KR20240030281A - Composition for preventing and treating a pancreatic cancer comprising extracts of Commiphora myrrha Engler - Google Patents
Composition for preventing and treating a pancreatic cancer comprising extracts of Commiphora myrrha Engler Download PDFInfo
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- KR20240030281A KR20240030281A KR1020220109074A KR20220109074A KR20240030281A KR 20240030281 A KR20240030281 A KR 20240030281A KR 1020220109074 A KR1020220109074 A KR 1020220109074A KR 20220109074 A KR20220109074 A KR 20220109074A KR 20240030281 A KR20240030281 A KR 20240030281A
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Abstract
본 발명은 몰약 추출물을 유효성분으로 포함하는 췌장암의 예방, 개선 또는 치료용 조성물에 관한 것으로, 본 발명에 따른 몰약 에탄올 추출물은 췌장암 세포인 PANC 1세포 내에서 암세포 증식 억제 효과를 나타내며, PARP의 절단 및 발현을 증가시켜 세포사멸(Apoptosis)을 촉진시키고, MMP 활성을 억제 및 미토콘드리아 막전위를 감소시켜 암세포의 사멸 유도를 통해서 암을 예방, 개선 또는 치료하기 위한 약학적 조성물 및 건강식품으로의 적용가능성을 확인하였다.The present invention relates to a composition for preventing, improving or treating pancreatic cancer containing myrrh extract as an active ingredient. The ethanol extract of myrrh according to the present invention exhibits an inhibitory effect on cancer cell proliferation in PANC 1 cells, which are pancreatic cancer cells, and cleaves PARP. and its applicability as a pharmaceutical composition and health food for preventing, improving, or treating cancer by promoting apoptosis by increasing expression, inhibiting MMP activity, and reducing mitochondrial membrane potential to induce death of cancer cells. Confirmed.
Description
본 발명은 몰약 추출물을 유효성분으로 함유하는 췌장암의 예방, 개선 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing, improving or treating pancreatic cancer containing myrrh extract as an active ingredient.
인간의 몸을 구성하고 있는 가장 작은 단위를 세포(cell)이라 부르는데 정상적인 세포는 세포 내 조절기능에 의해 분열하며 성장하고 죽어 없어지기도 하며 세포수의 균형을 유지한다. 어떤 원인으로 세포가 손상을 받은 경우, 치료를 받아 정상 세포로 역할을 하거나 회복이 안된 경우 스스로 사멸하게 된다. 그러나 여러 가지 이유로 인해 세포의 유전자에 변화가 일어나면 비정상적으로 세포가 변하여 불완전하게 성숙하고, 세포주기가 조절되지 않아 세포분열을 계속하는데 이를 암(cancer)이라 정의한다. 또한 암은 주의 조직 및 장기에 침입하고 이들을 파괴할 뿐만 아니라 다른 장기로 펴져 갈 수 있는 특징이 있다. 암에 의한 사망률은 국내에서 사망원인 1위로, 매년 그 수가 증가하고 있다. 특정 암의 의학적 치료에는 상당한 진보가 있어 왔지만, 모든 암에 대한 전반적인 5년 생존율은 과거 20년간 약 10％ 정도만 개선되었다. 암, 또는 악성종양은 제어되지 않는 방식으로 신속하게 전이 및 성장하기 때문에, 제시간에 이를 검출하고 치료하는 것이 극도로 어렵다.The smallest unit that makes up the human body is called a cell. Normal cells divide, grow, and die through intracellular regulatory functions, maintaining cell number balance. If a cell is damaged for some reason, it can receive treatment and function as a normal cell, or if it cannot recover, it can die on its own. However, when changes occur in the genes of a cell for various reasons, the cell changes abnormally, matures incompletely, and the cell cycle is not regulated and cell division continues, which is defined as cancer. Additionally, cancer has the characteristic of not only invading and destroying local tissues and organs, but also spreading to other organs. Cancer mortality is the number one cause of death in Korea, and the number is increasing every year. Although there have been significant advances in the medical treatment of certain cancers, the overall five-year survival rate for all cancers has improved by only about 10% over the past 20 years. Cancer, or malignant tumor, spreads and grows rapidly in an uncontrolled manner, making it extremely difficult to detect and treat in time.
췌장암(pancreatic cancer)은 보건복지부 통계자료에 따르면 2017년 전체 암 발생 중에서 8위를 차지하는 암으로 조기 진단이 어렵고 다른 장기로 전이가 잘 되어 예후가 좋지 않은 암으로 알려져 있다. 또한 췌장암은 치료 이후에도 재발이 되어 완치가 힘든 암으로, 5년 생존율이 약 12%정도로 위암, 대장암, 유방암이 각각 76.5%, 75%, 93%인 것에 비해 현저히 낮은 수준이다. According to statistics from the Ministry of Health and Welfare, pancreatic cancer ranks 8th among all cancers in 2017. It is difficult to diagnose early and is known to have a poor prognosis as it easily metastasizes to other organs. In addition, pancreatic cancer is a cancer that is difficult to cure because it recurs even after treatment, and the 5-year survival rate is about 12%, which is significantly lower than the 76.5%, 75%, and 93% for stomach cancer, colon cancer, and breast cancer, respectively.
현재, 암의 치료를 위해서는 수술요법, 방사선 치료 요법 및 화학요법 등이 사용되고 있다. 이 중에서, 화학요법은 항암제를 이용하여 암을 치료하는 방법을 말한다. 오늘날에는 약 60여 종의 다양한 항암제가 사용되고 있으며, 현재 사용되고 있는 젬시타빈(gemcitabine)과 같은 항암제와 방사선치료는 혈관계, 신경계, 혈액계, 피부 등에서 다양한 부작용을 초래할 수 있기 때문에 이를 최소화하고 보다 나은 치료효과를 갖는 새로운 치료제가 필요한 상황이다.Currently, surgery, radiation therapy, and chemotherapy are used to treat cancer. Among these, chemotherapy refers to a method of treating cancer using anticancer drugs. Today, about 60 different types of anticancer drugs are used, and the currently used anticancer drugs such as gemcitabine and radiation therapy can cause various side effects in the vascular system, nervous system, blood system, skin, etc., so it is necessary to minimize them and provide better treatment. There is a need for new effective treatments.
따라서 이러한 췌장암에 한약재를 이용하여 기존 항암제를 사용한 치료보다 부작용이 적으면서 효능이 좋은 새로운 치료제를 개발하기 위해 연구를 진행하였으며, 몰약추출물이 췌장암 세포에 대해서 세포사멸을 유도하는 항암효능이 있음을 확인하여 본 발명을 완성하였다.Therefore, research was conducted to develop a new treatment for pancreatic cancer using herbal medicine that is more effective and has fewer side effects than treatment using existing anticancer drugs, and it was confirmed that myrrh extract has an anticancer effect by inducing apoptosis in pancreatic cancer cells. Thus, the present invention was completed.
본 발명의 목적은 췌장암에서 몰약 추출물을 활용 및 이용하여 췌장암을 치료하거나 예방을 하는 것으로서 기존의 치료제로 몰약 추출물을 치료제로서 사용하여 췌장암을 치료하거나 예방하는 것이다.The purpose of the present invention is to treat or prevent pancreatic cancer by using myrrh extract as a treatment for pancreatic cancer, and to treat or prevent pancreatic cancer by using myrrh extract as a treatment.
상기 목적을 달성하기 위하여,In order to achieve the above purpose,
본 발명은 몰약 에탄올 추출물을 유효성분으로 포함하는 췌장암의 예방 또는 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating pancreatic cancer comprising an ethanol extract of myrrh as an active ingredient.
또한, 본 발명은 몰약 에탄올 추출물을 유효성분으로 포함하는 췌장암에 대한 항암보조제를 제공한다.Additionally, the present invention provides an anti-cancer adjuvant for pancreatic cancer containing myrrh ethanol extract as an active ingredient.
또한, 본 발명은 몰약 에탄올 추출물을 포함하는 췌장암의 예방 또는 개선용 식품 조성물을 제공한다.Additionally, the present invention provides a food composition for preventing or improving pancreatic cancer containing an ethanol extract of myrrh.
나아가, 본 발명은 몰약 추출물을 유효성분으로 함유하는, 인비트로(in vitro)에서 췌장암 세포의 MMP 활성을 억제하는 조성물을 제공한다.Furthermore, the present invention provides a composition that inhibits MMP activity of pancreatic cancer cells in vitro, containing myrrh extract as an active ingredient.
더 나아가, 본 발명은 몰약 추출물을 유효성분으로 함유하는, 인비트로(in vitro)에서 췌장암 세포의 세포사멸을 유도하는 조성물을 제공한다.Furthermore, the present invention provides a composition that induces apoptosis of pancreatic cancer cells in vitro, containing myrrh extract as an active ingredient.
