KR20200121250A - A pharmaceutical composition for treating cancer containing saponin as active ingredient - Google Patents

A pharmaceutical composition for treating cancer containing saponin as active ingredient Download PDF

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KR20200121250A
KR20200121250A KR1020200045213A KR20200045213A KR20200121250A KR 20200121250 A KR20200121250 A KR 20200121250A KR 1020200045213 A KR1020200045213 A KR 1020200045213A KR 20200045213 A KR20200045213 A KR 20200045213A KR 20200121250 A KR20200121250 A KR 20200121250A
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cancer
pharmaceutical composition
carcinoma
cells
ginsenoside
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김홍렬
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주식회사 진센
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Abstract

The present invention relates to a pharmaceutical composition for treating cancer comprising saponin as an active component. The pharmaceutical composition preferably further comprises an aldehyde inhibitor, and more preferably further comprises the aldehyde inhibitor and a biguanide compound, but is not limited to the same. The pharmaceutical composition has a very excellent effect of killing not only cancer cells, but also cancer stem cells, thereby being expected to be widely used in medical and health care fields for cancer treatment.

Description

사포닌을 유효성분으로 포함하는 암 치료용 약학조성물{A pharmaceutical composition for treating cancer containing saponin as active ingredient}A pharmaceutical composition for treating cancer containing saponin as active ingredient}

본 발명은 사포닌을 유효성분으로 포함하는 암 치료용 약학조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for cancer treatment comprising saponin as an active ingredient.

암은 전세계적으로 가장 보편적인 사망원인 중의 하나이다. 약 천만 건의 새로운 케이스가 매년 발생하며, 전체 사망원인의 약 12%를 차지하여 세 번째로 많은 사망의 원인이 되고 있다. 따라서 효과적인 항암제를 개발하고자 하는 노력이 지속되어 왔으나, 최근까지 개발된 항암제들은 대부분 일반적인 암세포를 표적으로 하는 것으로, 암 환자의 치료내성 및 재발에 중요한 역할을 하는 암 줄기세포의 사멸에는 효과적이지 못하다. 상기의 암 줄기세포란 일반적인 줄기세포와 유사하게 무제한의 재생능력을 가진 암세포로서 일반적인 암세포와 상이하게 천천히 증식하고, 줄기세포 특유의 능력인 자가재생이나 분화능력을 가지며, 기존에 알려져 있는 암세포들과 다른 기전(mechanism)을 가지는 것으로 알려져 있으나, 아직 암 줄기세포를 표적으로 하는 암 줄기세포 치료용 약물에 대한 개발은 매우 미비한 실정이다(국내출원특허 10-2011-0066035). 암 치료 후에도 체내에 암 줄기세포가 남게 되면 암의 재발 및 /또는 전이가 활발히 일어나므로, 암 줄기세포 치료제 개발은 시급한 과제라고 할 것이다.Cancer is one of the most common causes of death worldwide. About 10 million new cases occur every year, accounting for about 12% of all causes of death, making it the third-most cause of death. Therefore, efforts to develop effective anticancer agents have been continued, but anticancer drugs developed until recently are mostly targeting general cancer cells, and are not effective in killing cancer stem cells, which play an important role in treatment resistance and recurrence of cancer patients. The cancer stem cells described above are cancer cells that have unlimited regenerative ability similar to general stem cells. They proliferate slowly differently from general cancer cells, have self-renewal or differentiation ability, which is a unique ability of stem cells, and Although it is known to have a different mechanism, the development of a drug for treating cancer stem cells targeting cancer stem cells is still insufficient (Korean Patent Application No. 10-2011-0066035). If cancer stem cells remain in the body even after cancer treatment, recurrence and/or metastasis of cancer occurs actively, so the development of cancer stem cell therapeutics is an urgent task.

한편 사포닌(saponin)은 스테로이드, 스테로이드알카로이드 혹은 트리텔펜(triterpene)의 배당체로, 물에 녹아 비누식의 발포작용을 나타내는 물질의 총칭이다. 여러 식물에 존재하며, 일부의 극피동물(불가사리, 해삼)의 몸 안에도 포함되어 있다고 알려져 있으나, 특히 인삼에 함유된 사포닌 종류인 진세노사이드(ginsenoside)와 엘루테로사이드(eleutheroside)가 유명하다. 진세노사이드는 Rg1, Rb1, Rb2, Rh2, Rg3 등 34여종에 달하며, 성분 각각의 효과가 상이하다. 예를 들면, 한국 등록특허 제 KR 101539574 B1에는 “진세노사이드 Rg1에 의한 망막 재생 효과”가 기재되어 있고, 한국 공개특허 제 KR 2015-0099043 A에는 “Rg2 강화 홍삼의 골다골증 개선 효과”가 기재되어 있다.On the other hand, saponin is a glycoside of steroids, steroid alkaloids, or triterpene, and is a generic term for substances that dissolve in water and exhibit the foaming action of a soap type. It is present in various plants and is known to be included in the body of some echinoderms (starfish, sea cucumber), but ginsenoside and eleutheroside, which are saponin types contained in ginseng, are particularly famous. Ginsenosides reach over 34 species such as Rg1, Rb1, Rb2, Rh2, and Rg3, and the effects of each component are different. For example, Korean Patent No. KR 101539574 B1 describes “the retinal regeneration effect by ginsenoside Rg1”, and Korean Patent Publication No. KR 2015-0099043 A describes “the effect of improving osteoporosis of red ginseng enhanced with Rg2”. have.

본 발명은 상기의 진세노사이드, 특히 Rg3와 Rh2를 유효성분으로 포함하는 암 치료용 약학조성물에 관한 것이다. 본 발명의 약학조성물은 암세포, 특히 암줄기세포의 사멸 효과가 현저하므로, 의학 및 보건 분야에서 크게 이용될 것으로 기대된다.The present invention relates to a pharmaceutical composition for cancer treatment comprising the above ginsenosides, in particular Rg3 and Rh2 as active ingredients. Since the pharmaceutical composition of the present invention has a remarkable killing effect of cancer cells, particularly cancer stem cells, it is expected to be widely used in the fields of medicine and health.

본 발명은 상기와 같은 종래의 기술상의 문제점을 해결하기 위해 안출된 것으로, 사포닌을 유효성분으로 포함하는 암 치료용 약학조성물에 관한 것이다.The present invention was conceived to solve the problems of the prior art as described above, and relates to a pharmaceutical composition for cancer treatment comprising saponin as an active ingredient.

그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당 업계에서 통상의 지식을 가진 자에게 명확하게 이해될 수 있을 것이다.However, the technical problem to be achieved by the present invention is not limited to the problems mentioned above, and other problems that are not mentioned may be clearly understood by those of ordinary skill in the art from the following description.

이하, 본원에 기재된 다양한 구체예가 도면을 참조로 기재된다. 하기 설명에서, 본 발명의 완전한 이해를 위해서, 다양한 특이적 상세사항, 예컨대, 특이적 형태, 조성물 및 공정 등이 기재되어 있다. 그러나, 특정의 구체예는 이들 특이적 상세 사항 중 하나 이상 없이, 또는 다른 공지된 방법 및 형태와 함께 실행될 수 있다. 다른 예에서, 공지된 공정 및 제조 기술은 본 발명을 불필요하게 모호하게 하지 않게 하기 위해서, 특정의 상세사항으로 기재되지 않는다. "한 가지 구체예" 또는 "구체예"에 대한 본 명세서 전체를 통한 참조는 구체예와 결부되어 기재된 특별한 특징, 형태, 조성 또는 특성이 본 발명의 하나 이상의 구체예에 포함됨을 의미한다. 따라서, 본 명세서 전체에 걸친 다양한 위치에서 표현된 "한 가지 구체예에서" 또는 "구체예"의 상황은 반드시 본 발명의 동일한 구체예를 나타내지는 않는다. 추가로, 특별한 특징, 형태, 조성, 또는 특성은 하나 이상의 구체예에서 어떠한 적합한 방법으로 조합될 수 있다.Hereinafter, various embodiments described herein are described with reference to the drawings. In the following description, for a thorough understanding of the invention, various specific details, such as specific forms, compositions and processes, etc. are set forth. However, certain embodiments may be practiced without one or more of these specific details, or with other known methods and forms. In other instances, well-known processes and manufacturing techniques have not been described in specific details in order not to unnecessarily obscure the present invention. Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, form, composition, or characteristic described in connection with the embodiment is included in one or more embodiments of the invention. Thus, the context of “in one embodiment” or “an embodiment” expressed in various places throughout this specification does not necessarily represent the same embodiment of the invention. Additionally, particular features, shapes, compositions, or properties may be combined in one or more embodiments in any suitable manner.

