KR101387966B1 - A Composition comprising cytochalasin b as an active ingredient for treating and preventing cancer disease - Google Patents
A Composition comprising cytochalasin b as an active ingredient for treating and preventing cancer disease Download PDFInfo
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- KR101387966B1 KR101387966B1 KR1020110113166A KR20110113166A KR101387966B1 KR 101387966 B1 KR101387966 B1 KR 101387966B1 KR 1020110113166 A KR1020110113166 A KR 1020110113166A KR 20110113166 A KR20110113166 A KR 20110113166A KR 101387966 B1 KR101387966 B1 KR 101387966B1
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- South Korea
- Prior art keywords
- cancer
- composition
- apoptosis
- cells
- cytochalasin
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Abstract
본 발명은 암 예방 및 치료용 조성물 및 이를 포함하는 건강기능식품에 관한 것으로, 보다 상세하게는 화학식 1로 나타내어지는 cytochalasin b, 약학적으로 허용 가능한 그의 염, 광학이성질체, 또는 다형체를 유효성분으로 포함하는 암 예방 및 치료용 조성물 및 이를 함유하는 건강기능식품에 관한 것이다.
본 발명의 화합물들은 미토콘드리아의 탈분극을 유도하며, DNA 합성을 저해하고, 조기 세포 사멸을 발생시켜 세포사멸(apoptosis)을 유도하고, 세포 성장의 저해를 나타냄으로서, 암세포의 세포사멸(apoptosis)을 유도하기 때문에 암 질환의 예방 및 치료에 유용하게 사용될 수 있다.The present invention relates to a composition for preventing and treating cancer, and a health functional food comprising the composition. More particularly, the present invention relates to a composition for preventing and / or treating cancer, which comprises cytochalasin b, a pharmaceutically acceptable salt thereof, an optical isomer or polymorph thereof And a health functional food containing the same.
The compounds of the present invention induce depolarization of mitochondria, inhibit DNA synthesis, induce apoptosis by inducing apoptosis of early cells, inhibit cell growth, induce apoptosis of cancer cells And thus can be useful for the prevention and treatment of cancer diseases.
Description
본 발명은 사이토칼라신 비(cytochalasin b)를 유효성분으로 함유하는 암 질환의 예방 및 치료용 조성물, 및 건강기능식품에 관한 것이다.
The present invention relates to a composition for the prevention and treatment of cancer diseases containing cytochalasin b as an active ingredient, and a health functional food.
암이란 주로 통제되지 않는 세포의 증식에서 시작되어 주위의 정상조직 또는 기관으로 침윤하여 파괴시키고 새로운 성장 장소를 만들 수 있어 개체의 생명을 빼앗아 갈 수 있는 질환 군을 총칭한다.Cancer is a group of diseases that can start from the growth of uncontrolled cells, infiltrate into the surrounding normal tissues or organs, destroy them, create new growth places, and take away the life of the individual.
지난 10 여년 동안 암을 정복하기 위해 세포주기나 세포사멸(apoptosis)의 조절과 발암유전자나 암억제 유전자들을 포함 한 새로운 표적을 모색함에 있어서 눈에 띄는 발전을 거듭해 왔음에도 불구하고 암의 발생률은 문명이 발달됨에 따라 증가 되고 있다. 현재, 암환자의 치료법은 외과적 수술, 방사선 치료, 40여종의 강한 세포독성을 보이는 항암물질 투여에 의한 화학요법에 의존하고 있는 상태인데, 이들 치료법도 대부분 조기 암환자나 특정 암에만 국한되어 암으로 인한 사망은 계속 증가하고 있는 추세이다.
In the past decade, despite the remarkable progress made in the search for new targets, including regulation of cell lineage or apoptosis and the development of oncogenes or cancer-suppressing genes to conquer cancer, It is increasing with development. Currently, the treatment of cancer patients depends on surgical treatment, radiation therapy, chemotherapy using 40 kinds of strong cytotoxic anticancer drugs. Most of these treatments are limited to early cancer patients or specific cancers, The number of deaths caused by the disease continues to increase.
세포사멸(apoptosis)은 세포 내부에 프로그램된 신호를 따라 여러 유전자 및 단백질들의 발현과 활성이 조절되어 일어나는 능동적인 죽음이며, 그 과정을 통해 생성된 아포토소체(apoptosome)들은 주변의 세포들이나 대식세포(macrophage) 등의 식세포 작용에 의해 제거됨으로서, 염증을 유발하지 않는다. 세포사멸의 형태적, 생리적 특징으로는 세포질 축소(cytoplasm shrinkage), 세포막(membrane blebbing), 염색체의 응축(chromatin condensation), DNA의 분절(DNA fragmentation), 세포막을 이루는 지질인 포스파티딜세린(phosphatidylserine)의 세포 외부로의 노출, 아포토소체(apoptosome)의 형성 등이 보고되고 있다.
Apoptosis is an active death in which the expression and activity of various genes and proteins are regulated by a signal programmed inside the cell, and apoptosomes generated through the process are released into surrounding cells or macrophages (macrophage), such as by phagocytosis is eliminated, does not cause inflammation. The morphological and physiological characteristics of apoptosis include cytoplasm shrinkage, membrane blebbing, chromatin condensation, DNA fragmentation, phosphatidylserine, which is a lipid of the cell membrane Exposure to the outside of the cell, and formation of apoptosome have been reported.
반면에 세포괴사는 외부적 환경의 변화에 의해 급격히 일어나는 수동적 죽음이며, 염색사의 다형태적 덩어리(irregular clumping)와 세포질의 팽창(swelling of cytoplasm) 과정을 거치게 되고, 최종적으로 세포들의 분해를 통해 세포 파편(cell debris)이 생성되고, 이들이 염증을 유발하게 된다(Barry, M.A. et al., Activation of programmed cell death (apoptosis) by cisplatin, other anticancer drugs, toxins and hyperthermia. Biochem Pharmacol 40, pp 2353-2362, 1990; Hickman et al., Apoptosis induced by anticancer drugs. Cancer Metastasis Rev. 11, pp121-129, 1992).On the other hand, cell death is a passive death that occurs suddenly due to changes in the external environment, and is followed by irregular clumping of the chromosome and swelling of cytoplasm. Finally, cell debris are generated and they cause inflammation (Barry, MA et al., Activation of programmed cell death (apoptosis) by cisplatin, other anticancer drugs, toxins and hyperthermia. Biochem Pharmacol 40 , pp 2353-2362, 1990; Hickman et al., Apoptosis induced by anticancer drugs. Cancer Metastasis Rev. 11 , pp121-129, 1992).
세포사멸은 생명체의 여러 정상적인 생리적 현상에서 쉽게 관찰된다. 예를 들면 세포사멸은 생명체의 초기 발생단계에서 관찰되는 여러 형태적 변화과정(morphogenesis)과 면역계 또는 신경계의 기능적 자가 조직화(functional self-organization)과정에서 중요한 역할을 담당한다. 또한, 성인이 된 이후에도 조직 항상성(tissue homeostasis), 세포 수의 조절, 손상된 세포의 제거, 감염에 대한 방어 기작으로서 필수적으로 작용한다. 세포사멸은 여러 질환들의 발병과정에도 깊이 관여하는데 비정상적인 세포사멸의 발생은 퇴행성뇌신경질환(neurogegenerative disorder), 면역계 이상(immune disorder), 그리고 심장 혈관계질환(cardiovascular disease) 등의 원인이 될 수 있으며, 세포사멸의 비정상적인 억제는 암의 원인이 될 수 있다. 세포사멸이 정상적인 조절과정에서 벗어나 비정상적으로 발행하거나 억제되어 나타나는 질병을 좀 더 자세히 살펴보면, p53, p16와 Bcl-2 등의 유전자의 이상 발현에 의해 유도되는 암들, HIV Herpes 및 독감(influenza) 바이러스들에 의한 감염증, 그리고 당뇨(Type 1 diabetes), 류마티스 관절염(Rheumatoid arthritis), 다발성 경화증(multiple sclerosis)과 근무력(Myasthenia gravis) 등과 같은 자가면역 질환들이 있다. 이와 같이, 세포사멸은 생명체의 다양한 생리작용을 정상적으로 유지하는데 중요한 역할을 할 뿐만 아니라, 여러 질병들의 발병과정에도 밀접한 관련이 있다. 개체를 구성하는 각 세포의 세포사멸은 유전적으로 손상을 입은 세포나 분화 자극제에 의해 부적절한 분화의 유도에 의한 종양의 발달을 막기 위해 이들 비정상적인 세포를 개체에서 제거하기 위한 수단, 즉 회복 불가능한 유전적 상처를 지닌 세포들을 개체에서 제거하기 위한 일반적인 수단이다. 이 개념은 일반적으로 사용되는 항암제가 암세포의 증식억제와 연관된 세포사멸 과정을 통해 암세포의 사멸을 유도한다는 사실에 의해 뒷받침되고 있다(Barry, M.A., et al., Biochem Pharmacol , 40, pp 2353-2362, 1990; Hickman, J.A., Cancer Metastasis Rev . 11, pp 121-129, 1992).Cell death is easily observed in many normal physiological phenomena of life. For example, apoptosis plays an important role in morphogenesis and functional self-organization of the immune system or nervous system, which are observed in the early stages of life. In addition, even after becoming an adult, it plays an essential role in tissue homeostasis, regulation of cell numbers, removal of damaged cells, and protection against infection. Cell death is deeply involved in the pathogenesis of various diseases. The occurrence of abnormal cell death may be a cause of neurogegenerative disorder, immune disorder, and cardiovascular disease, Abnormal inhibition of death can be a cause of cancer. A closer look at diseases that are abnormally released or inhibited by apoptosis beyond normal regulation can lead to cancer induced by abnormal expression of genes such as p53, p16 and Bcl-2, HIV Herpes and influenza viruses And autoimmune diseases such as diabetes (
따라서 세포사멸 과정의 교란은 손상되거나 손상이 시작된 세포의 생존과 그들 세포의 성장을 유도하기 때문에 세포 사멸의 억제는 암화 과정에서 중요한 역할을 한다.