본 발명에 따른 몰약 추출물은 췌장암 세포인 PANC 1세포 내에서 세포 증식 억제 효과를 나타내며 몰약 추출물이 농도 의존적으로 PARP의 절단 및 발현을 증가시켜 세포사멸(Apoptosis)을 촉진시키고, MMP 활성을 억제 및 미토콘드리아 막전위를 감소시켜 암세포의 사멸을 유도하는 효과를 나타내므로, 암을 예방, 개선 또는 치료하기 위한 약학적 조성물 또는 식품 조성물의 활성 성분으로 유용하게 사용될 수 있다.The myrrh extract according to the present invention exhibits a cell proliferation inhibitory effect in PANC 1 cells, which are pancreatic cancer cells. The myrrh extract increases the cleavage and expression of PARP in a concentration-dependent manner, thereby promoting apoptosis, inhibiting MMP activity and mitochondrial Since it has the effect of inducing the death of cancer cells by reducing the membrane potential, it can be usefully used as an active ingredient in pharmaceutical compositions or food compositions to prevent, improve, or treat cancer.
도 1은 췌장암 세포주인 PANC 1세포에 대한 몰약 추출물의 세포 독성을 나타낸 그래프이다.
도 2는 몰약 에탄올 추출물 처리에 의한 췌장암 세포주 PANC-1의 세포사멸 관련 단백질 발현 정도를 나타낸 도이다.
도 3은 몰약 에탄올 추출물 처리에 의한 췌장암 세포주 PANC-1의 미토콘드리아 막전위를 JC-1 assay를 통해 분석한 결과를 나타낸 그래프이다.Figure 1 is a graph showing the cytotoxicity of myrrh extract against PANC 1 cells, a pancreatic cancer cell line.
Figure 2 is a diagram showing the expression level of apoptosis-related proteins in the pancreatic cancer cell line PANC-1 by treatment with myrrh ethanol extract.
Figure 3 is a graph showing the results of analyzing the mitochondrial membrane potential of pancreatic cancer cell line PANC-1 by treatment with myrrh ethanol extract through JC-1 assay.
이하, 첨부된 도면을 참조하여 본 발명의 구현예로 본 발명을 상세히 설명하기로 한다. 다만, 하기 구현예는 본 발명에 대한 예시로 제시되는 것으로, 당업자에게 주지 저명한 기술 또는 구성에 대한 구체적인 설명이 본 발명의 요지를 불필요하게 흐릴 수 있다고 판단되는 경우에는 그 상세한 설명을 생략할 수 있고, 이에 의해 본 발명이 제한되지는 않는다. 본 발명은 후술하는 특허청구범위의 기재 및 그로부터 해석되는 균등 범주 내에서 다양한 변형 및 응용이 가능하다.Hereinafter, the present invention will be described in detail through embodiments of the present invention with reference to the attached drawings. However, the following embodiments are provided as examples of the present invention, and if it is judged that a detailed description of a technology or configuration well known to those skilled in the art may unnecessarily obscure the gist of the present invention, the detailed description may be omitted. , the present invention is not limited thereby. The present invention is capable of various modifications and applications within the description of the claims described below and the scope of equivalents interpreted therefrom.
또한, 본 명세서에서 사용되는 용어(terminology)들은 본 발명의 바람직한 실시예를 적절히 표현하기 위해 사용된 용어들로서, 이는 사용자, 운용자의 의도 또는 본 발명이 속하는 분야의 관례 등에 따라 달라질 수 있다. 따라서, 본 용어들에 대한 정의는 본 명세서 전반에 걸친 내용을 토대로 내려져야 할 것이다. 명세서 전체에서, 어떤 부분이 어떤 구성요소를 "포함"한다고 할 때, 이는 특별히 반대되는 기재가 없는 한 다른 구성요소를 제외하는 것이 아니라 다른 구성 요소를 더 포함할 수 있는 것을 의미한다.In addition, the terminology used in this specification is a term used to appropriately express preferred embodiments of the present invention, and may vary depending on the intention of the user or operator or the customs of the field to which the present invention belongs. Therefore, definitions of these terms should be made based on the content throughout this specification. Throughout the specification, when a part is said to “include” a certain element, this means that it may further include other elements rather than excluding other elements, unless specifically stated to the contrary.
일 측면에서, 본 발명은 몰약 에탄올 추출물을 유효성분으로 포함하는 췌장암의 예방 또는 치료용 약학적 조성물에 관한 것이다.In one aspect, the present invention relates to a pharmaceutical composition for preventing or treating pancreatic cancer comprising an ethanol extract of myrrh as an active ingredient.
일 구현예에서, 상기 추출물은 0 내지 100%(v/v) 에탄올 수용액을 추출용매로 이용하여 추출되는 것일 수 있고, 100% 에탄올로 추출되는 것이 더욱 바람직하며, 에탄올 수용액을 이용하여 추출되는 추출물 대비 100% 에탄올로 추출된 추출물에서 더 우수한 항췌장암 효과가 나타나는 것일 수 있다.In one embodiment, the extract may be extracted using 0 to 100% (v/v) ethanol aqueous solution as an extraction solvent, more preferably extracted with 100% ethanol, and the extract extracted using an ethanol aqueous solution. In comparison, extracts extracted with 100% ethanol may have a better anti-pancreatic cancer effect.
본 발명에서 사용되는 용어 "추출물(extract)"은 생약을 적절한 침출액으로 짜내고 침출액을 증발시켜 농축한 제제를 의미하는 것으로, 이에 제한되지는 않으나, 추출처리에 의해 얻어지는 추출액, 추출액의 희석액 또는 농축액, 추출액을 건조하여 얻어지는 건조물, 이들의 조정제물 또는 정제물일 수 있다. 상기 몰약 에탄올 추출물은 통상의 기술분야에 공지된 일반적인 추출방법, 분리 및 정제방법을 이용하여 제조할 수 있다. 상기 추출방법으로는, 이에 제한되지는 않으나, 바람직하게 열탕 추출, 열수 추출, 냉침 추출, 환류 냉각 추출 또는 초음파 추출 등의 방법을 사용할 수 있다.The term "extract" used in the present invention refers to a preparation obtained by squeezing a herbal medicine into an appropriate leachate and evaporating the leachate to concentrate. It is not limited thereto, but is not limited to the extract, dilution or concentrate of the extract obtained by extraction treatment, It may be a dried product obtained by drying the extract, a crude product thereof, or a purified product. The ethanol extract of myrrh can be prepared using general extraction, separation and purification methods known in the art. The extraction method is not limited thereto, but preferably includes boiling water extraction, hot water extraction, cold needle extraction, reflux cooling extraction, or ultrasonic extraction.
일 구현예에서, 본 발명의 몰약 에탄올 추출물은 MMP(Matrix metalloproteinase) 활성을 억제시켜, 암 전이 및 암세포 성장을 억제시키는 것일 수 있으나, 이에 제한되지는 않는다.In one embodiment, the ethanol extract of myrrh of the present invention may inhibit MMP (Matrix metalloproteinase) activity, thereby inhibiting cancer metastasis and cancer cell growth, but is not limited thereto.
일 구현예에서, 본 발명의 몰약 에탄올 추출물은 미토콘드리아 막전위를 감소시켜 암 전이 및 암세포 성장을 조절하는 것일 수 있으나, 이에 제한되지는 않는다.In one embodiment, the ethanol extract of myrrh of the present invention may regulate cancer metastasis and cancer cell growth by reducing mitochondrial membrane potential, but is not limited thereto.
일 구현예에서, 본 발명의 몰약 에탄올 추출물은 췌장암 세포의 세포사멸을 유발하는 것일 수 있고, 상기 세포사멸 유발은 PARP(poly(ADP-ribose) polymerase)의 절단 또는 발현이 증가하여 유도되는 것일 수 있으나, 이에 제한되지는 않는다.In one embodiment, the ethanol extract of myrrh of the present invention may induce apoptosis of pancreatic cancer cells, and the apoptosis may be induced by cleavage or increased expression of PARP (poly(ADP-ribose) polymerase). However, it is not limited to this.