명세서에서 특별한 정의가 없으면 본 명세서에 사용된 모든 과학적 및 기술적인 용어는 본 발명이 속하는 기술분야에서 당업자에 의하여 통상적으로 이해되는 것과 동일한 의미를 가진다.Unless otherwise defined in the specification, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention belongs.

본 발명의 일 구체예에서 “암”이란, 제어되지 않은 세포성장으로 특징지어지며, 이러한 비정상적인 세포성장에 의해 종양이라고 불리는 세포 덩어리가 형성되어 주위의 조직으로 침투하고 심한 경우에는 신체의 다른 기관으로 전이되기도 하는 것을 말한다. 학문적으로는 신생물이라고 명명되기도 한다. 암은 수술, 방사선 및 화학요법으로 치료를 하더라도 많은 경우에 근본적인 치유가 되지 못하고 환자에게 고통을 주며 궁극적으로는 죽음에 이르게 하는 난치성 만성질환으로, 암의 발생요인으로는 여러 가지가 있으나, 내적 요인과 외적 요인으로 구분한다. 정상세포가 어떠한 기전을 거처 암세포로 형질전환이 되는지에 대해서는 정확하게 규명되지 않았으나, 상당수의 암이 환경요인 등 외적인자에 의해 영향을 받아 발생하는 것으로 알려져 있다. 내적 요인으로는 유전 인자, 면역학적 요인 등이 있으며, 외적 요인으로는 화학물질, 방사선, 바이러스 등이 있다. 암의 발생에 관련되는 유전자에는 종양형성유전자 (oncogenes)와 종양억제유전자 (tumor suppressor genes)가 있는데, 이들 사이의 균형이 위에서 설명한 내적 혹은 외적 용인들에 의해 무너질 때 암이 발생하게 된다. 암은 그 발생 부위에 따라 구강암, 간암, 위암, 결장암, 유방암, 폐암, 골암, 췌장암, 피부암, 두부암, 경부암, 피부암, 자궁경부암, 난소암, 대장암, 소장암, 직장암, 나팔관암종, 항문부근암, 자궁내막암종, 질암종, 음문암종, 호지킨병(Hodgkin's disease), 식도암, 임파선암, 방광암, 담낭암, 내분비선암, 갑상선암, 부갑상선암, 부신암, 연조직 육종, 요도암, 음경암, 전립선암, 만성 백혈병, 급성 백혈병, 림프구 림프종, 신장암, 수뇨관암, 신장세포암종, 신장골반암종, 중추신경계 종양, 1차 중추신경계 림프종, 척수 종양, 뇌간 신경교종 및 뇌하수체 선종으로 구분할 수 있으나, 이에 한정하는 것은 아니다.In one embodiment of the present invention, "cancer" is characterized by uncontrolled cell growth, and by such abnormal cell growth, a mass of cells called a tumor is formed and penetrates into surrounding tissues, and in severe cases, to other organs of the body. It refers to something that can be transferred. In academic terms, it is sometimes referred to as a neoplasm. Cancer is an intractable chronic disease that in many cases cannot be cured by surgery, radiation, and chemotherapy, causes pain to the patient, and ultimately leads to death.There are various causes of cancer, but internal factors Classify by external factors. The mechanism by which normal cells are transformed into cancer cells has not been accurately identified, but it is known that a significant number of cancers are affected by external factors such as environmental factors. Internal factors include genetic factors and immunological factors, and external factors include chemicals, radiation, and viruses. Genes involved in the occurrence of cancer include oncogenes and tumor suppressor genes, and cancer occurs when the balance between them is broken by the internal or external factors described above. Cancer is oral cancer, liver cancer, stomach cancer, colon cancer, breast cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, cervical cancer, skin cancer, cervical cancer, ovarian cancer, colon cancer, small intestine cancer, rectal cancer, fallopian tube carcinoma, anus. Peripheral cancer, endometrial carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, lymph node cancer, bladder cancer, gallbladder cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, Prostate cancer, chronic leukemia, acute leukemia, lymphocytic lymphoma, kidney cancer, ureter cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system tumor, primary central nervous system lymphoma, spinal cord tumor, brainstem glioma, and pituitary adenoma. It is not limited to this.

본 발명의 일 구체예에서 “암 줄기세포(cancer stem cell)”란, 줄기세포 특유의 능력인 자가재생이나 분화능력을 가지고 있는 포괄적인 의미의 암세포를 의미하며, 예를 들어 구(sphere) 형태의 암세포 집단이나, 저분화성 암과 같이 형태가 불분명하고 예후가 좋지 않은 암 조직을 포함할 수 있다. 상기 암 줄기세포의 정상적인 종양 생장 조건(상기 "정상적인 종양의 생장 조건"이란 세포 성장에 필요한 영양분(포도당)이 충분하고 종양미세환경의 생장 여건이 풍족하여 세포 스트레스가 없는 상태를 칭한다.)에서 일반적인 암세포와 상이하게 느린 속도로 증식하거나 휴지기(dormant state) 상태를 유지하여 항암제에 대한 저항성을 가지고 있을 수 있으며, 예를 들어, PGC-1a 등의 전사조절인자의 발현이 정상적인 종양세포와 달리 통제되어 주요 대사조절물질의 기능이 일반 암세포와 비교하여 상이할 수 있다. 이러한 상이한 대사조절 능력과 이에 기전(mechanism)적으로 연계된 세포신호전달계의 조절을 통해 영양 결핍 상태에서 세포 사멸(apoptosis)에 대한 저항성을 획득하고 침윤 및/또는 전이능이 있는 세포를 포괄적으로 지칭한다. 그러나 일반적인 암세포로 분화할 수 있는 세포라면 이에 제한되지 않는다.In one embodiment of the present invention, the term “cancer stem cell” refers to a cancer cell in a comprehensive sense that has a self-renewal or differentiation ability, which is a unique ability of stem cells, for example, in a sphere shape. It may include cancerous tissues of unclear form and poor prognosis, such as cancer cell populations or hypodifferentiated cancers. Under normal tumor growth conditions of the cancer stem cells (the "normal tumor growth conditions" refers to a state in which nutrients (glucose) required for cell growth are sufficient and the growth conditions of the tumor microenvironment are sufficient and there is no cellular stress.) Unlike cancer cells, it may proliferate at a slow rate or maintain a dormant state to have resistance to anticancer drugs.For example, the expression of transcriptional regulators such as PGC-1a is controlled unlike normal tumor cells. The functions of major metabolic modulators may be different compared to normal cancer cells. These different metabolic regulatory abilities and mechanisms linked thereto, through the regulation of the cell signaling system, obtain resistance to apoptosis in a nutrient-deficient state, and collectively refer to cells with invasion and/or metastasis. . However, any cell capable of differentiating into a general cancer cell is not limited thereto.

본 발명의 일 구체예에서 “사포닌(saponin)”이란, 스테로이드, 스테로이드알카로이드 혹은 트리텔펜(triterpene)의 배당체로, 물에 녹아 비누식의 발포작용을 나타내는 물질의 총칭이다. 여러 식물에 존재하며, 일부의 극피동물(불가사리, 해삼)의 몸 안에도 포함되어 있다고 알려져 있으나, 특히 인삼에 함유된 사포닌 종류인 진세노사이드(ginsenoside)와 엘루테로사이드(eleutheroside)가 유명하다. 진세노사이드는 Rg1, Rb1, Rb2, Rh2, Rg3 등 34여종에 달하며, 성분 각각의 효과가 상이하다. 예를 들면, 한국 등록특허 제 KR 101539574 B1에는 “진세노사이드 Rg1에 의한 망막 재생 효과”가 기재되어 있고, 한국 공개특허 제 KR 2015-0099043 A에는 “Rg2 강화 홍삼의 골다골증 개선 효과”가 기재되어 있다.In one embodiment of the present invention, "saponin" is a glycoside of steroids, steroid alkaloids, or triterpene, and is a generic term for a substance that dissolves in water and exhibits the foaming action of a soap type. It is present in various plants and is known to be included in the body of some echinoderms (starfish, sea cucumber), but ginsenoside and eleutheroside, which are saponin types contained in ginseng, are particularly famous. Ginsenosides reach over 34 species such as Rg1, Rb1, Rb2, Rh2, and Rg3, and the effects of each component are different. For example, Korean Patent No. KR 101539574 B1 describes “the retinal regeneration effect by ginsenoside Rg1”, and Korean Patent Publication No. KR 2015-0099043 A describes “the effect of improving osteoporosis of red ginseng enhanced with Rg2”. have.