Thus, disturbance of apoptosis plays an important role in the process of cancer cell death, since it induces the survival of damaged or damaged cells and their growth.
아울러 암예방 효과가 있는 물질들은 이러한 비정상적인 세포의 세포사멸을 유도하며, 이들에 의한 세포사멸의 유발은 최소한 그들의 암예방 활성과 연관되어 있음이 보고되었다(Fesus, L., J Cell Biochem. 22, pp 151-161, 1995; Reddy, B.S. Cancer Res . 57, pp 420-425, 1997)In addition, it has been reported that substances having cancer-preventing effects induce apoptosis of such abnormal cells, and induction of apoptosis by them is at least associated with their cancer-preventing activity (Fesus, L., J Cell Biochem . 22 , pp 151-161, 1995; Reddy, BS Cancer Res . 57 , pp 420-425, 1997)
[문헌 1] Barry, M.A. et al., Activation of programmed cell death (apoptosis) by cisplatin, other anticancer drugs, toxins and hyperthermia. Biochem Pharmacol 40, pp 2353-2362, 1990[Patent Document 1] Barry, MA et al., Activation of programmed cell death (apoptosis) by cisplatin, other anticancer drugs, toxins and hyperthermia. Biochem Pharmacol 40 , pp 2353-2362, 1990
[문헌 2] Hickman et al., Apoptosis induced by anticancer drugs. Cancer Metastasis Rev . 11, pp121-129, 1992[Literature 2] Hickman et al., Apoptosis induced by anticancer drugs. Cancer Metastasis Rev. 11 , pp121-129, 1992
[문헌 3] Barry, M.A., et al., Biochem Pharmacol , 40, pp 2353-2362, 1990[Literature 3] Barry, MA, et al., Biochem Pharmacol. , 40 , pp 2353-2362, 1990
[문헌 4] Hickman, J.A., Cancer Metastasis Rev . 11, pp 121-129, 1992[Document 4] Hickman, JA , Cancer Metastasis Rev. 11 , pp 121-129, 1992
[문헌 5] Fesus, L., J Cell Biochem. 22, pp 151-161, 1995[Literature 5] Fesus, L., J Cell Biochem . 22 , pp 151-161, 1995
[문헌 6] Reddy, B.S. Cancer Res . 57, pp 420-425, 1997[Literature 6] Reddy, BS Cancer Res . 57 , pp 420-425, 1997
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[문헌 10] Tominaga H., Anal . Commun ., 36, pp47-50, 1999[Literature 10] Tominaga H., Anal . Commun . , 36 , pp47-50, 1999
[문헌 11] Singh NP: Microgels for estimation of DNA strand breaks, DNA protein crosslinks and apoptosis, Mutant Res 455 : 111-127, 2000[Literature 11] Singh NP: Microgels for estimation of DNA strand breaks, DNA protein crosslinks and apoptosis, Mutant Res 455: 111-127, 2000
[문헌 12] Lin SY, Liu JD, Chang HC, Yeh SD, Lin CH and Lee WS: Magnolol suppresses proliferation of cultured human colon and liver cancer cells by inhiting DNA Synthesis and activating apoptosis. J Cell Biochem 84: 532-544, 2002[Literature 12] Lin SY, Liu JD, Chang HC, Yeh SD, Lin CH and Lee WS: Magnolol suppresses proliferation of cultured human colon and liver cancer cells by inhiting DNA synthesis and activating apoptosis. J Cell Biochem 84: 532-544, 2002
[문헌 13] Lin SY, Liu JD, Chang HC, Yeh SD, Lin CH and Lee WS: Magnolol suppresses proliferation of cultured human colon and liver cancer cells by inhibiting DNA Synthesis and activating apoptosis. J Cell Biochem 84: 532-544, 2002[Literature 13] Lin SY, Liu JD, Chang HC, Yeh SD, Lin CH and Lee WS: Magnolol suppresses proliferation of cultured human colon and liver cancer cells by inhibiting DNA synthesis and activating apoptosis. J Cell Biochem 84: 532-544, 2002
[문헌 14] Kalejta, R.F., T.Shenk, and A.J.Beavia. 1997. Use of a membrane-localized green fluorescent protein allows simultaneous identification of transfected cells and cell cycle analysis by flow cytometry. Cytometry 29:286-291[14] Kalejta, R. F., T.Shenk, and A.J.Beavia. 1997. Use of a membrane-localized green fluorescent protein allows simultaneous identification of transfected cells and cell cycle analysis by flow cytometry. Cytometry 29: 286-291
[문헌 15] Koopman G., Blood, 84, pp1415-1420, 1994
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본 발명은 암세포의 세포 사멸을 유도하는 활성을 갖는 화합물을 유효 성분으로 포함하는 암 예방 및 치료용 조성물을 제공하는 것을 목적으로 한다.
The present invention provides a composition for preventing and treating cancer, which comprises, as an active ingredient, a compound having an activity of inducing apoptosis of cancer cells.
본 발명은 상기와 같은 과제를 해결하기 위하여, 본 발명은 하기 구조식 (1)로 표기되는 사이토칼라신 비(cytochalasin b)를 유효성분으로 함유하는 암 질환의 예방 및 치료를 위한 약학 조성물을 제공한다.In order to solve the above-mentioned problems, the present invention provides a pharmaceutical composition for the prevention and treatment of cancer diseases containing cytochalasin b represented by the following structural formula (1) as an active ingredient .
<화학식 1>≪ Formula 1 >
또한, 본 발명은 사이토칼라신 비(cytochalasin b), 약학적으로 허용 가능한 그의 염, 광학이성질체, 또는 다형체를 유효성분으로 함유하는 암 예방 및 치료용 건강기능식품을 제공한다.
The present invention also provides a health functional food for cancer prevention and treatment, comprising cytochalasin b, a pharmaceutically acceptable salt thereof, an optical isomer or polymorph thereof as an active ingredient.
본 발명에 의한 암 질환의 예방 및 치료를 위한 약학 조성물은 사이토칼라신 비(cytochalasin b), 약학적으로 허용 가능한 그의 염, 광학이성질체, 또는 다형체를 포함한다. The pharmaceutical composition for the prevention and treatment of cancer diseases according to the present invention includes cytochalasin b, a pharmaceutically acceptable salt thereof, an optical isomer, or a polymorph.
사이토칼라신(cytochalasin)은 곰팡이의 대사 산물로서 세포질 분열을 방해하고 세포 운동을 억제하며 핵의 배출을 일으키며, 세균 생물학의 연구에 쓰이는 것으로 알려져 있다. Cytochalasin is a metabolite of fungi that inhibits cytoplasmic breakdown, inhibits cell movement, releases nuclei, and is known to be used in the study of bacterial biology.
본 발명의 약학적으로 허용 가능한 염은, 달리 언급되지 않는 한, 본 발명의 화합물에 존재할 수 있는 산성 또는 염기성염을 포함한다. 예를 들면, 약학적으로 허용 가능한 염으로는 히드록시기의 나트륨, 칼슘 및 칼륨염이 포함되며, 아미노기의 기타 약학적으로 허용 가능한 염으로는 히드로브로마이드(hydrobromide), 황산염(sulfate), 수소 황산염(hydrogen sulfate), 인산염(phosphate), 수소 인산염(hydrogen sulfate), 이수소 인산염(dihydrogen sulfate), 아세테이트(acetate), 숙시네이트(succinate), 시트레이트(citrate), 타르트레이트(tartrate), 락테이트(lactate), 메탄설포네이트(메실레이트, methane sulfonate) 및 p-톨루엔설포네이트(토실레이트, p-toluen sulfonate)염이 있으며, 당업계에서 알려진 염의 제조방법이나 제조과정을 통하여 제조 될 수 있다.
The pharmaceutically acceptable salts of the present invention include, unless otherwise stated, acidic or basic salts which may be present in the compounds of the present invention. For example, pharmaceutically acceptable salts include the sodium, calcium, and potassium salts of the hydroxy group, and other pharmaceutically acceptable salts of the amino group include hydrobromides, sulphates, hydrogen sulphates sulfate, phosphate, hydrogen sulfate, dihydrogen sulfate, acetate, succinate, citrate, tartrate, lactate, Methane sulfonate and p-toluen sulphonate salt, and can be prepared by a method or a process for producing a salt known in the art.
본 발명의 조성물에 의한 예방 또는 치료 대상 질병인 암(cancer) 은 세포가 정상적인 성장 한계를 무시하고 분열 및 성장하는 공격적(aggressive) 특성, 주위 조직에 침투하는 침투적(invasive) 특성 및 체내의 다른 부위로 퍼지는 전이적(metastatic) 특성을 갖는 세포에 의한 질병을 총칭하는 의미이다. The cancer, which is a disease to be prevented or treated by the composition of the present invention, is an aggressive characteristic that cells ignore the normal growth limit and divide and grow, invasive characteristic penetrating into surrounding tissues, It is a generic term for diseases caused by cells with metastatic characteristics spreading to the site.
본 명세서에서 상기 암은 악성 종양(malignant tumor)과 동일한 의미로도 사용되며, 고체 종양 및 혈액 종양(blood born tumor)을 포함하고, 자궁경부암, 대장암, 소장암, 직장암, 항문암, 식도암, 췌장암, 위암, 신장암, 설암, 구강암, 피부암, 자궁암, 유방암, 임파선암, 갑상선암, 전립선암, 간암, 백혈병, 피부암, 결장암, 뇌종양, 방광암, 난소암, 또는 담낭암을 포함하며, 이에 한정되지 않는다.
In the present specification, the cancer is also used in the same sense as a malignant tumor, and includes solid tumors and blood born tumors, and can be used for treatment of cervical cancer, colon cancer, small intestine cancer, rectal cancer, But are not limited to, pancreatic cancer, stomach cancer, renal cancer, tongue cancer, oral cancer, skin cancer, uterine cancer, breast cancer, lymphoma cancer, thyroid cancer, prostate cancer, liver cancer, leukemia, skin cancer, colon cancer, brain tumor, bladder cancer, ovarian cancer, .
본 발명에 의한 상기 암 예방 및 치료용 조성물은 암세포의 세포사멸(apoptosis)를 유도하는 것을 특징으로 한다. The composition for preventing and treating cancer according to the present invention is characterized by inducing apoptosis of cancer cells.