본 발명의 일 실시예에서는 몰약 에탄올 추출물 처리에 의한 췌장암 세포의 사멸이 증가하는 것을 확인하였으며(도 1), 이와 같은 항암 활성 기작을 확인하기 위하여 세포 사멸과 관련된 단백질 발현을 확인한 결과, Survivin 발현 및 Pro PARP의 발현량이 감소함으로써(도 2), PARP가 활성화되어 절단이 이루어져 췌장암 세포의 세포사멸을 유도해 항암 활성을 나타내는 것임을 유추할 수 있다. 또한, 몰약 에탄올 추출물은 MMP(Matrix metalloproteinase) 활성을 억제시키고, 미토콘드리아 막전위를 감소시킴으로써, 암 전이 및 암세포 성장을 조절할 수 있음을 확인하였다(도 3).In one embodiment of the present invention, it was confirmed that the death of pancreatic cancer cells increased by treatment with myrrh ethanol extract (Figure 1). In order to confirm this anticancer activity mechanism, the expression of proteins related to cell death was confirmed, and as a result, Survivin expression and As the expression level of Pro PARP decreases (Figure 2), it can be inferred that PARP is activated and cleaved to induce apoptosis of pancreatic cancer cells, thereby exhibiting anticancer activity. In addition, it was confirmed that myrrh ethanol extract can control cancer metastasis and cancer cell growth by inhibiting MMP (Matrix metalloproteinase) activity and reducing mitochondrial membrane potential (Figure 3).
본 발명에서 사용되는 용어, "세포사멸"은 아폽토시스 또는 세포자멸사라고도 하며, 일종의 계획된 세포 죽음(programmed cell death; PCD)으로서, 우리 몸 안에 입력되어 있는 생체 프로그램에 의해 비정상 세포, 손상된 세포, 노화된 세포가 스스로 자살해 사멸함으로써 전체적인 신체 건강을 유지하도록 하는 메커니즘이다.The term "apoptosis" used in the present invention is also called apoptosis or apoptosis, and is a type of programmed cell death (PCD), which refers to abnormal cells, damaged cells, and aged cells caused by biological programs entered into our bodies. It is a mechanism by which cells commit suicide to maintain overall body health.
본 발명에서, 용어 "예방"이란 본 발명에 따른 약학적 조성물의 투여에 의해 암의 발생, 확산 및 재발을 억제 또는 지연시키는 모든 행위를 의미하고, "치료"란 상기 약학적 조성물의 투여에 의해 암의 의심 및 발병 개체의 증상이 호전되거나 이롭게 변경하는 모든 행위를 의미한다.In the present invention, the term "prevention" refers to all actions that inhibit or delay the occurrence, spread, and recurrence of cancer by administration of the pharmaceutical composition according to the present invention, and "treatment" refers to all actions that inhibit or delay the occurrence, spread, and recurrence of cancer by administration of the pharmaceutical composition according to the present invention. It refers to all actions that improve or beneficially change the symptoms of an individual suspected of having cancer or developing cancer.
본 발명에서 사용되는 용어 "치료"란 본 발명의 약학적 조성물의 투여로 암세포의 사멸 또는 암의 증세를 호전시키거나 이롭게 변경하는 모든 행위를 의미한다. 본 발명이 속하는 기술분야에서 통상의 지식을 가진 자라면, 대한의학협회 등에서 제시된 자료를 참조하여 본원의 조성물이 효과가 있는 질환의 정확한 기준을 알고, 개선, 향상 및 치료된 정도를 판단할 수 있을 것이다.The term “treatment” used in the present invention refers to any action that improves or beneficially changes the death of cancer cells or the symptoms of cancer by administering the pharmaceutical composition of the present invention. Anyone with ordinary knowledge in the technical field to which the present invention pertains can refer to the data presented by the Korean Medical Association, etc. to know the exact criteria for diseases for which our composition is effective and to determine the degree of improvement, improvement, and treatment. will be.
본 발명에서 유효성분과 결합하여 사용된 "치료학적으로 유효한 양"이란 용어는 대상 질환을 예방 또는 치료하는데 유효한 몰약 에탄올 추출물의 약학적으로 허용가능한 염의 양을 의미하며, 본 발명의 조성물의 치료적으로 유효한 양은 여러 요소, 예를 들면 투여방법, 목적부위, 환자의 상태 등에 따라 달라질 수 있다. 따라서, 인체에 사용 시 투여량은 안전성 및 효율성을 함께 고려하여 적정량으로 결정되어야 한다. 동물실험을 통해 결정한 유효량으로부터 인간에 사용되는 양을 추정하는 것도 가능하다. 유효한 양의 결정시 고려할 이러한 사항은, 예를 들면 Hardman and Limbird, eds., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10thed.(2001), Pergamon Press; 및 E.W. Martin ed., Remington's Pharmaceutical Sciences, 18th ed.(1990), Mack Publishing Co.에 기술되어있다.The term "therapeutically effective amount" used in combination with the active ingredient in the present invention refers to the amount of a pharmaceutically acceptable salt of the ethanol extract of myrrh that is effective in preventing or treating the target disease, and refers to the amount of the pharmaceutically acceptable salt of the ethanol extract of myrrh that is effective in preventing or treating the target disease. The effective amount may vary depending on several factors, such as administration method, target site, and patient condition. Therefore, when used in the human body, the dosage must be determined as appropriate by considering both safety and efficiency. It is also possible to estimate the amount used in humans from the effective amount determined through animal testing. These considerations in determining an effective amount include, for example, Hardman and Limbird, eds., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10thed. (2001), Pergamon Press; and E.W. Martin ed., Remington's Pharmaceutical Sciences, 18th ed. (1990), Mack Publishing Co.
본 발명의 약학조성물은 약학적으로 유효한 양으로 투여한다. 본 발명에서 사용되는 용어, "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분하며 부작용을 일으키지 않을 정도의 양을 의미하며, 유효용량 수준은 환자의 건강상태, 암의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 방법, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고, 종래의 치료제와 순차적으로 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여, 부작용없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. As used in the present invention, the term "pharmaceutically effective amount" refers to an amount that is sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment and does not cause side effects, and the effective dose level is determined by the patient's Factors including health status, type and severity of cancer, activity of drug, sensitivity to drug, method of administration, time of administration, route of administration and excretion rate, duration of treatment, drugs combined or used simultaneously, and other factors well known in the field of medicine. It can be decided depending on The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. Considering all of the above factors, it is important to administer an amount that can achieve maximum effect with the minimum amount without side effects, and this can be easily determined by a person skilled in the art.
본 발명의 약학적 조성물은 생물학적 제제에 통상적으로 사용되는 담체, 희석제, 부형제 또는 둘 이상의 이들의 조합을 포함할 수 있다. 본 발명에서 사용되는 용어, "약학적으로 허용가능한"이란 상기 조성물에 노출되는 세포나 인간에게 독성이 없는 특성을 나타내는 것을 의미한다. 상기 담체는 조성물을 생체 내 전달에 적합한 것이면 특별히 제한되지 않으며, 예를 들면, Merck Index, 13th ed., Merck & Co. Inc. 에 기재된 화합물, 식염수, 멸균수, 링거액, 완충 식염수, 덱스트로스 용액, 말토 덱스트린 용액, 글리세롤, 에탄올 및 이들 성분 중 1 성분 이상을 혼합하여 이용할 수 있으며, 필요에 따라 항산화제, 완충액, 정균제 등 다른 통상의 첨가제를 첨가할 수 있다. 또한, 희석제, 분산제, 계면활성제, 결합제 및 윤활제를 부가적으로 첨가하여 수용액, 현탁액, 유탁액 등과 같은 주이용 제형, 환약, 캡슐, 과립 또는 정제로 제제화할 수 있다. 더 나아가 당 분야의 적정한 방법으로 또는 Remington's Pharmaceutical Science(Mack Publishing Company, Easton PA, 18th, 1990)에 개시되어 있는 방법을 이용하여 각 질환에 따라 또는 성분에 따라 바람직하게 제제화할 수 있다.The pharmaceutical composition of the present invention may contain a carrier, diluent, excipient, or a combination of two or more commonly used in biological products. As used in the present invention, the term “pharmaceutically acceptable” means that the composition exhibits non-toxic properties to cells or humans exposed to the composition. The carrier is not particularly limited as long as it is suitable for in vivo delivery of the composition, for example, Merck Index, 13th ed., Merck & Co. Inc. The compounds described in, saline solution, sterilized water, Ringer's solution, buffered saline solution, dextrose solution, maltodextrin solution, glycerol, ethanol, and one or more of these ingredients can be mixed and used, and if necessary, other ingredients such as antioxidants, buffers, and bacteriostatic agents. Normal additives can be added. In addition, diluents, dispersants, surfactants, binders, and lubricants can be additionally added to formulate dosage forms such as aqueous solutions, suspensions, emulsions, etc., into pills, capsules, granules, or tablets. Furthermore, it can be preferably formulated according to each disease or ingredient using an appropriate method in the art or a method disclosed in Remington's Pharmaceutical Science (Mack Publishing Company, Easton PA, 18th, 1990).