본 발명에 있어서, 암 치료용 약학조성물의 유효성분은 사포닌이라면 그 종류에 제한을 두는 것은 아니나, 진세노사이드 Rg3, 또는 Rh2인 것이 바람직하다.In the present invention, if the active ingredient of the pharmaceutical composition for cancer treatment is saponin, the type is not limited, but ginsenoside Rg3 or Rh2 is preferred.

본 발명의 일 구체예에서 “알데히드 억제제(aldehyde inhibitor)”란, 알데히드의 산화, 또는 환원 반응을 억제하는 물질을 의미한다. 알데히드는 탄화수소기에 포르밀기가 첨가된 화학물질의 총칭으로, 분자식 RCHO로 표현된다. 알코올의 불충분한 산화에 의하여 생기며 자극적인 냄새가 나고 포르밀기의 특성상 산화되기 쉬워 은거울반응이나 펠링반응을 일으키며, 산화한 후에는 카르복시산이 된다. 상기 상기 알데히드 억제제의 종류에는 베노밀(benomyl), 시스플라틴(cis-diamminedichloridoplatinum; CDDP), 클로르프로파마이드(chlorpropamide), 시트랄(citral), CVT-10216(3-[[[3-[4-[(Methylsulfonyl)amino]phenyl]-4-oxo-4H-1-benzopyran-7-yl]oxy]methyl]-benzoic acid, 3-[[[3-[4-[(Methylsulfonyl)amino]phenyl]-4-oxo-4H-chromen-7-yl]oxy]methyl]benzoic acid), 사이안아마이드(cyanamide), 다이진(daidzin), 디에틸아미노벤즈알데히드(Diethylaminobenzaldehyde; DEAB), 디설피람(disulfiram), 고시폴(gossypol), 모리네이트(molinate), N-아세틸-N-아세톡시-4-클로로벤젠설폰아미드(N-Acetyl-N-acetoxy-4-chlorobenzenesulfonamide), 파르질린(pargyline hydrochloride), 포스포(에놀)피루브산 모노나트륨염 수화물(phospho(enol)pyruvic acid monosodium salt hydrate), 페닐글리옥산(phenylglyoxal), 레티노산(reginoic acid), 키누렌산(kynurenic acid), 3-히드록시키누레닌(3-hydroxy-DL-kynurenine), 및 옥살산나트륨(sodium oxamate) 등이 있으나, 이에 제한되는 것은 아니다.In one embodiment of the present invention, the "aldehyde inhibitor" means a substance that suppresses the oxidation or reduction reaction of aldehyde. Aldehyde is a generic term for a chemical substance in which a formyl group is added to a hydrocarbon group, and is expressed by the molecular formula RCHO. It is caused by insufficient oxidation of alcohol and has an irritating odor. Due to the nature of the formyl group, it is easy to oxidize, causing silver mirror reaction or Pelling reaction, and after oxidation, it becomes carboxylic acid. The types of the aldehyde inhibitor include benomyl, cis-diamminedichloridoplatinum (CDDP), chlorpropamide, citral, CVT-10216(3-[[[3-[4-[ (Methylsulfonyl)amino]phenyl]-4-oxo-4H-1-benzopyran-7-yl]oxy]methyl]-benzoic acid, 3-[[[3-[4-[(Methylsulfonyl)amino]phenyl]-4 -oxo-4H-chromen-7-yl]oxy]methyl]benzoic acid), cyanamide, daidzin, diethylaminobenzaldehyde (DEAB), disulfiram, notice Gossypol, morinate, N-acetyl-N-acetoxy-4-chlorobenzenesulfonamide, pargyline hydrochloride, phospho( Enol) pyruvic acid monosodium salt hydrate, phenylglyoxal, retinoic acid, kynurenic acid, 3-hydroxykynurenine -DL-kynurenine), and sodium oxamate, but are not limited thereto.

본 발명의 일 구체예에서 “비구아니드(biguanide)계 화합물”이란, 바람직하게는 비구아나이드 계열 당뇨병 치료제이며, 더욱 바람직하게는 메트포민(metformin), 펜포르민(phenformin), 부포르민(buformine) 등 일 수 있으나, 세포 내 에너지 생성을 방해하여 영양 결핍 유사 상태를 유도하는 비구아나이드 계열 화합물이라면 이에 제한되지 않는다.In one embodiment of the present invention, "biguanide-based compound" is preferably a biguanide-based diabetes treatment agent, more preferably metformin, phenformin, buformine ) Or the like, but is not limited thereto if it is a biguanide-based compound that induces a nutrient-deficiency-like state by interfering with the generation of energy in cells.

본 발명의 일 구체예에서 “치료”란, 목적하는 질병의 완화 또는/및 개선을 위해 수행되는 일련의 활동을 의미한다. 본 발명의 목적상 치료는 암 줄기세포를 포함하는 암세포의 수적 또는 양적 증식을 억제시키거나, 암세포를 사멸시키거나, 암 조직의 성장을 억제시키거나, 암 조직의 크기를 감소시키거나, 암 조직 내의 신생혈관의 발달을 억제시키는 활동을 포함한다.In one embodiment of the present invention, "treatment" means a series of activities performed to alleviate or/and ameliorate a desired disease. For the purposes of the present invention, treatment is to inhibit the numerical or quantitative proliferation of cancer cells including cancer stem cells, kill cancer cells, inhibit the growth of cancer tissues, reduce the size of cancer tissues, or It includes activities that inhibit the development of new blood vessels within the body.

본 발명의 일 구체예에서 “전이”란, 암세포가 원발장기를 떠나 다른 장기로 가는 것이며, 상기의 “암”이란 “암 줄기세포”를 포함하는 의미이다. 암이 신체의 다른 부분으로 퍼지는 것은 크게 원발암에서 암조직이 성장하여 직접적으로 주위장기를 침윤하는 것과 멀리 있는 다른 장기로 혈관이나 림프관을 따라 원격전이를 하는 것으로 나눈다. 전이는 암 발생과 관련된 유전자의 발현 억제 또는 상기 유전자의 단백질 활성 억제를 통해 조절될 수 있다.In one embodiment of the present invention, "metastasis" means that cancer cells leave the primary organ and go to other organs, and "cancer" means including "cancer stem cells". The spread of cancer to other parts of the body is largely divided into the growth of cancerous tissues in primary cancer and directly infiltrating the surrounding organs, and distant metastasis along blood vessels or lymphatic vessels to other organs far away. Metastasis can be regulated through inhibition of expression of genes related to cancer development or inhibition of protein activity of the gene.

본 발명의 일 구체예에서 “약학조성물”이란, 특정한 목적을 위해 투여되는 조성물을 의미한다. 본 발명의 목적상, 본 발명의 약학조성물은 Rg3, 또는 Rh2에 알데히드 억제제를 추가로 포함하고, 암세포, 또는 암 줄기세포를 치료하거나 전이 억제하는 것이며, 이에 관여하는 화합물 및 약학적으로 허용 가능한 담체, 부형제 또는 희석제를 포함할 수 있다. 또한 본 발명에 따른 약학 조성물은 조성물 총 중량에 대하여 본 발명의 유효성분을 0.1 내지 50 중량%로 포함한다. 본 발명의 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있으나, 이에 제한되는 것은 아니다.In one embodiment of the present invention, the "pharmaceutical composition" means a composition administered for a specific purpose. For the purposes of the present invention, the pharmaceutical composition of the present invention further comprises an aldehyde inhibitor in Rg3 or Rh2, and treats or inhibits metastasis of cancer cells or cancer stem cells, and compounds involved therein and pharmaceutically acceptable carriers , Excipients or diluents. In addition, the pharmaceutical composition according to the present invention contains 0.1 to 50% by weight of the active ingredient of the present invention based on the total weight of the composition. Carriers, excipients and diluents that may be included in the composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil may be mentioned, but are not limited thereto.