본 발명에서 사용되는 용어 "세포사멸(아팝토시스 apoptosis)"란 세포가 유전자에 의해 제어되어 사멸하는 방법 중 하나로서, 세포의 괴사 (necrosis)와는 구별된다. 세포사멸은 이상이 생긴 세포를 제거하는 일을 수행하며, 괴사와는 달리 능동적인 사멸과정을 취한다. 다세포생물에서 유전자 발현에 의한 세포의 세포사멸은 발생과 항상성 유지를 위한 필수적 과정이다. 이 과정에서 세포 유전자의 조각화와 세포의 수축 등이 일어나며, 조각난 세포 유전자는 세포질에 싸여 작은 포낭 형태로 식세포활동에 의해 제거 (phagocytosis)된다. 따라서 세포사멸은 세포괴사 (necrosis)와는 달리 염증반응을 일으키지 않아 정상적인 발생에 중요한 기능을 수행하게 된다.As used herein, the term " apoptosis "is one of the ways in which a cell is controlled by a gene and is killed, and is distinguished from necrosis of a cell. Cell death is the process of eliminating cells with an abnormality and, unlike necrosis, takes an active process of death. Cellular apoptosis by gene expression in multicellular organisms is an essential process for development and maintenance of homeostasis. In this process, cell gene fragmentation and cell shrinkage occur. The fragmented cell gene is phagocytosed by phagocytosis in the form of a small cyst that is surrounded by the cytoplasm. Thus, apoptosis does not cause an inflammatory reaction, unlike necrosis, and thus plays an important role in normal development.
세포사멸(apoptosis)은 크게 외경로(extrinsic pathway) 혹은 사멸수용체(death receptor) 경유경로와 내경로(intrinsicpathway) 혹은 사립체(mitochondria) 경로로 대별된다. 두 경로 모두 세포사멸 과정은 caspase라 하는 세포내 cysteine protease에 의해 수행된다. Apoptosis is largely divided into extrinsic pathway or death receptor pathway and intrinsic pathway or mitochondria pathway. Both pathways are carried out by intracellular cysteine proteases called caspases.
외경로는 주로 Fas ligand 등 tumor necrosis factor 계열의 리간드가 세포 표면의 사멸수용체에 결합한 후 Fas-associated death domain (FADD) 단백질 등 연결기 단백질을 경유하여 caspase 8을 활성화시켜 세포사멸을 유발한다. 내경로는 DNA 손상 등 외적 스트레스가 가해지면 사립체 외막의 투과(permeabilization)에 의한 cytochrome-c의 유리 및 이에 수반되는 Apaf-1과 caspase-9 의 활성화에 의해 진행된다. 두가지 경로에 의해 각각 활성화되는 caspase-8 및 9는 경로 하류(down-stream)에 있는 수행 caspase (caspase-3, 6, 7)를 활성화시키며 이들은 세포단백질들을 절단하여 세포사멸을 유도한다. The extracellular pathway mainly induces apoptosis by activating caspase 8 via a linker protein such as Fas-associated death domain (FADD) protein after a ligand of tumor necrosis factor such as Fas ligand binds to a cell death receptor. When the external stress such as DNA damage is applied to the internal cavity, the cytochrome-c is released by the permeabilization of the outer membrane of the mitochondria and the subsequent activation of Apaf-1 and caspase-9. Caspase-8 and caspase-9, which are activated by two pathways, activate caspase-3 (caspase-3, caspase-6, caspase-7) in the down-stream pathway.
항암제에 의한 세포사멸 유도는 주로 내경로와 관여되는 것으로 알려져 있다. 내경로는 대부분 Bcl-2 계열 단백질에 의해 억제 혹은 활성화되는데 내경로의 활성화에 하류에서 관여하는 대표적인 단백질이 Bax이다. Induction of apoptosis by anticancer drugs is known to be mainly involved in the inner diameter route. Most of the internal pathways are inhibited or activated by Bcl-2 family proteins. Bax is a representative protein involved downstream of the activation of the internal pathway.
Bax 단백질은 주로 세포질에 존재하지만 DNA 손상 등 스트레스가 전해지면 사립체 외막으로 이동하여 이의 투과를 유발하여 cytochrome-c를 유리시켜 세포사멸을 유도한다. 즉 세포 사멸을 유도하는 것으로 알려진 Bax, Cytochrome C 단백질의 증가로 세포 사멸이 유도됨을 알 수 있으며, Bcl-2 의 단백질의 증가가 암 발생의 불량한 예후의 증거가 되고 있으므로 Bcl-2 단백질의 감소로 조기 세포사멸이 유도됨을 알 수 있다. 상기 세포사멸의 경로에 따르면 세포사멸의 경로는 내경로에 따른 Bax 단백질에 의해 의한 것임을 알 수 있다.
Bax protein is mainly present in the cytoplasm, but if stress such as DNA damage is transmitted, it migrates to the outer membrane of the mitochondria and induces permeation thereof, thereby inducing apoptosis by liberating cytochrome-c. The increase in Bcl-2 protein, which is known to induce apoptosis, is induced by apoptosis of Bcl-2 protein, and the increase of Bcl-2 protein is evidence of a poor prognosis of cancer. Early cell death is induced. According to the pathway of apoptosis, the pathway of apoptosis is caused by the Bax protein according to the inner diameter pathway.
본 발명에 의한 상기 암 예방 및 치료용 조성물은 세포 사멸의 여러 경로 중에서 DNA합성을 저해시키고, 조기 세포 사멸을 발생시키며, 산화적 스트레스를 일으키고, 미토콘드리아 막 탈분극(mitochondrial membrane depolarization)을 통하여 세포사멸(apoptosis)을 유도하는 것을 특징으로 한다.
The composition for preventing and treating cancer according to the present invention inhibits DNA synthesis in various pathways of apoptosis, causes premature cell death, induces oxidative stress, and mitochondrial membrane depolarization apoptosis.
본 발명의 사이토칼라신 비(cytochalasin b), 약학적으로 허용 가능한 그의 염, 광학이성질체, 또는 다형체는 이를 유효 성분으로 포함하는 조성물 총 중량에 대하여 0.02 내지 50 중량 % 로 포함됨을 특징으로 하는 암 예방 및 치료용 조성물을 제공한다.The cytochalasin b, pharmaceutically acceptable salt, optical isomer or polymorph thereof of the present invention is contained in an amount of 0.02 to 50% by weight based on the total weight of the composition containing it as an active ingredient. Thereby providing a composition for prevention and treatment.
본 발명의 암 예방 및 치료용 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 또는 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 제형화 과정에서 통상의 방법에 따른 적절한 담체, 부형제 또는 희석제를 더 포함할 수 있다. The composition for preventing and treating cancer according to the present invention can be formulated in the form of powders, granules, tablets, capsules, oral formulations such as suspensions, emulsions, syrups and aerosols, external preparations, suppositories, Can be used. In the formulation, it may further comprise an appropriate carrier, excipient or diluent according to a conventional method.
상세하게는, 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 제조될 수 있다. 경구투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형 제제는 상기 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose), 락토오스(lactose), 젤라틴 등을 섞어 조제될 수 있다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용될 수 있다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는 데, 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제 및 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜 (propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있다.
Specifically, in the case of formulation, it may be prepared using diluents or excipients such as fillers, extenders, binders, humectants, disintegrants, surfactants and the like which are usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose ), Lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, syrups and the like, and various excipients such as wetting agents, sweeteners, fragrances, preservatives, etc. in addition to commonly used diluents such as water and liquid paraffin . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Examples of the suppository base include witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like.
본 발명의 조성물은 암의 예방 또는 치료를 위하여 항암제 전에, 동시에 또는 차후에 투여될 수 있다. 이를 임상적인 목적으로 투여 시에 치료학적으로 유효한 양으로 투여한다. 용어 "치료학적으로 유효한 양(therapeutically effective amount)"는 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 특정 환자에 대한 유효량은 연령, 성별, 체중, 건강 상태, 투여시간, 투여 경로, 배출 비율, 약제혼합 및 질환의 중증도에 따라 변화될 수 있다.The composition of the present invention may be administered before, concurrently with, or after an anticancer agent for prevention or treatment of cancer. It is administered in a therapeutically effective amount at the time of administration for clinical purposes. The term "therapeutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and an effective amount for a particular patient will vary with the age, sex, , The time of administration, the route of administration, the rate of release, the drug mix and the severity of the disease.
본 발명의 사이토칼라신 비(cytochalasin b), 약학적으로 허용 가능한 그의 염, 광학이성질체, 또는 다형체의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 그러나, 바람직한 효과를 위해서, 본 발명의 화합물의 일일투여용량은 0.0001~100mg/kg으로, 바람직하게는 0.001~100mg/kg의 양을 일일 1회 내지 수회로 나누어 투여할 수 있다.
Preferred dosages of cytochalasin b, pharmaceutically acceptable salts, optical isomers, or polymorphs of the present invention will depend upon the condition and weight of the patient, the severity of the condition, the drug form, But may be suitably selected by those skilled in the art. However, for the desired effect, the daily dose of the compound of the present invention may be administered in an amount of 0.0001 to 100 mg / kg, preferably 0.001 to 100 mg / kg, once or several times a day.
또한, 본 발명의 사이토칼라신 비(cytochalasin b), 약학적으로 허용 가능한 그의 염, 광학이성질체, 또는 다형체의 약학적 투여 형태는 이들의 약학적 허용 가능한 염의 형태로도 사용될 수 있고, 또한 단독으로 또는 타 약학적 활성 화합물과 결합뿐만 아니라 적당한 집합으로 사용될 수 있다. 즉, 상기 암 예방 및 치료용 약학 조성물은 제 2의 항암제를 추가로 포함할 수 있다.In addition, the pharmaceutical dosage forms of the cytochalasin b, pharmaceutically acceptable salts, optical isomers, or polymorphs of the present invention may be used in the form of their pharmaceutically acceptable salts, As well as in combination with other pharmacologically active compounds. That is, the pharmaceutical composition for cancer prevention and treatment may further comprise a second anticancer agent.
