS production in multiple myeloma cells (Fig. 3).
Claims (1)
상기 추출물은 100 ㎍/ml의 양으로 투여되고,
상기 추출물은 다발성 골수종 세포 내의 ROS 생성을 증가시키고, 소포체(endoplasmic reticulum, ER) 스트레스를 유발하여 세포사멸을 유도하는 것을 특징으로 하는 다발성 골수종(multiple myeloma)의 예방 또는 치료용 약학적 조성물.
A pharmaceutical composition for the prevention or treatment of multiple myeloma comprising ethanol extract of Carthamus tinctorius as an active ingredient,
The extract was administered in an amount of 100 占 퐂 / ml,
Wherein said extract increases ROS production in multiple myeloma cells and induces endoplasmic reticulum (ER) stress to induce apoptosis. The present invention also provides a pharmaceutical composition for preventing or treating multiple myeloma.
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