본 발명의 일 구체예에서 “투여”란, 어떠한 적절한 방법으로 환자에게 본 발명의 조성물을 도입하는 것을 의미하며, 본 발명의 조성물의 투여경로는 목적 조직에 도달할 수 있는 한 어떠한 일반적인 경로를 통하여 투여될 수 있다. 경구 투여, 복강 내 투여, 정맥 내 투여, 근육 내 투여, 피하 투여, 피내 투여, 비내 투여, 폐내 투여, 직장내 투여, 강내 투여, 복강 내 투여, 경막 내 투여가 이루어질 수 있으나, 이에 제한되지는 않는다. 본 발명에서 유효량은 질환의 종류, 질환의 중증도, 조성물에 함유된 유효 성분 및 다른 성분의 종류 및 함량, 제형의 종류 및 환자의 연령, 체중, 일반 건강 상태, 성별 및 식이, 투여 시간, 투여 경로 및 조성물의 분비율, 치료 기간, 동시 사용되는 약물을 비롯한 다양한 인자에 따라 조절될 수 있다. 성인의 경우, 상기 치료용 약학조성물을 1회 50ml~500ml의 양으로 체내에 투여 가능하며, 화합물일 경우 0.1ng/kg-10㎎/kg, 모노클로날 항체일 경우 0.1ng/kg-10㎎/kg의 용량으로 투여될 수 있다. 투여간격은 1일 1회 내지 12회일 수 있으며, 1일 12회 투여할 경우에는 2시간마다 1회씩 투여할 수 있다. 또한 본 발명의 약학조성물은 목적하고자 하는 암 줄기세포의 치료를 위해 단독 또는 당업계에 공지된 다른 치료법, 예를 들어 화학요법제, 방사선 및 수술과 같이 투여될 수 있다. 또한 본 발명의 약학조성물은 면역 반응을 증진하기 위하여 고안된 다른 치료, 예를 들어 당업계에 주지된 것과 같은 어쥬번트 또는 사이토카인(또는 사이토카인을 코딩하는 핵산)과 혼합하여 투여될 수 있다. 바이오리스틱(biolistic) 전달 또는 생체 외(ex vivo) 처리와 같은 다른 표준 전달 방법들이 사용될 수도 있다. 생체 외 처리에서 예를 들어 항원제시 세포들(APCs), 수지상세포들, 말초혈액 단핵구 세포들, 또는 골수세포들을 환자 또는 적당한 공여자로부터 얻어서 본 약학조성물로 생체 외에서 활성화된 후 그 환자에게 투여될 수 있다.In one embodiment of the present invention, "administration" means introducing the composition of the present invention to a patient by any suitable method, and the route of administration of the composition of the present invention is through any general route as long as it can reach the target tissue. Can be administered. Oral administration, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, intranasal administration, intrapulmonary administration, rectal administration, intranasal administration, intraperitoneal administration, intrathecal administration, but not limited thereto. Does not. In the present invention, the effective amount is the type of disease, the severity of the disease, the type and content of the active ingredient and other ingredients contained in the composition, the type of formulation and the age, weight, general health condition, sex and diet, administration time, route of administration And the secretion rate of the composition, duration of treatment, and drugs used simultaneously. In the case of adults, the therapeutic pharmaceutical composition can be administered in the body in an amount of 50ml~500ml once, 0.1ng/kg-10mg/kg in the case of a compound, 0.1ng/kg-10mg in the case of a monoclonal antibody It can be administered at a dose of /kg. The administration interval may be 1 to 12 times a day, and in the case of administration 12 times a day, it may be administered once every 2 hours. In addition, the pharmaceutical composition of the present invention may be administered alone or with other treatments known in the art, such as chemotherapeutic agents, radiation, and surgery, for the treatment of desired cancer stem cells. In addition, the pharmaceutical composition of the present invention may be administered in combination with other treatments designed to enhance the immune response, for example, adjuvants or cytokines (or nucleic acids encoding cytokines) as well known in the art. Other standard delivery methods may be used such as biolistic delivery or ex vivo treatment. In ex vivo treatment, for example, antigen presenting cells (APCs), dendritic cells, peripheral blood mononuclear cells, or bone marrow cells can be obtained from a patient or a suitable donor, activated in vitro with this pharmaceutical composition, and then administered to the patient. have.

본 발명의 일 구체예에서, 진세노사이드 Rg3, 또는 Rh2을 유효성분으로 포함하고, 알데히드 억제제를 추가로 포함하며, 상기 알데히드 억제제는 베노밀(benomyl), 시스플라틴(cis-diamminedichloridoplatinum; CDDP), 클로르프로파마이드(chlorpropamide), 시트랄(citral), CVT-10216(3-[[[3-[4-[(Methylsulfonyl)amino]phenyl]-4-oxo-4H-1-benzopyran-7-yl]oxy]methyl]-benzoic acid, 3-[[[3-[4-[(Methylsulfonyl)amino]phenyl]-4-oxo-4H-chromen-7-yl]oxy]methyl]benzoic acid), 사이안아마이드(cyanamide), 다이진(daidzin), 디에틸아미노벤즈알데히드(Diethylaminobenzaldehyde; DEAB), 디설피람(disulfiram), 고시폴(gossypol), 모리네이트(molinate), N-아세틸-N-아세톡시-4-클로로벤젠설폰아미드(N-Acetyl-N-acetoxy-4-chlorobenzenesulfonamide), 파르질린(pargyline hydrochloride), 포스포(에놀)피루브산 모노나트륨염 수화물(phospho(enol)pyruvic acid monosodium salt hydrate), 페닐글리옥산(phenylglyoxal), 레티노산(reginoic acid), 키누렌산(kynurenic acid), 3-히드록시키누레닌(3-hydroxy-DL-kynurenine), 및 옥살산나트륨(sodium oxamate)으로 구성된 그룹으로부터 선택되는 어느 하나 이상인 암의 예방 또는 치료용 약학조성물을 제공한다.In one embodiment of the present invention, ginsenoside Rg3 or Rh2 is included as an active ingredient, and an aldehyde inhibitor is further included, and the aldehyde inhibitor is benomyl, cis-diamminedichloridoplatinum (CDDP), chlorpro Chlorpropamide, citral, CVT-10216(3-[[[3-[4-[(Methylsulfonyl)amino]phenyl]-4-oxo-4H-1-benzopyran-7-yl]oxy ]methyl]-benzoic acid, 3-[[[3-[4-[(Methylsulfonyl)amino]phenyl]-4-oxo-4H-chromen-7-yl]oxy]methyl]benzoic acid), cyanamide ( cyanamide), daidzin, diethylaminobenzaldehyde (DEAB), disulfiram, gossypol, morinate, N-acetyl-N-acetoxy-4-chloro Benzenesulfonamide (N-Acetyl-N-acetoxy-4-chlorobenzenesulfonamide), pargyline hydrochloride, phospho (enol) pyruvic acid monosodium salt hydrate (phospho (enol) pyruvic acid monosodium salt hydrate), phenylglyoxane ( Cancer of any one or more selected from the group consisting of phenylglyoxal), retinoic acid, kynurenic acid, 3-hydroxy-DL-kynurenine, and sodium oxamate It provides a pharmaceutical composition for the prevention or treatment of.

상기 진세노사이드 Rg3, 또는 Rh2는 홍삼, 또는 인삼 유래 추출물인 것이 바람직하나, 이제 제한되는 것은 아니다.The ginsenoside Rg3, or Rh2 is preferably a red ginseng or ginseng-derived extract, but is not limited thereto.

또한 상기 약학조성물에 비구아니드계 화합물을 추가로 포함하는 약학조성물을 제공하고, 상기 비구아니드계 화합물은 메트포민(metformin), 펜포르민(phenformin), 및 부포르민(buformine)으로 구성된 그룹으로부터 선택되는 어느 하나 이상인 약학조성물을 제공한다.In addition, it provides a pharmaceutical composition further comprising a biguanide-based compound in the pharmaceutical composition, wherein the biguanide-based compound is selected from the group consisting of metformin, phenformin, and buformine. It provides any one or more pharmaceutical compositions.