제 2의 항암제로는 인터페론(interferon), 인터루킨-2(interleukin-2), 파클리탁셀(paclitaxel), 빈크리스틴(vincristine), 빈블라스틴(vinblastin), 독소루비신(doxorubicin), 에토포시드(etoposide), 이리노테칸 히드로클로라이드(irinotecan hydrochloride), 시스플라틴(cisplatin), 암사크린(amsacrine), 사이토신 아라비노시드(cytosine arabinoside), 플루오로우라실(fluoro uracil) 또는 탁솔 중에서 선택된 하나 이상을 추가할 수 있다. 그러나, 항암효과를 목적으로 하는 본 발명에 따른 사이토칼라신 비(cytochalasin b), 약학적으로 허용 가능한 그의 염, 광학이성질체, 또는 다형체를 함유하는 제제는 상기 기술된 것으로 제한되는 것은 아니며, 암의 치료나 예방에 유용한 제제라면 어떠한 것도 포함될 수 있다.
Examples of the second anticancer agent include interferon, interleukin-2, paclitaxel, vincristine, vinblastin, doxorubicin, etoposide, One or more selected from the group consisting of irinotecan hydrochloride, cisplatin, amsacrine, cytosine arabinoside, fluoro uracil or taxol may be added. However, preparations containing cytochalasin b, a pharmaceutically acceptable salt thereof, an optical isomer, or a polymorph according to the present invention for the purpose of anticancer effect are not limited to those described above, Or any agent useful for the treatment or prevention of < / RTI >
또한, 본 발명에서는 사이토칼라신 비(cytochalasin b), 약학적으로 허용 가능한 그의 염, 광학이성질체, 또는 다형체와 식품학적으로 허용 가능한 식품 보조 첨가제를 포함하는 암 예방 및 치료용 건강기능식품을 제공한다. In addition, the present invention provides a health functional food for cancer prevention and treatment, including cytochalasin b, a pharmaceutically acceptable salt thereof, an optical isomer, or a polymorph and a food-acceptable food-aid additive do.
본 발명에서 정의되는 건강기능식품은 건강기능식품에 관한 법률 제6727호에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 의미하며, 기능이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미한다.The health functional food defined in the present invention means a food prepared and processed by using a raw material or ingredient having a useful function in the human body according to the Health Functional Food No. 6727. The function refers to the structure and function of the human body To be used for the purpose of obtaining a beneficial effect for health use such as controlling nutrients or physiological action.
본 발명의 암 예방 및 치료용 건강기능식품은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 또는 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 제형화 과정에서 통상의 방법에 따른 적절한 담체, 부형제 또는 희석제를 더 포함할 수 있다. 본 발명의 사이토칼라신 비(cytochalasin b), 약학적으로 허용 가능한 그의 염, 광학이성질체, 또는 다형체는 독성 및 부작용은 거의 없으므로 예방 목적으로 장기간 복용 시에도 안심하고 사용할 수 있다. 따라서, 사이토칼라신 비(cytochalasin b), 약학적으로 허용 가능한 그의 염, 광학이성질체, 또는 다형체를 유효성분으로 포함하는 조성물은 암 예방 및 치료용 약제, 식품 및 음료 등의 건강기능식품에 다양하게 이용될 수 있다.The health functional food for cancer prevention and treatment according to the present invention may be formulated into oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups and aerosols, external preparations, suppositories or sterilized injection solutions Can be used. In the formulation, it may further comprise an appropriate carrier, excipient or diluent according to a conventional method. The cytochalasin b, pharmaceutically acceptable salts, optical isomers, or polymorphs of the present invention have little toxicity and side effects, so that they can be safely used for prophylactic purposes over a long period of time. Accordingly, a composition comprising cytochalasin b, a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a polymorph thereof as an active ingredient can be applied to a variety of health functional foods such as medicines for cancer prevention and treatment, foods and beverages Lt; / RTI >
본 발명의 건강기능식품에 첨가할 수 있는 식품으로는, 예를 들어, 각종 식품류, 음료, 껌, 차, 비타민 복합제, 건강보조 식품류 등이 있고, 분말, 과립, 정제, 캡슐 또는 음료인 형태로 사용할 수 있다.Examples of foods that can be added to the health functional foods of the present invention include various foods, beverages, gums, tea, vitamin complexes, health supplements, and the like, and may be in the form of powders, granules, tablets, Can be used.
이때, 식품 또는 음료 중의 상기 화합물의 양은 일반적으로 본 발명의 건강식품 조성물은 전체 식품 중량의 0.01 내지 15 중량%로 가할 수 있으며, 건강 음료 조성물은 100 ㎖를 기준으로 0.02 내지 10 g, 바람직하게는 0.3 내지 1 g의 비율로 가할 수 있다.At this time, the amount of the compound in the food or beverage is generally 0.01 to 15% by weight of the total food weight of the health food composition of the present invention, and 0.02 to 10 g, Can be added in a proportion of 0.3 to 1 g.
본 발명의 건강 음료 조성물은 지시된 비율로 필수 성분으로서 상기 사이토칼라신 비(cytochalasin b), 약학적으로 허용 가능한 그의 염, 광학이성질체, 또는 다형체 외의 액체성분에는 특별한 제한점은 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등의 디사카라이드, 예를 들어 말토스, 슈크로스 등의 및 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진등) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 ㎖당 일반적으로 약 1 내지 20g, 바람직하게는 약 5 내지 12 g이다.The health beverage composition of the present invention has no particular limitation on the cytochalasin b, its pharmaceutically acceptable salt, optical isomer, or polymorphic liquid component as an essential ingredient in the indicated ratios, As well as various flavors or natural carbohydrates as an additional ingredient. Examples of the above-mentioned natural carbohydrates include monosaccharides such as disaccharides such as glucose and fructose such as maltose, sucrose and the like and polysaccharides such as dextrin, cyclodextrin and the like Sugar, and sugar alcohols such as xylitol, sorbitol, and erythritol. Natural flavors (tau martin, stevia extracts (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavors (saccharin, aspartame, etc.) can be advantageously used as flavors other than those described above The ratio of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 ml of the composition of the present invention.
상기 외에 본 발명의 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그밖에 본 발명의 조성물들은 천연 과일 쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 그렇게 중요하진 않지만 본 발명의 조성물 100 중량부 당 0 내지 약 20 중량부의 범위에서 선택되는 것이 일반적이다.
In addition to the above-mentioned composition, the composition of the present invention can be used as a flavoring agent such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, coloring agents and intermediates (cheese, chocolate etc.), pectic acid and its salts, Salts, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated beverages and the like. In addition, the compositions of the present invention may contain flesh for the production of natural fruit juices and fruit juice drinks and vegetable drinks. These components may be used independently or in combination. The proportion of such additives is not so critical, but is generally selected in the range of 0 to about 20 parts by weight per 100 parts by weight of the composition of the present invention.
본 발명의 사이토칼라신 비(cytochalasin b)를 유효 성분으로 함유하는 조성물은 미토콘드리아의 탈분극을 유도하며, DNA 합성을 저해하고, 조기 세포 사멸을 발생시켜 세포사멸(apoptosis)을 유도하고, 세포 성장의 저해를 나타냄으로서, 암의 예방 및 치료에 유용하게 사용될 수 있다.
The composition containing the cytochalasin b of the present invention as an active ingredient induces depolarization of mitochondria, inhibits DNA synthesis, induces apoptosis by inducing apoptosis, By inhibiting it, it can be usefully used for prevention and treatment of cancer.
도 1은 사람의 자궁경부암 HeLa 세포주의 생존에 미치는 사이토칼라신 비(cytochalasin b)의 독성효과를 나타낸 도이다.
도 2는 유세포 분석기를 이용한 사이토칼라신 비(cytochalasin b)의 HeLa 자궁암 세포사멸의 발생 및 세포주기를 분석한 도이다.
도 3은 HeLa 자궁암 세포에서 사이토칼라신 비(cytochalasin b)가 DNA합성을 저해시키는지 여부를 [H]Thymidine incorporation 측정법에 의하여 분석한 결과도이다.
도 4는 유세포 분석기를 이용한 사이토칼라신 비(cytochalasin b)가 조기 세포 사멸을 발생시키는지 여부를 분석한 도이다.
도 5는 유세포 분석기를 이용한 사이토칼라신 비(cytochalasin b)의 산화적 스트레스로 인해 세포 사멸을 유도하는지 확인한 도이다.
도 6은 사이토칼라신 비(cytochalasin b)의 미토콘드리아 막 탈분극(mitochondrial membrane depolarization)을 통하여 세포사멸(apoptosis)을 유도하는지 확인한 도이다.1 is a diagram showing the toxic effect of cytochalasin b on the survival of human cervical cancer HeLa cell line.
2 is an analysis of the development and cell cycle of HeLa cervical cancer cell death of cytochalasin b using a flow cytometer.
FIG. 3 shows the result of analysis of [H] Thymidine incorporation assay to determine whether cytochalasin b inhibits DNA synthesis in HeLa cervical cancer cells.
FIG. 4 is an analysis of whether or not cytochalasin b using the flow cytometry analyzer causes premature cell death. FIG.
FIG. 5 is a graph showing the induction of apoptosis due to oxidative stress of cytochalasin b using a flow cytometer.
FIG. 6 is a graph showing the induction of apoptosis through mitochondrial membrane depolarization of cytochalasin b.
이하, 본 발명을 하기 실시예에 의거하여 좀 더 상세하게 설명하고자 한다. 단, 하기 실시예는 본 발명을 예시하기 위한 것일 뿐, 본 발명의 범위가 이들만으로 제한되는 것은 아니다.
Hereinafter, the present invention will be described in more detail based on the following examples. However, the following examples are intended to illustrate the present invention, but the scope of the present invention is not limited thereto.
참고예Reference example 1. 실험 준비 및 기기 1. Experimental preparation and instrument
1-1. 분석기기1-1. Analytical instrument
본 실험에서 얻은 생성물의 구조 확인을 위해 사용된 기기는 하기와 같다. 핵자기 공명 스펙트럼 (1H NMR, 13C NMR) 은 400MHz 를, 용매는 CDCl3, DMSO-d 6 를 사용하였다. 짝지음(Coupling) 상수 (J)는 Hz로 표시하였다. 질량(Mass)은 m/z 형태로 표시하였다.