본 발명의 약학적 조성물은 약학적으로 허용 가능한 첨가제를 더 포함할 수 있으며, 이때 약학적으로 허용 가능한 첨가제로는 전분, 젤라틴화 전분, 미결정셀룰로오스, 유당, 포비돈, 콜로이달실리콘디옥사이드, 인산수소칼슘, 락토스, 만니톨, 엿, 아라비아고무, 전호화전분, 옥수수전분, 분말셀룰로오스, 히드록시프로필셀룰로오스, 오파드라이, 전분글리콜산나트륨, 카르나우바 납, 합성규산알루미늄, 스테아린산, 스테아린산마그네슘, 스테아린산알루미늄, 스테아린산칼슘, 백당, 덱스트로스, 소르비톨 및 탈크 등이 사용될 수 있다. 본 발명에 따른 약학적으로 허용 가능한 첨가제는 상기 조성물에 대해 0.1 중량부 내지 90 중량부 포함되는 것이 바람직하나, 이에 한정되는 것은 아니다.The pharmaceutical composition of the present invention may further include pharmaceutically acceptable additives, wherein the pharmaceutically acceptable additives include starch, gelatinized starch, microcrystalline cellulose, lactose, povidone, colloidal silicon dioxide, and calcium hydrogen phosphate. , lactose, mannitol, taffy, gum arabic, pregelatinized starch, corn starch, powdered cellulose, hydroxypropyl cellulose, Opadry, sodium starch glycolate, lead carnauba, synthetic aluminum silicate, stearic acid, magnesium stearate, aluminum stearate, Calcium stearate, white sugar, dextrose, sorbitol, and talc may be used. The pharmaceutically acceptable additive according to the present invention is preferably contained in an amount of 0.1 to 90 parts by weight based on the composition, but is not limited thereto.
본 발명의 약학적 조성물은 유효성분으로서 몰약 에탄올 추출물 이외에 공지된 항암제를 추가로 포함할 수 있고, 이들 질환의 치료를 위해 공지된 다른 치료와 병용될 수 있다. 다른 치료에는 화학요법, 방사선치료, 호르몬치료, 골수 이식, 줄기-세포 대체치료, 다른 생물학적 치료, 면역치료 등이 포함되지만, 이에 한정되는 것은 아니다.The pharmaceutical composition of the present invention may further contain a known anticancer agent in addition to the ethanol extract of myrrh as an active ingredient, and may be used in combination with other known treatments for the treatment of these diseases. Other treatments include, but are not limited to, chemotherapy, radiation therapy, hormone therapy, bone marrow transplantation, stem-cell replacement therapy, other biological treatments, and immunotherapy.
본 발명의 약학적 조성물에 포함될 수 있는 항암제의 예시에는 DNA 알킬화제(DNA alkylating agents)로 메클로에타민(mechloethamine), 클로람부칠(chlorambucil), 페닐알라닌(phenylalanine), 무스타드(mustard), 사이클로포스파미드(cyclophosphamide), 이포스파미드(ifosfamide), 카르무스틴(carmustine: BCNU), 로무스틴(lomustine: CCNU), 스트렙토조토신(streptozotocin), 부술판(busulfan), 티오테파(thiotepa), 시스플라틴(cisplatin) 및 카보플라틴(carboplatin); 항암 항생제(anti-cancer antibiotics)로 닥티노마이신(dactinomycin: actinomycin D), 독소루비신(doxorubicin: adriamycin), 다우노루비신(daunorubicin), 이다루비신(idarubicin), 미토크산트론(mitoxantrone), 플리카마이신(plicamycin), 마이토마이신 C(mitomycin C) 및 블레오마이신(bleomycin); 및 식물 알카로이드(plant alkaloids)로 빈크리스틴(vincristine), 빈블라스틴(vinblastine), 파클리탁셀(paclitaxel), 도세탁셀(docetaxel), 에토포시드(etoposide), 테니포시드(teniposide), 토포테칸(topotecan) 및 이리도테칸(iridotecan) 등이 포함되지만, 이에 한정되는 것은 아니다.Examples of anticancer agents that can be included in the pharmaceutical composition of the present invention include DNA alkylating agents such as mechloethamine, chlorambucil, phenylalanine, mustard, and cyclophospha. Cyclophosphamide, ifosfamide, carmustine (BCNU), lomustine (CCNU), streptozotocin, busulfan, thiotepa, cisplatin ( cisplatin) and carboplatin; Anti-cancer antibiotics include dactinomycin (actinomycin D), doxorubicin (adriamycin), daunorubicin, idarubicin, mitoxantrone, and plicama. plicamycin, mitomycin C, and bleomycin; and plant alkaloids such as vincristine, vinblastine, paclitaxel, docetaxel, etoposide, teniposide, and topotecan. and iridotecan, but are not limited thereto.
일 측면에서, 본 발명은 몰약 에탄올 추출물을 이를 필요로 하는 개체에게 혼합하여 투여하거나 각각의 추출물을 동시에 투여하는 단계를 포함하는, 췌장암을 예방 또는 치료하는 방법에 관한 것이다.In one aspect, the present invention relates to a method for preventing or treating pancreatic cancer, comprising administering a mixture of ethanol extracts of myrrh to an individual in need thereof or administering each extract simultaneously.
본 발명에서 사용되는 용어, "개체"란, 상기 암이 발병하였거나 발병할 수 있는 인간을 포함한 원숭이, 소, 말, 양, 돼지, 닭, 칠면조, 메추라기, 고양이, 개, 마우스, 쥐, 토끼 또는 기니아 피그를 포함한 모든 동물을 의미하고, 본 발명의 약학적 조성물을 개체에게 투여함으로써 상기 질환들을 효과적으로 예방 또는 치료할 수 있다.As used in the present invention, the term "individual" refers to a monkey, cow, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, or This refers to all animals, including guinea pigs, and the above diseases can be effectively prevented or treated by administering the pharmaceutical composition of the present invention to the subject.
본 발명의 약학적 조성물은 기존의 치료제와 병행하여 투여될 수 있다.The pharmaceutical composition of the present invention can be administered in combination with existing therapeutic agents.
본 발명에서 사용되는 용어, "투여"란, 임의의 적절한 방법으로 환자에게 소정의 물질을 제공하는 것을 의미하며, 목적하는 방법에 따라 비 경구 투여(예를 들어 정맥 내, 피하, 복강 내 또는 국소에 주사 제형으로 적용)하거나 경구 투여할 수 있으며, 투여량은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설률 및 질환의 중증도 등에 따라 그 범위가 다양하다. 본 발명의 조성물의 경구 투여를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데, 통상적으로 사용되는 단순 희석제인 물, 액체 파라핀 이외에 다양한 부형제, 예컨대 습윤제, 감미제, 방향제, 보존제 등이 함께 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성 용제, 현탁제, 유제, 동결건조 제제, 좌제 등이 포함된다. 본 발명의 약학적 조성물은 활성 물질이 표적 세포로 이동할 수 있는 임의의 장치에 의해 투여될 수도 있다. 바람직한 투여방식 및 제제는 정맥 주사제, 피하 주사제, 피내주사제, 근육 주사제, 점적 주사제 등이다. 주사제는 생리식염액, 링겔액 등의 수성용제, 식물유, 고급 지방산 에스테르(예, 올레인산에칠 등), 알코올 류(예, 에탄올, 벤질알코올, 프로필렌글리콜, 글리세린 등) 등의 비수성 용제 등을 이용하여 제조할 수 있고, 변질 방지를 위한 안정화제(예, 아스코르빈산, 아황산수소나트륨, 피로아황산나트륨, BHA, 토코페롤, EDTA 등), 유화제, pH 조절을 위한 완충제, 미생물 발육을 저지하기 위한 보존제 (예, 질산페닐수은, 치메로살, 염화벤잘코늄, 페놀, 크레솔, 벤질알코올 등) 등의 약학적 담체를 포함할 수 있다.As used in the present invention, the term "administration" means providing a predetermined substance to a patient by any suitable method, and is administered parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically) depending on the desired method. It can be applied as an injection formulation) or orally administered, and the dosage range varies depending on the patient's weight, age, gender, health status, diet, administration time, administration method, excretion rate, and severity of the disease. Liquid preparations for oral administration of the composition of the present invention include suspensions, oral solutions, emulsions, syrups, etc., and in addition to the commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives are used. etc. may be included together. Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, suppositories, etc. The pharmaceutical composition of the present invention may be administered by any device capable of transporting the active agent to target cells. Preferred administration methods and formulations include intravenous injection, subcutaneous injection, intradermal injection, intramuscular injection, and drip injection. Injections include aqueous solvents such as physiological saline solution and Ringer's solution, non-aqueous solvents such as vegetable oil, higher fatty acid esters (e.g., ethyl oleate, etc.), and alcohols (e.g., ethanol, benzyl alcohol, propylene glycol, glycerin, etc.). It can be manufactured using stabilizers to prevent deterioration (e.g., ascorbic acid, sodium bisulfite, sodium pyrosulphite, BHA, tocopherol, EDTA, etc.), emulsifiers, buffers for pH adjustment, and agents to prevent microbial growth. It may contain pharmaceutical carriers such as preservatives (e.g., phenylmercuric nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.).