상기의 약학조성물에 있어서, 상기 암은 암 줄기세포를 포함하는 것인 약학조성물을 제공하며, 상기 암은 구강암, 간암, 위암, 결장암, 유방암, 폐암, 골암, 췌장암, 피부암, 두부암, 경부암, 피부암, 자궁경부암, 난소암, 대장암, 소장암, 직장암, 나팔관암종, 항문부근암, 자궁내막암종, 질암종, 음문암종, 호지킨병(Hodgkin's disease), 식도암, 임파선암, 방광암, 담낭암, 내분비선암, 갑상선암, 부갑상선암, 부신암, 연조직 육종, 요도암, 음경암, 전립선암, 만성 백혈병, 급성 백혈병, 림프구 림프종, 신장암, 수뇨관암, 신장세포암종, 신장골반암종, 중추신경계 종양, 1차 중추신경계 림프종, 척수 종양, 뇌간 신경교종 및 뇌하수체 선종으로 구성된 그룹으로부터 선택되는 어느 하나 이상인 약학조성물을 제공한다.In the above pharmaceutical composition, the cancer provides a pharmaceutical composition comprising cancer stem cells, wherein the cancer is oral cancer, liver cancer, gastric cancer, colon cancer, breast cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, neck cancer, Skin cancer, cervical cancer, ovarian cancer, colon cancer, small intestine cancer, rectal cancer, fallopian tube carcinoma, anal cancer, endometrial carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, lymph adenocarcinoma, bladder cancer, gallbladder cancer, Endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic leukemia, acute leukemia, lymphocytic lymphoma, kidney cancer, ureter cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system tumor, It provides a pharmaceutical composition of any one or more selected from the group consisting of primary central nervous system lymphoma, spinal cord tumor, brainstem glioma, and pituitary adenoma.

본 발명의 다른 구체예에서, 진세노사이드 Rg3, 또는 Rh2을 유효성분으로 포함하고, 알데히드 억제제를 추가로 포함하며, 상기 알데히드 억제제는 베노밀(benomyl), 시스플라틴(cis-diamminedichloridoplatinum; CDDP), 클로르프로파마이드(chlorpropamide), 시트랄(citral), CVT-10216(3-[[[3-[4-[(Methylsulfonyl)amino]phenyl]-4-oxo-4H-1-benzopyran-7-yl]oxy]methyl]-benzoic acid, 3-[[[3-[4-[(Methylsulfonyl)amino]phenyl]-4-oxo-4H-chromen-7-yl]oxy]methyl]benzoic acid), 사이안아마이드(cyanamide), 다이진(daidzin), 디에틸아미노벤즈알데히드(Diethylaminobenzaldehyde; DEAB), 디설피람(disulfiram), 고시폴(gossypol), 모리네이트(molinate), N-아세틸-N-아세톡시-4-클로로벤젠설폰아미드(N-Acetyl-N-acetoxy-4-chlorobenzenesulfonamide), 파르질린(pargyline hydrochloride), 포스포(에놀)피루브산 모노나트륨염 수화물(phospho(enol)pyruvic acid monosodium salt hydrate), 페닐글리옥산(phenylglyoxal), 레티노산(reginoic acid), 키누렌산(kynurenic acid), 3-히드록시키누레닌(3-hydroxy-DL-kynurenine), 및 옥살산나트륨(sodium oxamate)으로 구성된 그룹으로부터 선택되는 어느 하나 이상인 암의 전이 억제용 약학조성물을 제공한다.In another embodiment of the present invention, ginsenoside Rg3 or Rh2 is included as an active ingredient, and an aldehyde inhibitor is further included, and the aldehyde inhibitor is benomyl, cis-diamminedichloridoplatinum (CDDP), chlorpro Chlorpropamide, citral, CVT-10216(3-[[[3-[4-[(Methylsulfonyl)amino]phenyl]-4-oxo-4H-1-benzopyran-7-yl]oxy ]methyl]-benzoic acid, 3-[[[3-[4-[(Methylsulfonyl)amino]phenyl]-4-oxo-4H-chromen-7-yl]oxy]methyl]benzoic acid), cyanamide ( cyanamide), daidzin, diethylaminobenzaldehyde (DEAB), disulfiram, gossypol, morinate, N-acetyl-N-acetoxy-4-chloro Benzenesulfonamide (N-Acetyl-N-acetoxy-4-chlorobenzenesulfonamide), pargyline hydrochloride, phospho (enol) pyruvic acid monosodium salt hydrate (phospho (enol) pyruvic acid monosodium salt hydrate), phenylglyoxane ( Cancer of any one or more selected from the group consisting of phenylglyoxal), retinoic acid, kynurenic acid, 3-hydroxy-DL-kynurenine, and sodium oxamate It provides a pharmaceutical composition for inhibiting the metastasis of.

상기 진세노사이드 Rg3, 또는 Rh2는 홍삼, 또는 인삼 유래 추출물인 것이 바람직하나, 이제 제한되는 것은 아니다.The ginsenoside Rg3, or Rh2 is preferably a red ginseng or ginseng-derived extract, but is not limited thereto.

또한 상기 약학조성물에 비구아니드계 화합물을 추가로 포함하는 약학조성물을 제공하고, 상기 비구아니드계 화합물은 메트포민(metformin), 펜포르민(phenformin), 및 부포르민(buformine)으로 구성된 그룹으로부터 선택되는 어느 하나 이상인 약학조성물을 제공한다.In addition, it provides a pharmaceutical composition further comprising a biguanide-based compound in the pharmaceutical composition, wherein the biguanide-based compound is selected from the group consisting of metformin, phenformin, and buformine. It provides any one or more pharmaceutical compositions.

상기의 약학조성물에 있어서, 상기 암은 암 줄기세포를 포함하는 것인 약학조성물을 제공하며, 상기 암은 구강암, 간암, 위암, 결장암, 유방암, 폐암, 골암, 췌장암, 피부암, 두부암, 경부암, 피부암, 자궁경부암, 난소암, 대장암, 소장암, 직장암, 나팔관암종, 항문부근암, 자궁내막암종, 질암종, 음문암종, 호지킨병(Hodgkin's disease), 식도암, 임파선암, 방광암, 담낭암, 내분비선암, 갑상선암, 부갑상선암, 부신암, 연조직 육종, 요도암, 음경암, 전립선암, 만성 백혈병, 급성 백혈병, 림프구 림프종, 신장암, 수뇨관암, 신장세포암종, 신장골반암종, 중추신경계 종양, 1차 중추신경계 림프종, 척수 종양, 뇌간 신경교종 및 뇌하수체 선종으로 구성된 그룹으로부터 선택되는 어느 하나 이상인 약학조성물을 제공한다.In the above pharmaceutical composition, the cancer provides a pharmaceutical composition comprising cancer stem cells, wherein the cancer is oral cancer, liver cancer, gastric cancer, colon cancer, breast cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, neck cancer, Skin cancer, cervical cancer, ovarian cancer, colon cancer, small intestine cancer, rectal cancer, fallopian tube carcinoma, anal cancer, endometrial carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, lymph adenocarcinoma, bladder cancer, gallbladder cancer, Endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic leukemia, acute leukemia, lymphocytic lymphoma, kidney cancer, ureter cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system tumor, It provides a pharmaceutical composition of any one or more selected from the group consisting of primary central nervous system lymphoma, spinal cord tumor, brainstem glioma, and pituitary adenoma.

이하 상기 본 발명을 단계별로 상세히 설명한다.Hereinafter, the present invention will be described in detail step by step.

본 발명은 사포닌을 유효성분으로 포함하는 암 치료용 약학조성물에 관한 것으로, 본 발명의 약학조성물은 암세포, 또는 암 줄기세포의 사멸에 현저한 효과가 있으므로, 의학 및 보건 분야에서 크게 이용될 것으로 기대된다.The present invention relates to a pharmaceutical composition for treating cancer comprising saponin as an active ingredient, and the pharmaceutical composition of the present invention has a remarkable effect on killing cancer cells or cancer stem cells, and is expected to be widely used in the fields of medicine and health. .