The equipment used to identify the structure of the product obtained in this experiment is as follows. The nuclear magnetic resonance spectrum ( 1 H NMR, 13 C NMR) was 400 MHz and the solvents were CDCl 3 and DMSO- d 6 . The coupling constant ( J ) is expressed in Hz. The mass was expressed in m / z form.
1-2. 1-2. TLCTLC 및 And 관크로마토그래피Tube chromatography
YMC ODS-H80 column (250 X 10 mm, 4 mm, 80 Å) 과 C18-5E Shodex packed column (250 X 10 mm, 5 mm, 100Å), Shodex RI-71 검출기를 사용하였다.YMC ODS-H80 column (250 × 10 mm, 4 mm, 80 Å), C18-5E Shodex packed column (250 × 10 mm, 5 mm, 100 Å) and Shodex RI-71 detector were used.
TLC (Thin layer chromatography)는 E. Merck 사 제품인 실리카겔(Merck F254)을 사용하였으며 관크로마토그래피(Column chromatography)를 위해서는 실리카(Merck EM9385, 230-400 mesh)를 사용하였다. 또한, TLC 상에서 분리된 물질을 확인하기 위해서 UV 램프(= 254 nm)를 이용하거나 아니스알데히드(Anisaldehyde), 과망간산칼륨(KMnO4) 발색 시약에 담근 후, 플레이트를 가열하여 확인하였다.
Silica gel (Merck F254) from E. Merck was used for thin layer chromatography (TLC) and silica (Merck EM9385, 230-400 mesh) was used for column chromatography. Further, in order to identify the substance separated on the TLC, the plate was heated by UV lamp (= 254 nm) or immersed in anisaldehyde, potassium permanganate (KMnO 4 ) color development reagent, and the plate was confirmed by heating.
1-3. 사용 시약1-3. Use reagent
본 실험에서 사용된 시약은 시그마-알드리치(Sigma-Aldrich), 란캐스터(Lancaster), 플루카(Fluka) 제품을 구입하여 사용하였으며, 반응에 사용된 용매는 시그마-알드리치(Sigma-Aldrich), 머크(Merck), 준세이 화학(Junsei Chemical Co.) 제품의 1급 시약을 정제 없이 사용하였다. 용매에 사용한 THF는 아르곤 기류에서 Na 금속과 벤조페논(Benzophenone)을 넣고 가열환류하여 청색으로 되었을 때 사용하였다. 또한, 디클로로메탄(CH2Cl2) 은 아르곤 기류에서 CaH2 를 넣고 가열환류하여 사용하였다. 에틸아세테이트와 헥산은 아르곤 기류에서 가열환류하여 정제하여 사용하였다. Sigma-Aldrich, Lancaster and Fluka were purchased from Sigma-Aldrich and Merck. The solvents used in the reaction were Sigma-Aldrich, (Merck) and Junsei Chemical Co. (1) were used without purification. The THF used in the solvent was used when the Na metal and benzophenone were added in the argon stream and the solution became blue by heating under reflux. Dichloromethane (CH 2 Cl 2 ) was obtained by adding CaH 2 in an argon stream and heating and refluxing. Ethyl acetate and hexane were purified by refluxing in an argon stream and used.
본 실험에서 사용된 시약은 시그마-알드리치(Sigma-Aldrich) 제품을 구입하여 사용하였으며 정제없이 사용하였다.
The reagents used in this experiment were purchased from Sigma-Aldrich and used without purification.
실시예Example 1. One. 사이토칼라신Cytochalasin 비( ratio( cytochalasincytochalasin b) 화합물의 분리 및 정제 b) Separation and purification of the compound
사이토칼라신 비(cytochalasin b) 화합물은 부산대학교 정지형 교수팀으로부터 제공받았다. 화합물은 DMSO에 용해시킨 후 -20℃에 보관하여 사용하였다. 그리고 모든 실험이 수행되기 전 샘플은 즉시 희석하여 사용하였다.
The cytochalasin b compound was provided by Prof. Seong-Hyung Kim of Pusan National University. The compounds were dissolved in DMSO and stored at -20 ° C. The samples were immediately diluted before all experiments were performed.
참고예Reference example 2. 세포배양 2. Cell culture
본 실험에 사용된 우 태아 혈청(fetal bovine serum; FBS), 100% 페니실린(penicillin)/스트렙토마이신(streptomycin)은 하이크론 연구소(Hyclone Laboratories, Logan, UT)에서 구입하였고, EMEM 배지(Eagle's minimum essential medium)는 Gibco-BRL(Gaithersburg, MD, USA)에서 구입하였으며 CCK-8은 도찐 연구소(Dojin Laboratories, Osaka, Japan)로부터 구입하였다. Fetal bovine serum (FBS), 100% penicillin / streptomycin used in this experiment were purchased from Hyclone Laboratories (Logan, UT), and EMEM medium (Eagle's minimum essential medium was purchased from Gibco-BRL (Gaithersburg, MD, USA) and CCK-8 was purchased from Dojin Laboratories, Osaka, Japan.
본 실험에 사용된 암 세포주로 자궁경부암(cervical carcinoma)세포인 HeLa 세포는 ATCC(American Type Culture Collection)로부터 분양받아 사용하였다. HeLa cells, cervical carcinoma cells, were used from the American Type Culture Collection (ATCC).
HeLa는 10% FBS와 1% 페니실린(penicillin)/스트렙토마이신(streptomycin)을 EMEM 배지(Eagle's minimum essential medium)에 첨가하여 37℃, 5% CO2 배양기(incubator; Forma Co., U.S.A.)에서 배양하였다.
HeLa was added to EMEM medium (Eagle's minimum essential medium) supplemented with 10% FBS and 1% penicillin / streptomycin and incubated at 37 ° C in a 5% CO 2 incubator (Forma Co., USA) .
이하 본 실험예에서 "세포"란 본 실험에 사용된 암 세포주로서 자궁경부암 세포인 HeLa세포를 말한다.
Hereinafter, the term "cell" used herein refers to a cervical cancer cell, HeLa cell, used in the present experiment.
실험예Experimental Example 1. 세포 1. Cells 생존률Survival rate 측정 Measure
5x104 세포/ml의 세포부유물을 96-웰(well) 바닥이 평편한 마이크로타이터 판(flat-bottom microtiter plates; Nalgen Nunc International, Tokyo)의 각 웰(well)에 100 μl씩 접종하고 24 시간 동안 배양시킨 후, 여러 가지의 농도의 cytochalasin b를 포함하고 있는 배지로 교체한 후, 다시 48 시간 배양시켰다. 그 후 살아있는 세포를 측정하기 위하여 수용성 테트라졸리움 염에 기초한 독성 분석(water-soluble tetrazolium salt based cytotoxic assay)을 수행하였다. 10 ㎕의 세포 카운팅 키트 용액(Cell Counting Kit solution; WST-8)을 각각의 웰(well)에 첨가한 후 3시간 동안 37℃에서 배양하였다. 살아있는 세포의 경우 노란색을 나타내는 2-(2-메톡시(methoxy)-4-니트로페닐(nitrophenyl))-3-(4-니트로페닐 (nitrophenyl))-5-(2,4-디설포페닐(disulfophenyl))-2H-테트라졸리움(tetrazolium) (WST-8)을 오렌지색의 포마쟌 염색시약(formazan dye)으로 색을 변화시키며 이를 450 nm에서 멀티 마이크로플레이트 판독기(multi microplate reader; synergy HT, BIO-TEK를 이용하여 흡광도를 측정하여 그 결과를 도 1에 나타내었다. Cell suspensions of 5 x 10 4 cells / ml were inoculated into each well of 96-well flat-bottom microtiter plates (Nalgen Nunc International, Tokyo) in a volume of 100 μl, And then cultured for 48 hours. The medium was replaced with medium containing various concentrations of cytochalasin b. After that, a water-soluble tetrazolium salt based cytotoxic assay was performed to measure living cells. 10 [mu] l of Cell Counting Kit solution (WST-8) was added to each well and incubated at 37 [deg.] C for 3 hours. In the case of living cells, 2- (2-methoxy-4-nitrophenyl) -3- (4-nitrophenyl) -5- (2,4-disulfophenyl disulfophenyl) -2H-tetrazolium (WST-8) was transformed into orange with a formazan dye, which was then applied to a micro microplate reader (synergy HT, BIO- TEK , And the results are shown in Fig.
도 1에서 나타내는 바와 같이, 사이토칼라신 비(cytochalasin b)는 농도 의존적으로 세포의 생존률을 감소시켰다. 50%의 세포독성을 보이는 농도인 IC50 (50% Inhibition concentration)은 8 μM을 나타내었다.
As shown in Fig. 1, cytochalasin b decreased the survival rate of cells in a concentration-dependent manner. IC 50 < RTI ID = 0.0 > (50% inhibition concentration) was 8 μM.
실험예Experimental Example 2. 세포 주기 저해 여부 분석 2. Cell cycle inhibition analysis
본 발명의 사이토칼라신 비(cytochalasin b)가 세포 주기 저해를 유도하는지 여부를 확인하기 위하여 하기와 같이 문헌에 개시된 실험방법을 응용하여 실험하였다(Kalejta, R.F., T.Shenk, and A.J.Beavia. 1997. Use of a membrane-localized green fluorescent protein allows simultaneous identification of transfected cells and cell cycle analysis by flow cytometry. Cytometry 29:286-291).
In order to confirm whether or not the cytochalasin b of the present invention induces cell cycle inhibition, the experiment described in the literature was applied (Kalejta, RF, T.Shenk, and AJ Beavia 1997. Use of a membrane-localized green fluorescent protein allows simultaneous identification of transfected cells and cell cycle analysis by flow cytometry. Cytometry 29: 286-291).