일 측면에서, 본 발명은 몰약 에탄올 추출물을 유효성분으로 함유하는 항암보조제에 관한 것이다.In one aspect, the present invention relates to an anticancer supplement containing myrrh ethanol extract as an active ingredient.
일 구현예에서, 본 발명의 항암보조제는 항암제와 병용하여 투여될 수 있다.In one embodiment, the anticancer adjuvant of the present invention can be administered in combination with an anticancer agent.
일 구현예에서, 상기 항암제는 화학요법 약물(chemotherapeutic drugs)일 수 있으며, 항-세포분열 약물일 수 있다.In one embodiment, the anti-cancer agent may be a chemotherapy drug or an anti-cell division drug.
일 구현예에서, 상기 항암제는 에리불린, 카보플라틴, 시스플라틴, 할라벤, 5-플루오로우라실(5-FU), 글리벡, 빈크리스틴, 빈블라스틴, 비노렐빈, 파클리탁셀, 도세탁셀, 에토포사이드, 토포테칸, 이리노테칸, 닥티노마이신, 독소루비신, 다우노루비신, 발루비신, 플로타미드, 젬시타빈, 미토마이신 또는 블레오마이신일 수 있다.In one embodiment, the anticancer agent is eribulin, carboplatin, cisplatin, Halaven, 5-fluorouracil (5-FU), Gleevec, vincristine, vinblastine, vinorelbine, paclitaxel, docetaxel, etoposide, It may be topotecan, irinotecan, dactinomycin, doxorubicin, daunorubicin, valrubicin, flotamide, gemcitabine, mitomycin or bleomycin.
일 구현예에서, 본 발명의 항암 보조제는 항암제와 병용하여 투여될 수 있으며, 항암제와 동시에, 별도로 또는 순차적으로 투여될 수 있다.In one embodiment, the anti-cancer adjuvant of the present invention may be administered in combination with an anti-cancer agent, and may be administered simultaneously, separately, or sequentially with the anti-cancer agent.
본 발명의 용어, "항암 보조제"는 항암제의 항암효과를 개선, 향상 또는 증대시킬 수 있는 제제로서, 그 자체로는 항암활성을 나타내지 않으나 항암제와 함께 사용될 경우, 상기 항암제의 항암효과를 개선, 향상 또는 증대시킬 수 있는 제제일 수 있다. 또한, 농도의존적인 항암활성을 나타내는 제제를 그 자체로는 항암활성을 나타내지 않은 수준으로 항암제와 함께 사용할 경우, 상기 항암제의 항암효과를 개선, 향상 또는 증대시킬 수 있는 제제일 수 있다.The term "anticancer adjuvant" of the present invention refers to an agent that can improve, improve or increase the anticancer effect of an anticancer agent. It does not exhibit anticancer activity by itself, but when used together with an anticancer agent, improves or enhances the anticancer effect of the anticancer agent. Or it may be an agent that can increase. In addition, when an agent that exhibits concentration-dependent anticancer activity is used together with an anticancer agent at a level that does not show anticancer activity on its own, it may be an agent that can improve, enhance, or increase the anticancer effect of the anticancer agent.
항암 보조제의 투여 경로는 목적 조직에 도달할 수 있는 한 어떠한 일반적인 경로를 통하여 투여될 수 있다. 본 발명의 항암 보조제는 목적하는 바에 따라 복강 내 투여, 정맥 내 투여, 근육 내 투여, 피하 투여, 피내 투여, 경구 투여, 비 내 투여, 폐 내 투여, 직장 내 투여될 수 있으나, 이에 제한되지는 않는다. 또한, 상기 항암 보조제는 활성 물질이 표적 세포로 이동할 수 있는 임의의 장치에 의해 투여될 수 있다.Anticancer adjuvants can be administered through any general route as long as they can reach the target tissue. The anti-cancer adjuvant of the present invention may be administered intraperitoneally, intravenously, intramuscularly, subcutaneously, intradermally, orally, intranasally, pulmonaryly, or rectally, depending on the purpose, but is not limited thereto. No. Additionally, the anti-cancer adjuvant can be administered by any device that allows the active substance to move to target cells.
일 측면에서, 본 발명은 몰약 에탄올 추출물을 함유하는 암의 예방 또는 개선용 식품 조성물에 관한 것이다.In one aspect, the present invention relates to a food composition for preventing or improving cancer containing an ethanol extract of myrrh.
본 발명의 조성물을 식품 조성물로 사용하는 경우, 상기 몰약 에탄올 추출물을 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용할 수 있고, 통상의 방법에 따라 적절하게 사용할 수 있다. 상기 조성물은 유효성분 이외에 식품학적으로 허용가능한 식품보조첨가제를 포함할 수 있으며, 유효성분의 혼합량은 사용 목적(예방, 건강 또는 치료적 처치)에 따라 적합하게 결정될 수 있다.When using the composition of the present invention as a food composition, the myrrh ethanol extract can be added as is or used together with other foods or food ingredients, and can be used appropriately according to conventional methods. In addition to the active ingredients, the composition may contain food additives acceptable to the food industry, and the mixing amount of the active ingredients can be appropriately determined depending on the purpose of use (prevention, health, or therapeutic treatment).
본 발명에서 사용되는 용어 "식품보조첨가제"란 식품에 보조적으로 첨가될 수 있는 구성요소를 의미하며, 각 제형의 건강기능식품을 제조하는데 첨가되는 것으로서 당업자가 적절히 선택하여 사용할 수 있다. 식품보조첨가제의 예로는 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 충진제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산음료에 사용되는 탄산화제 등이 포함되지만, 상기 예들에 의해 본 발명의 식품보조첨가제의 종류가 제한되는 것은 아니다.The term "food supplement" used in the present invention refers to a component that can be added as an auxiliary food additive, and can be appropriately selected and used by a person skilled in the art as it is added to manufacture each type of health functional food. Examples of food supplements include various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavors, colorants and fillers, pectic acid and its salts, alginic acid and its salts, organic acids, and protective colloidal thickeners. , pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc., but the types of food supplements of the present invention are not limited to the above examples.
본 발명의 식품 조성물에는 건강기능식품이 포함될 수 있다. 본 발명에서 사용되는 용어 "건강기능식품"이란 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 정제, 캅셀, 분말, 과립, 액상 및 환 등의 형태로 제조 및 가공한 식품을 말한다. 여기서 '기능성'이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적작용 등과 같은 보건용도에 유용한 효과를 얻는 것을 의미한다. 본 발명의 건강기능식품은 통상의 기술분야에서 통상적으로 사용되는 방법에 의하여 제조가능하며, 상기 제조시에는 통상의 기술분야에서 통상적으로 첨가하는 원료 및 성분을 첨가하여 제조할 수 있다. 또한 상기 건강기능식품의 제형 또한 건강기능식품으로 인정되는 제형이면 제한없이 제조될 수 있다. 본 발명의 식품용 조성물은 다양한 형태의 제형으로 제조될 수 있으며, 일반약품과는 달리 식품을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용 등이 없는 장점이 있고, 휴대성이 뛰어나, 본 발명의 건강기능식품은 항암제의 효과를 증진시키기 위한 보조제로 섭취가 가능하다.The food composition of the present invention may include health functional foods. The term “health functional food” used in the present invention refers to food manufactured and processed in the form of tablets, capsules, powders, granules, liquids, and pills using raw materials or ingredients with functional properties useful to the human body. Here, ‘functionality’ means controlling nutrients for the structure and function of the human body or obtaining useful effects for health purposes such as physiological effects. The health functional food of the present invention can be manufactured by methods commonly used in the field of technology, and can be manufactured by adding raw materials and components commonly added in the field of technology. Additionally, the formulation of the health functional food can also be manufactured without limitation as long as it is a formulation recognized as a health functional food. The food composition of the present invention can be manufactured in various types of formulations, and unlike general drugs, it is made from food as a raw material and has the advantage of not having side effects that may occur when taking the drug for a long period of time, and is excellent in portability, so the present invention Health functional foods can be consumed as supplements to enhance the effectiveness of anticancer drugs.