도 1은 본 발명의 일 실시예에 따른, 암세포에 진세노사이드 Rg3를 농도별로 투여 시 암세포 사멸 효과를 나타낸 것이다.
도 2는 본 발명의 일 실시예에 따른, 암세포에 진세노사이드 Rh2를 농도별로 투여 시 암세포 사멸 효과를 나타낸 것이다.
도 3은 본 발명의 일 실시예에 따른, 암세포에 다양한 알데히드 억제제를 농도별로 투여 시 암세포 사멸 효과를 나타낸 것이다.
도 4는 본 발명의 일 실시예에 따른, 암세포에 사멸 효과가 없었던 진세노사이드 Rg3 농도, 및 알데히드 억제제 농도를 병용 투여 시 암세포 사멸 효과를 나타낸 것이다.
도 5는 본 발명의 일 실시예에 따른, 암세포에 사멸 효과가 없었던 진세노사이드 Rh2 농도, 및 알데히드 억제제 농도를 병용 투여 시 암세포 사멸 효과를 나타낸 것이다.
도 6은 본 발명의 일 실시예에 따른, 암세포에 진세노사이드 Rg3, 알데히드 억제제, 및 비구아니드계 화합물을 병용 투여 시 암세포 사멸 효과를 나타낸 것이다.
도 7은 본 발명의 일 실시예에 따른, 암세포에 진세노사이드 Rh2, 알데히드 억제제, 및 비구아니드계 화합물을 병용 투여 시 암세포 사멸 효과를 나타낸 것이다.
도 8은 발명의 일 실시예에 따른, 암 줄기세포에 진세노사이드 Rg3, 알데히드 억제제, 및 비구아니드계 화합물을 병용 투여 시 암 줄기세포 사멸 효과를 나타낸 것이다.
도 9는 본 발명의 일 실시예에 따른, 암 줄기세포에 진세노사이드 Rh2, 알데히드 억제제, 및 비구아니드계 화합물을 병용 투여 시 암 줄기세포 사멸 효과를 나타낸 것이다.1 shows the effect of killing cancer cells when ginsenoside Rg3 is administered at different concentrations to cancer cells according to an embodiment of the present invention.
FIG. 2 shows the effect of killing cancer cells when ginsenoside Rh2 is administered by concentration to cancer cells according to an embodiment of the present invention.
3 is a diagram illustrating the effect of killing cancer cells when various aldehyde inhibitors are administered to cancer cells according to an embodiment of the present invention.
Figure 4 shows the cancer cell killing effect when the ginsenoside Rg3 concentration, which had no killing effect on cancer cells, and the aldehyde inhibitor concentration are administered in combination according to an embodiment of the present invention.
Figure 5 shows the cancer cell killing effect when the ginsenoside Rh2 concentration, which had no killing effect on cancer cells, and the aldehyde inhibitor concentration are administered in combination according to an embodiment of the present invention.
6 shows the effect of killing cancer cells when a ginsenoside Rg3, an aldehyde inhibitor, and a biguanide compound are administered in combination to cancer cells according to an embodiment of the present invention.
FIG. 7 shows the effect of killing cancer cells when a ginsenoside Rh2, an aldehyde inhibitor, and a biguanide-based compound are administered in combination to cancer cells according to an embodiment of the present invention.
FIG. 8 shows the effect of killing cancer stem cells when ginsenoside Rg3, an aldehyde inhibitor, and a biguanide compound are administered in combination to cancer stem cells according to an embodiment of the present invention.
9 shows the effect of killing cancer stem cells when a ginsenoside Rh2, an aldehyde inhibitor, and a biguanide compound are administered in combination to cancer stem cells according to an embodiment of the present invention.

이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로서, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail through examples. These examples are only for describing the present invention in more detail, and it will be apparent to those of ordinary skill in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .

실시예 1: 암세포, 및 암 줄기세포의 배양Example 1: Culture of cancer cells and cancer stem cells

미국 세포주 은행(American Type Culture Collection; ATCC)으로부터 인간 유방암 세포주인 MDA-MB-231을 수득한 뒤, FBS 5%가 첨가된 RPMI-1640 배지에서 배양하고 이를 '모세포주 MDA-MB231(이하, 'P-231'이라 한다.)'로 명명하였다.After obtaining the human breast cancer cell line MDA-MB-231 from the American Type Culture Collection (ATCC), culturing it in RPMI-1640 medium supplemented with 5% FBS, and culturing it in the'parent cell line MDA-MB231 (hereinafter)' It was named as'P-231'.)

암 줄기세포의 제조를 위해 종양 미세환경에서 대사성 스트레스를 유도하기 위하여, 암 세포 MDA-MB231을 30일 동안 배지를 교체하거나 보충하지 않았다. 시간이 경과할수록 부착된 세포의 수가 감소하였으나, 소수의 세포는 여전히 생존해 있었다. 2일 간격으로 3번 연속하여 세포 수를 측정한 결과 세포 수의 변화가 없었을 때, 배지를 5% FBS를 포함하는 신선한 배지로 보충하였다. 상기의 결과로 제조된 세포는 암 줄기세포로서, 생존한 세포를 '선별 세포주 MDA-MB231(이하, 'S-231'이라 한다.)'로 명명하였다.In order to induce metabolic stress in the tumor microenvironment for the production of cancer stem cells, the medium was not replaced or supplemented with cancer cells MDA-MB231 for 30 days. As time passed, the number of attached cells decreased, but a small number of cells were still alive. When there was no change in the number of cells as a result of measuring the number of cells three times at intervals of 2 days, the medium was supplemented with a fresh medium containing 5% FBS. The cells produced as a result of the above were cancer stem cells, and the cells that survived were named'selected cell line MDA-MB231 (hereinafter, referred to as'S-231')'.

상기 암 줄기세포의 제조 및 검증 과정은 한국 등록특허 KR 1915087호와 동일하게 진행하였다.The manufacturing and verification process of the cancer stem cells were carried out in the same manner as in Korean Patent No. 1915087.

실시예 2: 진세노사이드의 암세포 사멸 효과 확인Example 2: Confirmation of cancer cell killing effect of ginsenoside

실시예 1의 방법으로 준비한 P-231 세포를 96-웰 플레이트에 1×104 cell/well 농도로 파종하고, 37°C, 5% CO2 환경에서 하룻밤 배양하였다. 이후, 진세노사이드 Rg3(Embo Laboratory, Daejeon, Korea)와 Rh2(Chemfaces, Wuhan, China)를 각각 표 1의 농도로 투여하여 37°C, 5% CO2 환경에서 24시간 배양하고, 세포 생존율 측정 키트(Cell Counting Kit-8, Dojindo, Kumamoto, Japan)를 10㎕/well 처리한 후, 37°C, 5% CO2 환경에서 3시간 추가로 배양하고, 450nm 파장에서 흡광도 측정하여(Synergy HTX Multi-Reader, BioTek, Winooski, VT, USA) 세포 생존율을 평가하였다. 측정값은 음성대조군에 대비하여 백분율로 산출하였다. P-231 cells prepared by the method of Example 1 were seeded in a 96-well plate at a concentration of 1×10 4 cells/well, and cultured overnight at 37°C and 5% CO 2 . Thereafter, ginsenosides Rg3 (Embo Laboratory, Daejeon, Korea) and Rh2 (Chemfaces, Wuhan, China) were administered at the concentrations in Table 1, respectively, and cultured for 24 hours in an environment of 37°C and 5% CO 2 , and cell viability was measured. After 10 μl/well treatment of the kit (Cell Counting Kit-8, Dojindo, Kumamoto, Japan), incubate for an additional 3 hours in an environment of 37°C and 5% CO 2 , and measure the absorbance at 450 nm wavelength (Synergy HTX Multi -Reader, BioTek, Winooski, VT, USA) Cell viability was evaluated. The measured value was calculated as a percentage compared to the negative control group.

Figure pat00001
Figure pat00001

실험 결과, Rg3와 Rh2 모두 0.01uM~5uM 농도에서는 암세포의 사멸 효과가 없고, 10uM 이상 농도로 처리하여야 암세포 사멸 효과가 있는 것으로 나타났다. 상기 결과를 도 1과 도 2에 나타내었다.As a result of the experiment, it was found that both Rg3 and Rh2 had no effect on killing cancer cells at a concentration of 0.01uM to 5uM, and treatment with a concentration of 10uM or higher had the effect of killing cancer cells. The results are shown in FIGS. 1 and 2.

실시예 3: 알데히드 억제제의 암세포 사멸 효과 확인Example 3: Confirmation of the effect of aldehyde inhibitors on killing cancer cells

실시예 2와 동일한 방법으로 P-231 세포에 다양한 알데히드 억제제를 표 2의 농도로 투여한 후, 세포생존율을 평가하였다.In the same manner as in Example 2, various aldehyde inhibitors were administered to P-231 cells at the concentrations shown in Table 2, and then cell viability was evaluated.