60 mm-dish에 5x105 세포/ml의 농도로 24 시간 배양된 HeLa 세포에 8μM cytochalasin b를 포함하는 새로운 배지로 교체한 후 각기 다른 시간대에 트립신 처리(trypsinization)를 이용하여 세포를 모았다. 그리고 원심분리를 이용하여 세포 부유액을 차가운 인산 완충용액(PBS)으로 3회 세척한 후 4℃에서 70% 에탄올(v/v)에 1시간 이상 고정하였다. 이후, 다시 차가운 인산 완충용액(PBS)으로 원심분리를 통하여 세척된 세포는 PI/RNase 염색 완충제(550825, staining buffer; BD PharMingen)로 15분 동안 4℃에서 배양하였다. 이를 세포주기에 따른 DNA의 함량을 알아보기 위하여 FACScalibur (Becton Dickinson) 유세포 분석 시스템(flow cytometry system)의 CellQuest 소프트웨어를 사용하여 20,000개의 세포를 각각 측정하였다. Cells were harvested by trypsinization at different times after replacing HeLa cells cultured for 24 h at a concentration of 5x10 5 cells / ml in a 60 mm-dish with fresh medium containing 8 μM cytochalasin b. The cell suspension was washed three times with cold phosphate buffer solution (PBS) using centrifugation, and fixed in 70% ethanol (v / v) for 1 hour at 4 ° C. Cells washed with cold phosphate buffer solution (PBS) were then incubated with PI / RNase staining buffer (550825, BD PharMingen) for 15 min at 4 ° C. To determine the content of DNA according to the cell cycle, 20,000 cells were measured using the CellQuest software of a flow cytometry system (FACScalibur (Becton Dickinson)).
결과는 ModFit LT 2.0 소프트웨어(verity Software House, Topsham, ME, USA)를 이용하여 분석되었다. Cytochalasin b로 처리된 HeLa 암세포의 DNA를 프로피디움 요오드화물(propidium iodide, PI)로 염색을 하여 유세포분석기(flow cytometry)로 확인 및 분석한 결과를 도 2에 나타내었다. Results were analyzed using ModFit LT 2.0 software (verity Software House, Topsham, ME, USA). The DNA of HeLa cancer cells treated with Cytochalasin b was stained with propidium iodide (PI) and identified by flow cytometry and analyzed. The results are shown in FIG.
도 2는 세포주기인 G0/G1, S, 그리고 G2 기를 %로 나타내어졌으며 이 결과들은 각각 20,000개의 세포에 대한 분석결과이다. 도 2에서 보이는 바와 같이, 왼쪽은 대조군, 오른쪽은 8μM의 화합물을 처리한 실험군으로, 실험군에서는 12시간, 24시간, 36시간, 48시간이 지났을 때, G2/S phase arrest가 관찰되었으므로 이 화합물은 세포주기저해를 유도함을 확인할 수 있었다.
Figure 2 shows the cell cycle G0 / G1, S, and G2% in%, and these results are the result of analysis of 20,000 cells, respectively. As shown in FIG. 2, since the G2 / S phase arrest was observed at 12 hours, 24 hours, 36 hours, and 48 hours after administration in the test group treated with 8 μM of the compound on the left side and the control group on the left side, Inducing cell cycle inhibition.
실험예Experimental Example 3. [ 3. [ 33 H]H] ThymidineThymidine incorporationincorporation 측정법 Measurement method
본 발명의 사이토칼라신 비(cytochalasin b)가 DNA 합성에 미치는 영향을 확인하기 위하여 [3H]Thymidine incorporation 측정법을 하기와 같이 문헌에 개시된 실험방법을 응용하여 실험하였다( Lin SY, Liu JD, Chang HC, Yeh SD, Lin CH and Lee WS: Magnolol suppresses proliferation of cultured human colon and liver cancer cells by inhibiting DNA Synthesis and activating apoptosis. J Cell Biochem 84: 532-544, 2002).
In order to confirm the effect of cytochalasin b of the present invention on the DNA synthesis, [ 3 H] Thymidine incorporation assay was performed by applying the experimental method described in the literature (Lin SY, Liu JD, Chang HC, Yeh SD, Lin CH and Lee WS: Magnolol suppresses proliferation of cultured human colon and liver cancer cells by inhibiting DNA synthesis and activating apoptosis J Cell Biochem 84: 532-544, 2002).
0.5x105 세포를 12-웰(well)의 바닥이 평편한 마이크로타이터 판(flat-bottom microtiter plates; Nalgen Nunc International, Tokyo)에 각각 분주하여 24 시간 동안 배양시킨 후, 8 μM의 cytochalasin b를 포함하는 새로운 배지로 교체한 후, 다시 24 시간과 48 시간 동안 각각 배양시켰다. 0.5 × 10 5 cells were plated in 12-well flat-bottom microtiter plates (Nalgen Nunc International, Tokyo) and incubated for 24 hours. Subsequently, 8 μM of cytochalasin b , And cultured again for 24 hours and 48 hours, respectively.
그 후 각 웰에 있는 세포의 복제능을 알아보기 위하여 살아있는 세포를 측정하기 위해 동위원소인 삼중수소로 대체되어 있는 티미딘([3H]dTTP)을 1μCi/ml로 가한 후, 3시간을 더 배양하였다. 그리고, 각 웰에 있는 세포들은 트립신 처리에 의하여 모아졌으며, 차가운 인산 완충용액(PBS)으로 세척되었다. 원심분리를 통하여 모아진 세포는 5% TCA(tricholoracetic acid)로 다시 부유시켜 얼음에 30분 동안 놓아둔 후 다시 인산 완충용액(PBS)으로 세척하였다. 중수소의 티미딘과 복제에 의해 새로이 결합한 DNA는 세포용해 완충용액에 의하여 추출된 후, 산-불용성 방사능(acid-insoluble radioactivity)측정법(Lin SY, Liu JD, Chang HC, Yeh SD, Lin CH and Lee WS: Magnolol suppresses proliferation of cultured human colon and liver cancer cells by inhibiting DNA Synthesis and activating apoptosis. J Cell Biochem 84: 532-544, 2002)에 의하여 Tri-carb 2000CA scintillation counter(Tri-carb 2000CA scintillation counter, Packard, Groningen, The Netherlands)(Packard, Groningen, The Netherlands)로 측정하여 도 3에 나타내었다.Then, in order to measure the viability of the cells in each well, 1 μCi / ml of thymidine ([ 3 H] dTTP), which is replaced by isotope tritium, was added to measure living cells. Lt; / RTI > Cells in each well were collected by trypsinization and washed with cold phosphate buffered saline (PBS). Cells collected by centrifugation were floated again with 5% TCA (tricholoracetic acid), placed on ice for 30 minutes, and washed again with phosphate buffered saline (PBS). The DNA newly bound by the replication with deuterium deuterium was extracted by a cell lysis buffer and then analyzed by acid-insoluble radioactivity (Lin SY, Liu JD, Chang HC, Yeh SD, Lin CH and Lee Carb 2000CA scintillation counter (Packard, St. Louis, MO) according to the following protocol: WS: Magnolol suppresses proliferation of cultured human colon and liver cancer cells by inhibiting DNA synthesis and activating apoptosis. J Cell Biochem 84: 532-544, Groningen, The Netherlands) (Packard, Groningen, The Netherlands).
도 3에서 보는 바와 같이 HeLa 암세포의 DNA 합성은 24시간 후엔 약 50%, 48시간 후엔 약 70% 의 저해를 보였다.
As shown in FIG. 3, the DNA synthesis of HeLa cancer cells showed about 50% inhibition after 24 hours and about 70% after 48 hours.
실험예Experimental Example 4. 4. 아넥신Annexin V와 V and PIPI 염색을 이용한 세포사멸(Cell death using staining apoptosisapoptosis ) 분석) analysis
세포사멸의 특징 중의 하나는 세포막을 이루는 지질인 포스파티딜세린(phosphatidylserine)의 세포 외부로의 노출이다. 이는 세포사멸 과정 중에서 DNA의 단편화 이전에 일어나는 현상이므로 포스파티딜세린(phosphatidylserine)의 노출 여부가 조기 세포사멸(early apoptosis)을 알아내는 지표로 이용된다.
One of the features of apoptosis is the extracellular exposure of phosphatidylserine, which is the lipid of cell membrane. This is a phenomenon that occurs prior to DNA fragmentation in the cell death process, so that exposure to phosphatidylserine is used as an index to detect early apoptosis.
본 발명의 사이토칼라신 비(cytochalasin b)가 세포 사멸을 유도하는 여부를 알아보기 위하여 아넥신 V와 PI염색을 이용한 세포사멸(apoptosis) 분석을 하기와 같이 문헌에 개시된 실험방법을 응용하여 실험하였다(Koopman G., Blood, 84, pp1415-1420, 1994).
In order to determine whether cytochalasin b of the present invention induces apoptosis, apoptosis analysis using annexin V and PI staining was performed using the experimental method disclosed in the literature (Koopman G., Blood , 84 , pp 1415-1420, 1994).
60 mm-dish에 2x105 세포/ml의 농도로 24 시간 배양된 HeLa 세포에 8 μM의 사이토칼라신 비(cytochalasin b)를 포함한 새로운 배지로 각각 교체한 후 각기 다른 시간대에 따라 트립신 처리(trypsinization)를 이용하여 세포를 모았다. 그리고, 원심분리를 이용하여 세포 부유액을 인산 완충용액(PBS)으로 세척한 후 세포 펠렛(pellet)을 100 ㎕의 결합완충용액(binding buffer)에 부유시킨 다음 5 ㎕의 annexin V-FITC (556419, BD PharMingen) (BD PharMingen)와 10 ㎕의 PI (50 ㎍/ml)를 가한 후 실온(15~25℃)의 어두운 곳에서 15분간 염색한다. 그리고 이 세포들은 488nm의 여기파장의 FACScalibur 유세포분석기(FACScalibur-기기모델, BD Bioscience)를 이용하여 측정하고 이(BD Instruments)에 제공된 프로그램에 의하여 분석된 결과를 도 4에 나타내었다. HeLa cells cultured for 24 hours at a concentration of 2 × 10 5 cells / ml in a 60-mm dish were replaced with fresh medium containing 8 μM cytochalasin b, and trypsinization was performed at different time intervals. To collect cells. The cell suspension was washed with phosphate buffered saline (PBS) using centrifugation, the cell pellet was suspended in 100 μl of binding buffer, and 5 μl of annexin V-FITC (556419, BD PharMingen (BD PharMingen) and 10 μl of PI (50 μg / ml), and then stained in the dark at room temperature (15-25 ° C) for 15 minutes. These cells were measured using a FACScalibur flow cytometer (FACScalibur-device model, BD Bioscience) at an excitation wavelength of 488 nm, and the results analyzed by the program provided in BD Instruments are shown in FIG.