또한, 본 발명의 조성물이 사용될 수 있는 건강식품의 종류에는 제한이 없다. 아울러 본 발명의 몰약 에탄올 추출물을 활성성분으로 포함하는 조성물은 당업자의 선택에 따라 건강기능식품에 함유될 수 있는 적절한 기타 보조 성분과 공지의 첨가제를 혼합하여 제조할 수 있다. 첨가할 수 있는 식품의 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림 류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등이 있으며, 본 발명에 따른 추출물을 주성분으로 하여 제조한 즙, 차, 젤리 및 주스 등에 첨가하여 제조할 수 있다.Additionally, there is no limitation to the types of health foods in which the composition of the present invention can be used. In addition, the composition containing the ethanol extract of myrrh of the present invention as an active ingredient can be prepared by mixing known additives with other appropriate auxiliary ingredients that can be contained in health functional foods according to the selection of a person skilled in the art. Examples of foods that can be added include meat, sausages, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, and There are vitamin complexes, etc., and they can be manufactured by adding them to juices, teas, jellies, juices, etc. prepared using the extract according to the present invention as a main ingredient.
본 발명의 몰약 에탄올 추출물은 천연 식물을 원료로 하므로 약학적 조성물 또는 식품 조성물로 사용할 경우에도 일반적인 합성 화합물에 비하여 부작용이 덜할 수 있으므로, 안전하게 약학적 조성물 및 건강기능식품에 포함되어 유용하게 사용될 수 있다.Since the ethanol extract of myrrh of the present invention is made from natural plants, it may have fewer side effects than common synthetic compounds even when used in pharmaceutical compositions or food compositions, so it can be safely included in pharmaceutical compositions and health functional foods and usefully used. .
일 측면에서, 본 발명은 몰약 추출물을 유효성분으로 함유하는, 인비트로(in vitro)에서 췌장암 세포의 MMP 활성을 억제하는 조성물에 관한 것이다.In one aspect, the present invention relates to a composition that inhibits MMP activity of pancreatic cancer cells in vitro, containing myrrh extract as an active ingredient.
일 측면에서, 본 발명은 인비트로에서 췌장암 세포에 몰약 추출물을 처리하여 췌장암 세포의 MMP 활성을 억제하는 방법에 관한 것이다.In one aspect, the present invention relates to a method of inhibiting MMP activity of pancreatic cancer cells in vitro by treating them with myrrh extract.
일 측면에서, 본 발명은 몰약 추출물을 유효성분으로 함유하는, 인비트로(in vitro)에서 췌장암 세포의 세포사멸을 유도하는 조성물에 관한 것이다.In one aspect, the present invention relates to a composition that induces apoptosis of pancreatic cancer cells in vitro, containing myrrh extract as an active ingredient.
일 측면에서, 본 발명은 인비트로에서 췌장암 세포에 몰약 추출물을 처리하여 췌장암 세포의 세포사멸을 유도하는 방법에 관한 것이다.In one aspect, the present invention relates to a method of inducing apoptosis of pancreatic cancer cells in vitro by treating them with myrrh extract.
일 구현예에 있어서, 상기 몰약 추출물은 몰약 에탄올 추출물일 수 있고, 바람직하게는 몰약 100% 에탄올 추출물인 것일 수 있다.In one embodiment, the myrrh extract may be an ethanol extract of myrrh, and preferably may be a 100% ethanol extract of myrrh.
일 구현예에 있어서, 상기 췌장암 세포는 PANC 1세포일 수 있으나, 이에 제한되지는 않는다.In one embodiment, the pancreatic cancer cells may be PANC 1 cells, but are not limited thereto.
일 구현예에 있어서, 상기 세포사멸 유발은 PARP(poly(ADP-ribose) polymerase)의 절단 또는 발현이 증가하여 유도되는 것일 수 있다.In one embodiment, the apoptosis may be induced by cleavage or increased expression of PARP (poly(ADP-ribose) polymerase).
일 구현예에 있어서, 상기 몰약 추출물은 췌장암 세포의 MMP 활성을 억제하여 미토콘드리아 막전위를 감소시켜 세포사멸을 유도하는 것일 수 있다.In one embodiment, the myrrh extract may inhibit MMP activity of pancreatic cancer cells and reduce mitochondrial membrane potential, thereby inducing apoptosis.
하기의 실시예를 통하여 본 발명을 보다 상세하게 설명한다. 그러나 하기 실시예는 본 발명의 내용을 구체화하기 위한 것일 뿐 이에 의해 본 발명이 한정되는 것은 아니다.The present invention will be described in more detail through the following examples. However, the following examples are only for illustrating the content of the present invention and are not intended to limit the present invention.
실시예 1. 몰약 추출물의 제조Example 1. Preparation of myrrh extract
몰약은 100% 에탄올을 이용하여 추출을 하였으며 72시간 동안 100% 에탄올에 몰약을 넣어 추출을 해주고 72시간이 지난 후에 evavolrator를 이용하여 에탄올을 증발시켜서 추출물만 모아주었다. 이후에 동결건조기를 이용하여 -110도에서 동결건조를 시켜주고 중량을 측정하여 50ml 튜브에 옮겨 담아서 -80도에서 보관을 하였다. 이렇게 완성된 몰약 추출물을 200mg을 DMSO 1mL에 녹여서 200mg/mL농도로 만들어서 연구에 이용하였다.Myrrh was extracted using 100% ethanol. Myrrh was placed in 100% ethanol for 72 hours and extracted. After 72 hours, the ethanol was evaporated using an evavolator to collect only the extract. Afterwards, it was freeze-dried at -110 degrees using a freeze dryer, its weight was measured, transferred to a 50ml tube, and stored at -80 degrees. 200 mg of the myrrh extract completed in this way was dissolved in 1 mL of DMSO to make a concentration of 200 mg/mL and used for research.
실험예 1. 몰약 추출물의 췌장암 세포주에 대한 세포 독성 확인Experimental Example 1. Confirmation of cytotoxicity of myrrh extract against pancreatic cancer cell lines
상기 실시예에서 제조한 몰약 에탄올 추출물의 췌장암 세포주에 대한 항암 활성을 확인하기 위하여, 췌장암 세포주인 PANC-1 세포주 (한국세포주은행) 100㎕를 96웰-플레이트에 1 내지 1.5×104 세포/웰이 되도록 분주한 뒤, 10% 불활성화 FBS(inactivated fetal bovine serum) 및 1% 페니실린-스트렙토마이신(penicillin-streptomycin)을 첨가한 DMEM 배지에서, 37℃의 5% CO2 인큐베이터 (MCO-15AC, Sanyo, Osaka, Japan)로 배양하였다. 배양한 96웰-플레이트에서 배지만 걷어내고 상기 실시예에서 제조한 몰약 에탄올 추출물을 0, 50, 100, 125, 150, 175, 200 및 225㎍/ml의 농도로 각각 100㎕씩 처리한 뒤, 24시간 동안 인큐베이션하였다. 인큐베이션한 세포에 EZ-Cytox 시약 (DoGen)을 10㎕ 처리하고 30분 내지 4시간 동안 인큐베이션하였다. 인큐베이션한 뒤 마이크로플레이트 리더기 (Bio-rad Model 680)를 이용하여 450nm 파장대에서 흡광도를 측정함으로써 세포 생존율을 확인하였다.In order to confirm the anticancer activity of the ethanol extract of myrrh prepared in the above example against pancreatic cancer cell lines, 100 ㎕ of the pancreatic cancer cell line PANC-1 cell line (Korea Cell Line Bank) was cultured in a 96-well plate at 1 to 1.5 × 10 4 cells/well. After aliquoting, incubate in DMEM medium supplemented with 10% inactivated fetal bovine serum (FBS) and 1% penicillin-streptomycin, in a 5% CO 2 incubator (MCO-15AC, Sanyo) at 37°C. , Osaka, Japan). Only the medium was removed from the cultured 96-well plate, and the myrrh ethanol extract prepared in the above example was treated with 100 μl each at concentrations of 0, 50, 100, 125, 150, 175, 200, and 225 μg/ml, and then treated with 100 μl each of the myrrh ethanol extract prepared in the above example. Incubated for an hour. The incubated cells were treated with 10 μl of EZ-Cytox reagent (DoGen) and incubated for 30 minutes to 4 hours. After incubation, cell viability was confirmed by measuring absorbance in the 450 nm wavelength range using a microplate reader (Bio-rad Model 680).