Figure pat00002
Figure pat00002

실험 결과, 고시폴의 경우에는 10uM~20uM 농도에서는 암세포의 사멸 효과가 없고, 30uM 이상 농도로 처리하여야 암세포 사멸 효과가 있는 것으로 나타났다. 디설피람은 0.2uM, DEAB는 1uM, 시트랄은 50uM 농도에서 암세포의 사멸 효과가 없는 것으로 나타났다. 상기 결과를 도 3에 나타내었다.As a result of the experiment, it was found that in the case of Gosifol, there was no effect of killing cancer cells at concentrations of 10 μM to 20 μM, and treatment with a concentration of 30 μM or higher had the effect of killing cancer cells. Disulfiram was found to have no effect on killing cancer cells at concentrations of 0.2uM, DEAB 1uM, and citral 50uM. The results are shown in FIG. 3.

실시예 4: 진세노사이드, 및 알데히드 억제제의 암세포 사멸 효과 확인Example 4: Confirmation of cancer cell killing effect of ginsenoside and aldehyde inhibitor

실시예 2와 동일한 방법으로 P-231 세포에 다양한 알데히드 억제제와 진세노사이드를 표 3과 표 4의 농도로 투여한 후, 세포생존율을 평가하였다.In the same manner as in Example 2, various aldehyde inhibitors and ginsenosides were administered to P-231 cells at the concentrations shown in Tables 3 and 4, and then cell viability was evaluated.

Figure pat00003
Figure pat00003

Figure pat00004
Figure pat00004

실험 결과, 상기 실시예 2와 3을 통해서 암세포 사멸 효과가 없었던 진세노사이드 농도, 및 알데히드 억제제 농도를 병용 투여시, 현저하게 암세포 사멸 효과가 있는 것으로 나타났다. 상기 결과를 도 4와 도 5에 나타내었다.As a result of the experiment, when the ginsenoside concentration, which had no cancer cell killing effect, and the aldehyde inhibitor concentration, were administered together, it was found that the cancer cell killing effect was remarkably. The results are shown in FIGS. 4 and 5.

실시예 5: 진세노사이드, 알데히드 억제제, 및 비구아니드계 화합물의 암세포 사멸 효과 확인Example 5: Confirmation of cancer cell killing effects of ginsenosides, aldehyde inhibitors, and biguanide compounds

실시예 2와 동일한 방법으로 P-231 세포에 다양한 알데히드 억제제, 진세노사이드, 및 비구아니드계 화합물을 표 5와 표 6의 농도로 투여한 후, 세포생존율을 평가하였다.In the same manner as in Example 2, various aldehyde inhibitors, ginsenosides, and biguanide compounds were administered to P-231 cells at the concentrations shown in Tables 5 and 6, and then cell viability was evaluated.

Figure pat00005
Figure pat00005

Figure pat00006
Figure pat00006

실험 결과, 상기 표 3, 표 4와 동일한 조건에서 비구아니드계 화합물(펜포르민) 100μM을 추가로 병용 처리 시, 암세포 사멸 효과가 더욱 현저한 것으로 나타났다. 상기 결과를 도 6과 도 7에 나타내었다.As a result of the experiment, when an additional 100 μM of a biguanide-based compound (phenformin) was added in combination under the same conditions as in Tables 3 and 4, it was found that the cancer cell killing effect was more remarkable. The results are shown in FIGS. 6 and 7.

실시예 6: 진세노사이드, 알데히드 억제제, 및 비구아니드계 화합물의 암 줄기세포 사멸 효과 확인Example 6: Confirmation of cancer stem cell killing effect of ginsenoside, aldehyde inhibitor, and biguanide compound

실시예 2와 동일한 방법으로 S-231 세포에 다양한 알데히드 억제제, 진세노사이드, 및 비구아니드계 화합물을 표 7과 표 8의 농도로 투여한 후, 세포생존율을 평가하였다.In the same manner as in Example 2, various aldehyde inhibitors, ginsenosides, and biguanide compounds were administered to S-231 cells at the concentrations shown in Tables 7 and 8, and then cell viability was evaluated.

Figure pat00007
Figure pat00007

Figure pat00008
Figure pat00008

실험 결과, 암세포(표 5, 및 표 6)에서와 마찬가지로 암 줄기세포에서도 진세노사이드, 알데히드 억제제, 및 비구아니드계 화합물을 병용 투여 시, 세포 사멸 효과가 현저한 것으로 나타났다. 상기 결과를 도 8과 도 9에 나타내었다.As a result of the experiment, it was found that the apoptosis effect was remarkable when ginsenoside, an aldehyde inhibitor, and a biguanide-based compound were administered in combination in cancer stem cells as in cancer cells (Tables 5 and 6). The results are shown in FIGS. 8 and 9.

주목할만한 점은 일반적으로 동일한 항암제 투여 시 암 줄기세포가 암세포보다 세포 사멸 효과가 미비한 데 비하여, 본 발명의 약학조성물(진세노사이드, 알데히드 억제제, 및 비구아니드계 화합물을 병용 투여)을 처리한 경우에는 암 줄기세포에서 암세포보다 세포 사멸 효과가 더욱 현저하게 나타났다는 것이다. 따라서 본 발명의 약학조성물은 암 줄기세포를 포함하는 암의 치료에 매우 유용할 것으로 기대된다.It is noteworthy that, in general, when the same anticancer agent is administered, cancer stem cells have less apoptosis effect than cancer cells, but when the pharmaceutical composition of the present invention (ginsenoside, aldehyde inhibitor, and biguanide compound are administered in combination) E, cancer stem cells showed more remarkable apoptosis than cancer cells. Therefore, the pharmaceutical composition of the present invention is expected to be very useful in the treatment of cancer including cancer stem cells.

이상으로 본 발명의 특정한 부분을 상세히 기술하였는바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적인 기술은 단지 바람직한 구현예일 뿐이며, 이에 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 따라서 본 발명의 실질적인 범위는 첨부된 청구항과 그의 등가물에 의하여 정의된다고 할 것이다.As the specific parts of the present invention have been described in detail above, it is clear that these specific techniques are only preferred embodiments for those of ordinary skill in the art, and thus the scope of the present invention is not limited thereto. Therefore, it will be said that the practical scope of the present invention is defined by the appended claims and their equivalents.

Claims (12)