도 4에서 보는 바와 같이, 왼쪽의 대조군에 비해서 8 μM의 사이토칼라신 비(cytochalasin b)를 처리한 결과를 나타내는 오른쪽에서 48시간 후에 조기 세포사멸이 증가하는 것을 확인할 수 있으며, 이러한 결과로부터 본 발명의 조성물이 세포 사멸을 유도한다는 것을 확인하였다.
As shown in FIG. 4, it can be seen that apoptosis is increased 48 hours after the right side of the result of treatment with cytochalasin b of 8 μM compared to the control group on the left. From these results, ≪ / RTI > induces apoptosis.
실험예Experimental Example 5. 활성 5. Active 산소종(reactive oxygen species, ROS)을Reactive oxygen species (ROS) 이용한 세포 사멸( Cell death using apoptosisapoptosis ) 유도 확인) Induction confirmation
활성 산소종(reactive oxygen species, ROS)의 발생으로 인해 산화 환원의 균형이 무너져 산화적 스트레스가 일어나는데 이 때 미토콘드리아 막 포텐셜(mitochondrial membrane potential)이 감소하고 세포 사멸을 유도하게 된다.
The production of reactive oxygen species (ROS) destroys the balance of redox and oxidative stress, which causes mitochondrial membrane potential to decrease and induce apoptosis.
본 발명의 사이토칼라신 비(cytochalasin b)가 산화적 스트레스로 인해 세포 사멸을 유도하는지 여부를 확인하기 위하여 하기와 같이 문헌에 개시된 실험방법을 응용하여 실험하였다.(Manjari Chaudhari, R. Jayaraj, A.S.B Bhaskar, P.V. Lakshmana Rao : Oxidative stress induction by T-2 toxin causes DNA damage and triggers apoptosis via caspase pathway in human cervical cancer cells Toxicology 262(2009) 153-161)
In order to confirm whether cytochalasin b of the present invention induces apoptosis due to oxidative stress, experiments were carried out as described below (Manjari Chaudhari, R. Jayaraj, ASB Bhaskar, PV Lakshmana Rao: Oxidative stress induction by T-2 toxin causes DNA damage and triggers apoptosis via caspase pathway in human cervical cancer cells Toxicology 262 (2009) 153-161)
60 mm-dish에 1x105 세포/ml의 농도로 24 시간 배양된 HeLa 세포에 8μM cytochalasin b를 포함하는 새로운 배지로 교체한 후 각기 다른 시간대(0, 1, 2, 3, 4, 6hr)에 트립신 처리(trypsinization)를 이용하여 세포를 모았다. 그리고, 원심분리를 이용하여 세포 부유액을 인산 완충용액(PBS)으로 세척한 후 새 PBS에 2 ㎕ H2DCFDA를 가한 후 37℃의 어두운 곳에서 5분에 한 번씩 섞으면서 30분 간 염색한다. 유세포분석기(flow cytometry)로 확인 및 분석한 결과를 도 5에 나타내었다. HeLa cells cultured for 24 hours at a concentration of 1 × 10 5 cells / ml in a 60-mm dish were replaced with fresh medium containing 8 μM cytochalasin b and incubated at different time points (0, 1, 2, 3, 4, Cells were harvested using trypsinization. After washing the cell suspension with phosphate buffered saline (PBS) using centrifugation, add 2 μl of H 2 DCFDA to fresh PBS, and stain for 30 minutes in the dark at 37 ° C for 5 minutes. The results confirmed by flow cytometry and analyzed are shown in FIG.
도 5에서 보는 바와 같이, 8 μM의 사이토칼라신 비(cytochalasin b)를 처리하였을 때 3시간 후의 결과가 가장 형광 밀도가 높았다. 이 결과를 통해 본 발명의 조성물이 활성 산소종 생성을 유도하는 것을 알 수 있었다.
As shown in FIG. 5, when the cytochalasin b of 8 μM was treated, the fluorescence intensity was the highest after 3 hours. From these results, it was found that the composition of the present invention induces the production of active oxygen species.
실험예Experimental Example
6. 미토콘드리아 막 탈분극( 6. Mitochondrial membrane depolarization (
MitochondrialMitochondrial
MembraneMembrane
DepolarizationDepolarization
)에 의한 세포사멸(Cell death by
apoptosisapoptosis
) 유도 확인) Induction confirmation
미토콘드리아 막 탈분극(Mitochondrial Membrane Depolarization)은 세포사멸과 연관이 있다. Mitochondrial membrane depolarization is associated with apoptosis.
Rhodamine 123을 형광 물질로 사용하여 탈분극을 확인 할 수 있다. 정상 세포일 경우, 미토콘드리아 매트릭스가 미토콘드리아 막 분극(Mitochondrial Membrane Polarization)으로 인해 rhodamine 123을 빨리 격리시켜 미토콘드리아 안에서 강한 형광을 발생하게 한다. 하지만 세포 사멸이 일어난 세포인 경우, 미토콘드리아 막이 붕괴 되어 탈분극이 일어나고 미토콘드리아 침투 전이 기공(Mitochondrial Permeability Transition Pores, MPTP)이 열리면서 안에 있던 rhodamine 123이 밖으로 방출되어 형광의 세기가 정상 세포보다 약해진다.
Rhodamine 123 can be used as a fluorescent substance to confirm depolarization. In normal cells, the mitochondrial matrix rapidly isolates rhodamine 123 by mitochondrial membrane polarization, resulting in strong fluorescence in the mitochondria. However, in the case of apoptotic cells, the mitochondrial membrane collapses and depolarization occurs, and the mitochondrial permeability transition (MPTP) opens, releasing the rhodamine 123 from inside the cell, resulting in weaker fluorescence than normal cells.
본 발명의 사이토칼라신 비(cytochalasin b)의 미토콘드리아 막 탈분극(mitochondrial membrane depolarization)으로 인해 세포 사멸이 일어났는지의 여부를 확인하기 위하여 하기와 같이 문헌에 개시된 실험방법을 응용하여 실험하였다.(Yashu WANG, Linhong DENG, Hongzhe ZHONG, Yajie WANG, Xuemei JIANG, and Jun CHEN : Natural Plant Extract Tubeimoside I Promotes Apoptosis-Mediated Cell Death in Cultured Human Hepatoma (HepG2) Cells Biol. Pharm. Bull. 34(6) 831-838(2011)
To confirm whether mitochondrial membrane depolarization of the cytochalasin b of the present invention caused apoptosis, experiments were conducted as described below (Yashu WANG , Linhong DENG, Hongzhe ZHONG, Yajie WANG, Xuemei JIANG, and Jun CHEN: Natural Plant Extract Tubeimoside I Promotes Apoptosis-Mediated Cell Death in Cultured Human Hepatoma (HepG2) Cells Biol. Pharm. Bull. 34 (6) 831-838 2011)
60 mm-dish에 1x105 세포/ml의 농도로 24 시간 배양된 HeLa 세포에 8μM 사이토칼라신 비(cytochalasin b)를 포함하는 새로운 배지로 교체한 후 각기 다른 시간대(3, 6, 12hr)에 트립신 처리(trypsinization)를 이용하여 세포를 모았다. 그리고, 원심분리를 이용하여 세포 부유액을 인산 완충용액(PBS)으로 세척한 후 새 PBS에 5 ㎕ rhodamine 123를 가한 후 37℃의 어두운 곳에서 5분에 한 번씩 섞으면서 30분 간 염색한다. 염색 후 원심분리를 이용하여 세포 부유액을 인산 완충용액(PBS)으로 두 번 세척한다. 그리고 인산 완충용액(PBS) 1ml를 넣은 후 유세포분석기(flow cytometry)로 확인 및 분석한 결과를 도 6에 나타내었다.
HeLa cells cultured for 24 hours at a concentration of 1 × 10 5 cells / ml in a 60 mm-dish were replaced with fresh medium containing 8 μM cytochalasin b and incubated at different times (3, 6, 12 hr) with trypsin Cells were harvested using trypsinization. After centrifugation, the cell suspension is washed with phosphate buffered saline (PBS), and 5 μl of rhodamine 123 is added to fresh PBS. The cells are stained for 30 minutes in the dark at 37 ° C for 5 minutes. After staining, the cell suspension is washed twice with phosphate buffered saline (PBS) using centrifugation. Then, 1 ml of phosphate buffered saline (PBS) was added thereto, and the results were confirmed by flow cytometry and analyzed. The results are shown in FIG.
도 6에서 보는 바와 같이, 8 μM의 사이토칼라신 비(cytochalasin b)를 처리하였을 때 미토콘드리아 막 탈분극(mitochondrial membrane depolarization)이 일어난다. 시간이 지날수록 rhodamine 123이 미토콘드리아 밖으로 많이 방출하게 되어서 형광의 세기가 점점 약해지는 것으로 보아 이 화합물은 미토콘드리아 막 탈분극에 의해 세포 사멸을 유도 한다는 것을 확인하였다.
As shown in FIG. 6, mitochondrial membrane depolarization occurs when cytochalasin b of 8 μM is treated. As the time elapsed, rhodamine 123 was released from the mitochondria and the intensity of fluorescence gradually weakened, confirming that this compound induces apoptosis by mitochondrial membrane depolarization.
제제예Formulation example 1. One. 산제의Sanje 제조 Produce
화합물 300 mgCompound 300 mg
유당 100 mg
탈크 10 mg
상기의 성분들을 혼합하고 기밀포에 충진하여 산제를 제조한다.
The above components are mixed and filled in airtight bags to prepare powders.
제제예Formulation example 2. 정제의 제조 2. Preparation of tablets
화합물 300 mgCompound 300 mg
옥수수전분 100 mg
유당 100 mg
스테아린산 마그네슘 2 mg
상기의 성분들을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조한다.