그 결과, 도 1에 나타난 바와 같이, 췌장암 세포주인 PANC 1세포에 대하여 몰약 에탄올 추출물의 처리 농도가 증가함에 따라서 세포 독성도 증가하는 것을 확인하였다. 따라서 몰약 추출물은 췌장암 세포에 대해서 독성이 있으며 이러한 독성은 췌장암 세포를 사멸시키거나 증식을 억제하는 효능이 있음을 나타낸다. 특히 최고 농도인 225mg/mL농도에서는 생존률이 거의 0%에 이르는 것을 확인할 수 있다. 이러한 세포독성 결과를 토대로 90%정도의 생존률을 나타내는 50mg/mL농도와 60%정도 생존률을 나타내는 100mg/mL농도를 선정하여 추가적인 연구를 진행을 하였다.As a result, as shown in Figure 1, it was confirmed that the cytotoxicity of the pancreatic cancer cell line, PANC 1 cells, increased as the treatment concentration of the myrrh ethanol extract increased. Therefore, myrrh extract is toxic to pancreatic cancer cells, and this toxicity indicates that it has the effect of killing pancreatic cancer cells or inhibiting their proliferation. In particular, it can be seen that at the highest concentration of 225 mg/mL, the survival rate reaches almost 0%. Based on these cytotoxicity results, additional studies were conducted by selecting a concentration of 50 mg/mL, which shows a survival rate of about 90%, and a concentration of 100 mg/mL, which shows a survival rate of about 60%.
실험예 2. 몰약 추출물에 의한 췌장암 세포주의 세포사멸 유발 효과 확인Experimental Example 2. Confirmation of the apoptosis-inducing effect of myrrh extract on pancreatic cancer cell lines
상기 실시예 1에서 제조한 몰약 에탄올 추출물이 세포자멸사와 관련된 단백질의 발현을 조절시키는지 확인하였다.It was confirmed whether the ethanol extract of myrrh prepared in Example 1 regulates the expression of proteins related to apoptosis.
먼저, PARP(poly(ADP-ribose) polymerase)는 세포사멸에 관련하여 중요한 역할을 하는 인자이다. PARP는 활성화가 되면 절단이 되는데 절단이 된 PARP가 세포사멸을 유도하게 된다. 따라서, 세포사멸 진행시 절단되는 PARP와 세포사멸 억제 단백질 중 하나인 Survivin의 발현 정도를 웨스턴 블롯(western blot) 분석으로 확인하였다.First, PARP (poly(ADP-ribose) polymerase) is a factor that plays an important role in apoptosis. When PARP is activated, it is cleaved, and the cleaved PARP induces cell death. Therefore, the expression levels of PARP, which is cleaved during apoptosis, and Survivin, one of the apoptosis inhibitory proteins, were confirmed through western blot analysis.
구체적으로, 췌장암 세포주인 PANC-1 세포주에 상기 실시예 1에서 제조한 몰약 에탄올 추출물을 0, 50 및 100 ㎍/ml로 각각 처리하고 24시간 동안 37℃의 5% CO2 인큐베이터로 인큐베이션 후, 세포를 수집하여 PBS로 워싱하고, 세포 파쇄 버퍼 CETI Lysis Buffer with Inhibitor(TransLab, Korea)를 첨가하여 30분간 4℃에서 세포를 파쇄하였다. 세포파쇄물을 13,000 RPM에서 10분간 원심 분리하여 세포막 성분 등을 제거한 뒤, RC DC™ Protein Assay Kit II(protein assay kit) (Bio-rad, USA)를 사용하여 단백질을 정량하여 시료별 (몰약 에탄올 추출물 0, 50 및 100 ㎍/ml 처리군들)로 동일한 단백질의 양이 포함되도록 조절하였다. 준비된 단백질 시료에 5×로딩 다이를 넣고 5분 동안 95℃로 가열하여 단백질을 변성시켰다. 그 후, 10 내지 15% SDS-PAGE 젤에 시료를 로딩하여 100V로 1시간 20분 내지 1시간 40분 동안 전기영동을 수행하였으며, 젤 위에서 분리된 단백질들을 200mA 내지 300mA로 1시간 내지 2시간 동안 멤브레인으로 트랜스퍼하였다. 단백질이 트랜스퍼된 멤브레인을 5% 탈지유가 포함된 TBST (tris buffered saline, pH 7.5) 용액으로 상온에서 1시간 동안 블로킹한 뒤 1차 항체로서 항-survivin 및 항-pro-PARP 항체를 각각 1:1,000으로 희석하여 블로킹한 멤브레인과 4℃에서 오버나잇으로 반응시켰다. 반응 종료 후 멤브레인을 TBST로 3회 워싱한 뒤 2차 항체로서 horseradish peroxidase가 결합된 항-rabbit 및 항-mouse IgG를 각각 1:10,000으로 희석하여 상온에서 멤브레인과 2시간 동안 반응시킨 다음 TBST로 3회 워싱하였다. 워싱한 멤브레인을 chemiluminescent reagent와 1 내지 3분 동안 반응시키고 chemiluminescent western blot 이미징 장비(Corebiosystem, Korea)를 통해 단백질 밴드를 가시화하였다.Specifically, the PANC-1 cell line, a pancreatic cancer cell line, was treated with the myrrh ethanol extract prepared in Example 1 at 0, 50, and 100 μg/ml, respectively, and incubated in a 5% CO2 incubator at 37°C for 24 hours, and then the cells were Collected, washed with PBS, cell disruption buffer CETI Lysis Buffer with Inhibitor (TransLab, Korea) was added, and cells were disrupted at 4°C for 30 minutes. Cell lysates were centrifuged at 13,000 RPM for 10 minutes to remove cell membrane components, and then proteins were quantified using RC DC™ Protein Assay Kit II (protein assay kit) (Bio-rad, USA) for each sample (myrrh ethanol extract). 0, 50, and 100 μg/ml treatment groups) were adjusted to contain the same amount of protein. A 5×loading die was placed in the prepared protein sample and heated to 95°C for 5 minutes to denature the protein. Afterwards, the sample was loaded onto a 10 to 15% SDS-PAGE gel and electrophoresis was performed at 100 V for 1 hour 20 minutes to 1 hour 40 minutes, and the proteins separated on the gel were electrophoresed at 200 mA to 300 mA for 1 hour to 2 hours. Transferred to the membrane. The protein-transferred membrane was blocked for 1 hour at room temperature with TBST (tris buffered saline, pH 7.5) containing 5% skim milk, and then incubated with anti-survivin and anti-pro-PARP antibodies as primary antibodies at 1:1,000, respectively. It was diluted and reacted with the blocked membrane overnight at 4°C. After completion of the reaction, the membrane was washed three times with TBST, then horseradish peroxidase-conjugated anti-rabbit and anti-mouse IgG as secondary antibodies were diluted at 1:10,000, respectively, reacted with the membrane at room temperature for 2 hours, and then washed with TBST for 3 hours. Washed twice. The washed membrane was reacted with chemiluminescent reagent for 1 to 3 minutes, and the protein band was visualized using chemiluminescent western blot imaging equipment (Corebiosystem, Korea).
도 2는 세포독성 결과를 바탕으로 농도를 설정해서 세포사멸과 관련된 인자들을 확인해본 western blot결과이며, Pro PARP의 발현량이 감소하는 것을 확인할 수 있는데 이렇게 Pro PARP의 발현량이 감소하였다는 것은 활성화가 되어서 절단이 되었다는 것을 의미한다. 따라서 몰약 에탄올 추출물은 췌장암 세포에 대하여 세포 사멸을 유도하여 세포를 죽이는 기전을 가지고 있다고 볼 수 있다. 여기서 세포 생존 인자인 survivin 또한 감소하는데 세포 생존은 차단하고 세포 사멸을 유도하는 것으로 세포에 대한 독성을 나타낸다고 볼 수 있다.Figure 2 is a western blot result of confirming factors related to cell death by setting the concentration based on the cytotoxicity results. It can be seen that the expression level of Pro PARP is decreased. This decrease in the expression level of Pro PARP means that it is activated. It means that it has been cut. Therefore, it can be seen that myrrh ethanol extract has a mechanism to kill pancreatic cancer cells by inducing cell death. Here, survivin, a cell survival factor, is also reduced, which can be seen as toxic to cells by blocking cell survival and inducing cell death.
실험예 3. 몰약 추출물에 의한 췌장암 세포주의 미토콘드리아 막전위 확인Experimental Example 3. Confirmation of mitochondrial membrane potential of pancreatic cancer cell lines by myrrh extract
상기 실시예 1에서 제조한 몰약 에탄올 추출물이 췌장암 세포주의 세포사멸에 미치는 영향을 확인하기 위해, 미토콘드리아 막전위를 확인할 수 있는 JC-1 assay를 진행하였다.In order to confirm the effect of the myrrh ethanol extract prepared in Example 1 on apoptosis of pancreatic cancer cell lines, JC-1 assay, which can check mitochondrial membrane potential, was performed.