진세노사이드 Rg3, 또는 Rh2을 유효성분으로 포함하고, 알데히드 억제제를 추가로 포함하며,
상기 알데히드 억제제는 베노밀(benomyl), 시스플라틴(cis-diamminedichloridoplatinum; CDDP), 클로르프로파마이드(chlorpropamide), 시트랄(citral), CVT-10216(3-[[[3-[4-[(Methylsulfonyl)amino]phenyl]-4-oxo-4H-1-benzopyran-7-yl]oxy]methyl]-benzoic acid, 3-[[[3-[4-[(Methylsulfonyl)amino]phenyl]-4-oxo-4H-chromen-7-yl]oxy]methyl]benzoic acid), 사이안아마이드(cyanamide), 다이진(daidzin), 디에틸아미노벤즈알데히드(Diethylaminobenzaldehyde; DEAB), 디설피람(disulfiram), 고시폴(gossypol), 모리네이트(molinate), N-아세틸-N-아세톡시-4-클로로벤젠설폰아미드(N-Acetyl-N-acetoxy-4-chlorobenzenesulfonamide), 파르질린(pargyline hydrochloride), 포스포(에놀)피루브산 모노나트륨염 수화물(phospho(enol)pyruvic acid monosodium salt hydrate), 페닐글리옥산(phenylglyoxal), 레티노산(reginoic acid), 키누렌산(kynurenic acid), 3-히드록시키누레닌(3-hydroxy-DL-kynurenine), 및 옥살산나트륨(sodium oxamate)으로 구성된 그룹으로부터 선택되는 어느 하나 이상인, 암의 예방 또는 치료용 약학조성물.
It contains ginsenoside Rg3 or Rh2 as an active ingredient, and further contains an aldehyde inhibitor,
The aldehyde inhibitors are benomyl, cis-diamminedichloridoplatinum (CDDP), chlorpropamide, citral, CVT-10216(3-[[[3-[4-[(Methylsulfonyl) amino]phenyl]-4-oxo-4H-1-benzopyran-7-yl]oxy]methyl]-benzoic acid, 3-[[[3-[4-[(Methylsulfonyl)amino]phenyl]-4-oxo- 4H-chromen-7-yl]oxy]methyl]benzoic acid), cyanamide, daidzin, diethylaminobenzaldehyde (DEAB), disulfiram, gossypol ), morinate, N-Acetyl-N-acetoxy-4-chlorobenzenesulfonamide, pargyline hydrochloride, phospho(enol)pyruvate Phospho (enol) pyruvic acid monosodium salt hydrate, phenylglyoxal, retinoic acid, kynurenic acid, 3-hydroxy-DL- kynurenine), and sodium oxamate (sodium oxamate), any one or more selected from the group consisting of, a pharmaceutical composition for the prevention or treatment of cancer.
 제 1항에 있어서,
상기 진세노사이드 Rg3, 또는 Rh2는 홍삼, 또는 인삼 유래 추출물인 것을 특징으로 하는, 약학조성물.
The method of claim 1,
The ginsenoside Rg3, or Rh2 is a pharmaceutical composition, characterized in that the extract derived from red ginseng or ginseng.
 제 1항에 있어서,
상기 약학조성물은 비구아니드계 화합물을 추가로 포함하는, 약학조성물.
The method of claim 1,
The pharmaceutical composition further comprises a biguanide-based compound, a pharmaceutical composition.
 제 3항에 있어서,
상기 비구아니드계 화합물은 메트포민(metformin), 펜포르민(phenformin), 및 부포르민(buformine)으로 구성된 그룹으로부터 선택되는 어느 하나 이상인, 약학조성물.
The method of claim 3,
The biguanide-based compound is any one or more selected from the group consisting of metformin, phenformin, and buformine, a pharmaceutical composition.
 제 1항에 있어서,
상기 암은 암 줄기세포를 포함하는 것인, 약학조성물.
The method of claim 1,
The cancer comprising cancer stem cells, pharmaceutical composition.
 제 1항에 있어서,
상기 암은 구강암, 간암, 위암, 결장암, 유방암, 폐암, 골암, 췌장암, 피부암, 두부암, 경부암, 피부암, 자궁경부암, 난소암, 대장암, 소장암, 직장암, 나팔관암종, 항문부근암, 자궁내막암종, 질암종, 음문암종, 호지킨병(Hodgkin's disease), 식도암, 임파선암, 방광암, 담낭암, 내분비선암, 갑상선암, 부갑상선암, 부신암, 연조직 육종, 요도암, 음경암, 전립선암, 만성 백혈병, 급성 백혈병, 림프구 림프종, 신장암, 수뇨관암, 신장세포암종, 신장골반암종, 중추신경계 종양, 1차 중추신경계 림프종, 척수 종양, 뇌간 신경교종 및 뇌하수체 선종으로 구성된 그룹으로부터 선택되는 어느 하나 이상인, 약학조성물.
The method of claim 1,
The cancer is oral cancer, liver cancer, stomach cancer, colon cancer, breast cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, cervical cancer, skin cancer, cervical cancer, ovarian cancer, colon cancer, small intestine cancer, rectal cancer, fallopian tube carcinoma, anal muscle cancer, uterus Endocrine carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, lymph adenocarcinoma, bladder cancer, gallbladder cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic Any one or more selected from the group consisting of leukemia, acute leukemia, lymphocytic lymphoma, kidney cancer, ureteral cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system tumor, primary central nervous system lymphoma, spinal cord tumor, brainstem glioma, and pituitary adenoma. , Pharmaceutical composition.
 진세노사이드 Rg3, 또는 Rh2을 유효성분으로 포함하고, 알데히드 억제제를 추가로 포함하며,
상기 알데히드 억제제는 베노밀(benomyl), 시스플라틴(cis-diamminedichloridoplatinum; CDDP), 클로르프로파마이드(chlorpropamide), 시트랄(citral), CVT-10216(3-[[[3-[4-[(Methylsulfonyl)amino]phenyl]-4-oxo-4H-1-benzopyran-7-yl]oxy]methyl]-benzoic acid, 3-[[[3-[4-[(Methylsulfonyl)amino]phenyl]-4-oxo-4H-chromen-7-yl]oxy]methyl]benzoic acid), 사이안아마이드(cyanamide), 다이진(daidzin), 디에틸아미노벤즈알데히드(Diethylaminobenzaldehyde; DEAB), 디설피람(disulfiram), 고시폴(gossypol), 모리네이트(molinate), N-아세틸-N-아세톡시-4-클로로벤젠설폰아미드(N-Acetyl-N-acetoxy-4-chlorobenzenesulfonamide), 파르질린(pargyline hydrochloride), 포스포(에놀)피루브산 모노나트륨염 수화물(phospho(enol)pyruvic acid monosodium salt hydrate), 페닐글리옥산(phenylglyoxal), 레티노산(reginoic acid), 키누렌산(kynurenic acid), 3-히드록시키누레닌(3-hydroxy-DL-kynurenine), 및 옥살산나트륨(sodium oxamate)으로 구성된 그룹으로부터 선택되는 어느 하나 이상인, 암의 전이 억제용 약학조성물.
It contains ginsenoside Rg3 or Rh2 as an active ingredient, and further contains an aldehyde inhibitor,
The aldehyde inhibitors are benomyl, cis-diamminedichloridoplatinum (CDDP), chlorpropamide, citral, CVT-10216(3-[[[3-[4-[(Methylsulfonyl) amino]phenyl]-4-oxo-4H-1-benzopyran-7-yl]oxy]methyl]-benzoic acid, 3-[[[3-[4-[(Methylsulfonyl)amino]phenyl]-4-oxo- 4H-chromen-7-yl]oxy]methyl]benzoic acid), cyanamide, daidzin, diethylaminobenzaldehyde (DEAB), disulfiram, gossypol ), morinate, N-Acetyl-N-acetoxy-4-chlorobenzenesulfonamide, pargyline hydrochloride, phospho(enol)pyruvate Phospho(enol)pyruvic acid monosodium salt hydrate, phenylglyoxal, retinoic acid, kynurenic acid, 3-hydroxy-DL- kynurenine), and sodium oxalate (sodium oxamate) any one or more selected from the group consisting of, a pharmaceutical composition for inhibiting metastasis of cancer.
 제 7항에 있어서,
상기 진세노사이드 Rg3, 또는 Rh2는 홍삼, 또는 인삼 유래 추출물인 것을 특징으로 하는, 약학조성물.
The method of claim 7,
The ginsenoside Rg3, or Rh2 is a pharmaceutical composition, characterized in that the extract derived from red ginseng or ginseng.
 제 7항에 있어서,
상기 약학조성물은 비구아니드계 화합물을 추가로 포함하는, 약학조성물.
The method of claim 7,
The pharmaceutical composition further comprises a biguanide-based compound, a pharmaceutical composition.
 제 9항에 있어서,
상기 비구아니드계 화합물은 메트포민(metformin), 펜포르민(phenformin), 및 부포르민(buformine)으로 구성된 그룹으로부터 선택되는 어느 하나 이상인, 약학조성물.
The method of claim 9,
The biguanide-based compound is any one or more selected from the group consisting of metformin, phenformin, and buformine, a pharmaceutical composition.
 제 7항에 있어서,
상기 암은 암 줄기세포를 포함하는 것인, 약학조성물.
The method of claim 7,
The cancer comprising cancer stem cells, pharmaceutical composition.
 제 7항에 있어서,
상기 암은 구강암, 간암, 위암, 결장암, 유방암, 폐암, 골암, 췌장암, 피부암, 두부암, 경부암, 피부암, 자궁경부암, 난소암, 대장암, 소장암, 직장암, 나팔관암종, 항문부근암, 자궁내막암종, 질암종, 음문암종, 호지킨병(Hodgkin's disease), 식도암, 임파선암, 방광암, 담낭암, 내분비선암, 갑상선암, 부갑상선암, 부신암, 연조직 육종, 요도암, 음경암, 전립선암, 만성 백혈병, 급성 백혈병, 림프구 림프종, 신장암, 수뇨관암, 신장세포암종, 신장골반암종, 중추신경계 종양, 1차 중추신경계 림프종, 척수 종양, 뇌간 신경교종 및 뇌하수체 선종으로 구성된 그룹으로부터 선택되는 어느 하나 이상인, 약학조성물.The method of claim 7,
The cancer is oral cancer, liver cancer, stomach cancer, colon cancer, breast cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, cervical cancer, skin cancer, cervical cancer, ovarian cancer, colon cancer, small intestine cancer, rectal cancer, fallopian tube carcinoma, anal muscle cancer, uterus Endocrine carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, lymph adenocarcinoma, bladder cancer, gallbladder cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic Any one or more selected from the group consisting of leukemia, acute leukemia, lymphocytic lymphoma, kidney cancer, ureteral cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system tumor, primary central nervous system lymphoma, spinal cord tumor, brainstem glioma, and pituitary adenoma. , Pharmaceutical composition.
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