After mixing the above components, tablets are prepared by tableting according to the usual preparation method of tablets.
제제예Formulation example 3. 캅셀제의 제조 3. Preparation of capsules
화합물 300 mgCompound 300 mg
결정성 셀룰로오스 3 mg
락토오스 14.8 mgLactose 14.8 mg
마그네슘 스테아레이트 0.2 mgMagnesium stearate 0.2 mg
통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캡슐제를 제조한다.
The above components are mixed according to a conventional capsule preparation method and filled in gelatin capsules to prepare capsules.
제제예Formulation example 4. 주사제의 제조 4. Preparation of injections
화합물 300 mgCompound 300 mg
만니톨 180 mg180 mg mannitol
주사용 멸균 증류수 2974 mgSterile sterilized water for injection 2974 mg
Na2HPO4 ?12H2O 26 mgNa 2 HPO 4 ? 12H 2 O 26 mg
통상의 주사제의 제조방법에 따라 1 앰플당(2㎖) 상기의 성분 함량으로 제조한다.
(2 ml) per 1 ampoule according to the usual injection preparation method.
제제예Formulation example 5. 5. 액제의Liquid 제조 Produce
화합물 300 mgCompound 300 mg
이성화당 10 g10 g per isomer
만니톨 5 g5 g mannitol
정제수 적량Purified water quantity
통상의 액제의 제조방법에 따라 정제수에 각각의 성분을 가하여 용해시키고 레몬향을 적량 가한 다음 상기의 성분을 혼합한 다음 정제수를 가하여 전체를 정제수를 가하여 전체 100 ㎖로 조절한 후 갈색 병에 충진하여 멸균시켜 액제를 제조한다.
Each component was added to purified water in accordance with the usual liquid preparation method and dissolved, and the lemon flavor was added in an appropriate amount. Then, the above components were mixed, and purified water was added thereto. The whole was adjusted to 100 ml with purified water, And sterilized to prepare a liquid preparation.
제제예Formulation example 6. 건강 식품의 제조 6. Manufacture of health food
화합물 1000 ㎎1000 mg of compound
비타민 혼합물 적량Vitamin mixture quantity
비타민 A 아세테이트 70 ㎍70 [mu] g of vitamin A acetate
비타민 E 1.0 ㎎Vitamin E 1.0 mg
비타민 B1 0.13 ㎎0.13 mg of vitamin B 1
비타민 B2 0.15 ㎎0.15 mg of vitamin B 2
비타민 B6 0.5 ㎎0.5 mg of vitamin B 6
비타민 B12 0.2 ㎍Vitamin B 12 0.2 g
비타민 C 10 ㎎10 mg vitamin C
비오틴 10 ㎍Biotin 10 μg
니코틴산아미드 1.7 ㎎Nicotinic acid amide 1.7 mg
엽산 50 ㎍50 ㎍ of folic acid
판토텐산 칼슘 0.5 ㎎Calcium pantothenate 0.5 mg
무기질 혼합물 적량Mineral mixture quantity
황산제1철 1.75 ㎎1.75 mg of ferrous sulfate
산화아연 0.82 ㎎0.82 mg of zinc oxide
탄산마그네슘 25.3 ㎎Magnesium carbonate 25.3 mg
제1인산칼륨 15 ㎎15 mg of potassium phosphate monobasic
제2인산칼슘 55 ㎎Secondary calcium phosphate 55 mg
구연산칼륨 90 ㎎Potassium citrate 90 mg
탄산칼슘 100 ㎎100 mg of calcium carbonate
염화마그네슘 24.8 ㎎24.8 mg of magnesium chloride
상기의 비타민 및 미네랄 혼합물의 조성비는 비교적 건강식품에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 그 배합비를 임의로 변형 실시하여도 무방하며, 통상의 건강식품 제조방법에 따라 상기의 성분을 혼합한 다음, 과립을 제조하고, 통상의 방법에 따라 건강식품 조성물 제조에 사용할 수 있다.
Although the composition ratio of the above-mentioned vitamin and mineral mixture is comparatively mixed with a composition suitable for health food as a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional method for producing healthy foods , Granules can be prepared and used in the manufacture of health food compositions according to conventional methods.
제제예Formulation example 7. 건강 음료의 제조 7. Manufacture of health drinks
화합물 300 ㎎300 mg of compound
비타민 C 15 gVitamin C 15 g
비타민 E(분말) 100 gVitamin E (powder) 100 g
젖산철 19.75 g19.75 g of ferrous lactate
산화아연 3.5 g3.5 g of zinc oxide
니코틴산아미드 3.5 gNicotinic acid amide 3.5 g
비타민 A 0.2 gVitamin A 0.2 g
비타민 B1 0.25 gVitamin B 1 0.25 g
비타민 B2 0.3gVitamin B 2 0.3 g
물 정량Water quantification
통상의 건강음료 제조방법에 따라 상기의 성분을 혼합한 다음, 약 1시간동안 85℃에서 교반 가열한 후, 만들어진 용액을 여과하여 멸균된 2ℓ 용기에 취득하여 밀봉 멸균한 뒤 냉장 보관한 다음 본 발명의 건강음료 조성물 제조에 사용한다. The above components were mixed according to a conventional health drink manufacturing method, and the mixture was heated at 85 DEG C for about 1 hour with stirring, and the solution thus prepared was filtered to obtain a sterilized 2-liter container, which was sealed and sterilized, ≪ / RTI >
상기 조성비는 비교적 기호 음료에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만 수요계층이나, 수요국가, 사용용도 등 지역적, 민족적 기호도에 따라서 그 배합비를 임의로 변형 실시하여도 무방하다.Although the compositional ratio is relatively mixed with a component suitable for a favorite drink, it is also possible to arbitrarily modify the compounding ratio according to the regional or national preference such as the demand class, the demanding country, and the use purpose.
Claims (11)
<화학식 1>
(1), or a pharmaceutically acceptable salt thereof, as an active ingredient, induces apoptosis of cancer cells, inhibits DNA synthesis, inhibits apoptosis of early cell death Wherein the composition induces oxidative stress and induces apoptosis through mitochondrial membrane depolarization. ≪ Desc / Clms Page number 20 >
≪ Formula 1 >
상기 암은 자궁경부암, 대장암, 소장암, 직장암, 항문암, 식도암, 췌장암, 위암, 신장암, 설암, 구강암, 피부암, 자궁암, 유방암, 임파선암, 갑상선암, 전립선암, 간암, 백혈병, 피부암, 결장암, 뇌종양, 방광암, 난소암, 또는 담낭암인 암 예방 및 치료용 조성물.
The method according to claim 1,
Wherein said cancer is selected from the group consisting of cervical cancer, colon cancer, small intestine cancer, rectal cancer, esophageal cancer, pancreatic cancer, stomach cancer, kidney cancer, tongue cancer, oral cancer, skin cancer, uterine cancer, breast cancer, Colon cancer, brain tumor, bladder cancer, ovarian cancer, or gallbladder cancer.
상기 화학식 1로 나타내어지는 사이토칼라신 비(cytochalasin b), 또는 이의 약학적으로 허용 가능한 염은 조성물 총 중량에 대하여 0.02 내지 50 중량 % 로 포함됨을 특징으로 하는 암 예방 및 치료용 조성물.
The method according to claim 1,
Wherein the cytochalasin b represented by the formula 1 or a pharmaceutically acceptable salt thereof is contained in an amount of 0.02 to 50% by weight based on the total weight of the composition.
상기 암 예방 및 치료용 조성물의 일일 유효 용량은 0.0001 내지 100mg/kg 인 것을 특징으로 하는 암 예방 및 치료용 조성물.
The method according to claim 1,
Wherein the daily effective dose of the composition for preventing and treating cancer is 0.0001 to 100 mg / kg.
상기 암 예방 및 치료용 조성물은 제 2의 항암제를 추가로 포함하는 것을 특징으로 하는 암 예방 및 치료용 조성물.
The method according to claim 1,
Wherein the composition for preventing and treating cancer further comprises a second anticancer agent.
상기 제 2의 항암제는 인터페론(interferon), 인터루킨-2(interleukin-2), 파클리탁셀(paclitaxel), 빈크리스틴(vincristine), 빈블라스틴(vinblastin), 독소루비신(doxorubicin), 에토포시드(etoposide), 이리노테칸 히드로클로라이드(irinotecan hydrochloride), 시스플라틴(cisplatin), 암사크린(amsacrine), 사이토신 아라비노시드(cytosine arabinoside), 플루오로우라실(fluoro uracil) 또는 탁솔로 이루어진 그룹에서 선택된 하나 이상인 것을 특징으로 하는 암 예방 및 치료용 조성물.
8. The method of claim 7,
Wherein the second anticancer agent is selected from the group consisting of interferon, interleukin-2, paclitaxel, vincristine, vinblastin, doxorubicin, etoposide, Wherein the cancer is at least one selected from the group consisting of irinotecan hydrochloride, cisplatin, amsacrine, cytosine arabinoside, fluoro uracil or taxol. Composition for prevention and treatment.
상기 암 예방 및 치료용 조성물은 산제, 과립제, 정제, 캡슐제, 환제, 현탁제, 내용액제, 유제 및 시럽제 중에서 선택된 어느 하나의 제제인 것을 특징으로 하는 암 예방 및 치료용 조성물.
The method according to claim 1,
Wherein the composition for preventing and treating cancer is any one selected from powders, granules, tablets, capsules, pills, suspensions, solutions, emulsions and syrups.
A health functional food for cancer prevention and improvement comprising the composition for cancer prevention and treatment according to claim 1 and a food acceptable food supplementary additive.
상기 암 예방 및 개선용 건강기능식품은 산제, 과립제, 정제, 캡슐제, 환제, 현탁제, 내용액제, 유제 및 시럽제 중에서 선택된 어느 하나의 제제인 것을 특징으로 하는 암 예방 및 개선용 건강기능식품.11. The method of claim 10,
The health functional food for cancer prevention and improvement is any one selected from powders, granules, tablets, capsules, pills, suspensions, solutions, emulsions and syrups.
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