미토콘드리아의 막을 투과하는 JC-1 dye는 막을 잘 투과하는데, 세포 상태가 좋으면 투과력이 높아서 JC-1 dye들이 세포 내에 많이 뭉치게 되면 빨강계열의 형광을 보이며, 세포가 죽거나 상태가 안좋게 되면 막 투과성이 약해져서 투과율이 떨어지게 되어서 dye가 적어지게 되는데 이때 초록색 계열의 형광을 나타낸다. 이러한 형광 빛의 세기를 측정하는 것으로 MMP 상태를 알 수 있으며, 세포의 비율을 측정하여 나타낼 수 있다. 아무것도 처리를 안한 세포그룹에서 약품을 처리한 세포그룹을 나눈값으로 표시하며 녹색빛을 띄는 세포는 monomer라고 하며 빨강빛을 띄는 세포는 oligomer라고 한다. monomer/oligomer를 한 값이 JC-1 값이다. JC-1 dye, which penetrates the mitochondrial membrane, penetrates the membrane well. If the cell condition is good, the permeability is high. When the JC-1 dye accumulates in the cell, red fluorescence is displayed. When the cell dies or is in poor condition, the membrane permeability decreases. As it becomes weaker and the transmittance decreases, the amount of dye decreases, and at this time, green fluorescence appears. By measuring the intensity of this fluorescence, the MMP status can be known and can be expressed by measuring the ratio of cells. It is expressed as the value divided by the cell group treated with the drug from the cell group untreated. Green-colored cells are called monomers, and red-colored cells are called oligomers. The monomer/oligomer value is the JC-1 value.
MMP(세포외기질 금속함유 단백분해효소)는 암세포의 침습과 전이에 주된 역할을 하며, 암치료에 있어서 가장 큰 장벽으로 작용한다. 만약 MMP를 억제하게 된다면 암세포가 성장 및 전이를 못하게 되는데 이러한 방식의 항생제가 많이 임상시험 단계에 있는 상황이다. MMP를 억제하면 미토콘드리아 막의 탈분극을 유도하게 되고 이렇게 되면 제대로된 효소반응 등을 할 수 없게되어 세포의 성장이 억제가 된다. 이러한 JC-1 assay를 통하여 세포의 MMP를 측정하는 분석법으로 암세포의 상태를 파악 할 수 있다.MMPs (extracellular matrix metal-containing proteases) play a major role in the invasion and metastasis of cancer cells and act as the biggest barrier in cancer treatment. If MMPs are inhibited, cancer cells will not be able to grow and metastasize, and many antibiotics of this type are in the clinical trial stage. Inhibiting MMP induces depolarization of the mitochondrial membrane, which prevents proper enzymatic reactions and inhibits cell growth. Through this JC-1 assay, the status of cancer cells can be determined by measuring the MMP of cells.
MMP에 투과하는 물질인 JC-1 dye를 이용한 실험을 위하여, 췌장암 세포주인 PANC-1 세포주 (한국세포주은행) 100㎕를 96웰-플레이트에 1.3×104 세포/웰이 되도록 분주한 뒤, 10% inactivated fetal bovine serum 및 1% penicillin-streptomycin을 첨가한 DMEM 배지에서, 37℃의 5% CO2 인큐베이터 (MCO-15AC, Sanyo, Osaka, Japan)로 배양하였다. 배양한 96웰-플레이드에서 배지만 걷어내고 1mM JC-1을 처리하여 10분 동안 반응시켰다. 그 후 다시 배지를 걷어내고 페놀 레드가 포함되지 않은 DMEM배지로 워싱해주었다. 상기 실시예 1에서 제조한 몰약 에탄올 추출물을 0, 50, 100㎍/ml의 농도로 각각 100㎕씩 처리한 뒤, 4시간 동안 인큐베이션 하였다. 인큐베이션 한 뒤 마이크로플레이트 리더기를 이용하여 480nm와 530nm에서 monomer를, 535nm와 590nm에서 oligomer의 형광을 측정함으로써 미토콘드리아의 막전위를 확인하였다.For an experiment using JC-1 dye, a substance that permeates MMP, 100㎕ of the pancreatic cancer cell line PANC-1 cell line (Korea Cell Line Bank) was dispensed into a 96-well plate at 1.3 × 104 cells/well, then 10% Cultured in DMEM medium supplemented with inactivated fetal bovine serum and 1% penicillin-streptomycin, in a 5% CO2 incubator (MCO-15AC, Sanyo, Osaka, Japan) at 37°C. Only the medium was removed from the cultured 96-well plate, treated with 1mM JC-1, and reacted for 10 minutes. Afterwards, the medium was removed again and washed with DMEM medium that does not contain phenol red. 100 μl of the myrrh ethanol extract prepared in Example 1 was treated at concentrations of 0, 50, and 100 μg/ml, and then incubated for 4 hours. After incubation, the mitochondrial membrane potential was confirmed by measuring the fluorescence of monomers at 480 nm and 530 nm and of oligomers at 535 nm and 590 nm using a microplate reader.
도 3에 나타난 바와 같이, 몰약 추출물을 처리 하였을 때 처리하지 않은 군에 비해서 JC-1값이 감소하며 이는 농도 의존적으로 감소하는 것을 볼 수 있다. JC-1 값이 감소한다는 의미는 죽은 상태를 나타내는 초록색 형광 세기가 강하다는 것을 의미하며 따라서 몰약 추출물은 MMP의 활성을 억제하고 차단한다고 할 수 있다. 즉, 몰약 추출물은 MMP의 활성을 억제하여 세포를 죽게 만든다는 것을 알 수 있다.As shown in Figure 3, when treated with myrrh extract, the JC-1 value decreases compared to the untreated group, and this decrease can be seen in a concentration-dependent manner. A decrease in JC-1 value means that the green fluorescence intensity indicating a dead state is strong, and therefore, it can be said that myrrh extract inhibits and blocks the activity of MMP. In other words, it can be seen that myrrh extract inhibits the activity of MMP and causes cell death.
종합적으로, 도 1 내지 3의 결과를 토대로 몰약 에탄올 추출물은 췌장암 세포에 대하여 독성을 나타내며 이러한 독성은 세포의 MMP의 활성을 억제하고 차단하는 것으로 독성을 나타내며 이로 인해서 암세포가 미토콘드리아 막의 탈분극으로 인하여 효소활동이 억제 되어서 성장 및 전이를 차단하는 효과를 나타내어 최종적으로는 PARP의 활성화를 유도하고 생존 신호인 survivin을 억제하는 것으로 췌장암 세포를 죽게 만들어서 독성을 나타낸다고 할 수 있다. 따라서 몰약 에탄올 추출물은 췌장암에 대하여 항암효능이 있다고 볼 수 있으며 이로 인해서 몰약 에탄올 추출물을 췌장암에 대하여 치료제나 보조적 치료제로 사용이 가능하다고 할 수 있다.Overall, based on the results of Figures 1 to 3, myrrh ethanol extract is toxic to pancreatic cancer cells. This toxicity is caused by inhibiting and blocking the activity of cellular MMPs, which causes cancer cells to lose enzyme activity due to depolarization of the mitochondrial membrane. This inhibition has the effect of blocking growth and metastasis, ultimately inducing the activation of PARP and suppressing survivin, a survival signal, which causes pancreatic cancer cells to die and thus exhibits toxicity. Therefore, it can be said that myrrh ethanol extract has anti-cancer effects against pancreatic cancer, and because of this, it can be said that myrrh ethanol extract can be used as a treatment or auxiliary treatment for pancreatic cancer.
따라서, 본 발명의 몰약 추출물은 췌장암에 대한 항암 치료제 또는 예방목적으로써 활용을 할 수 있으며 더 나아가서 몰약 추출물을 유효성분으로 함유하는 췌장암의 예방 또는 개선용 식품 조성물을 제공하여 식품을 만들 수 있고 췌장암의 예방 또는 치료하는 방법을 제공할 수 있다. 추가로 세포사멸의 관여하는 인자들의 발현량을 증가시키는 방법을 이용하여 더 나은 치료 효과를 연구하는 분야에 활용할 수 있다.Therefore, the myrrh extract of the present invention can be used as an anti-cancer treatment or preventive agent for pancreatic cancer, and furthermore, a food composition for preventing or improving pancreatic cancer containing myrrh extract as an active ingredient can be provided to make food and prevent pancreatic cancer. Methods for prevention or treatment can be provided. Additionally, the method of increasing the expression level of factors involved in cell death can be used to study better therapeutic effects.
이제까지 본 발명에 대하여 그 바람직한 실시예들을 중심으로 살펴보았다. 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자는 본 발명이 본 발명의 본질적인 특성에서 벗어나지 않는 범위에서 변형된 형태로 구현될 수 있음을 이해할 수 있을 것이다. 그러므로 개시된 실시예들은 한정적인 관점이 아니라 설명적인 관점에서 고려되어야 한다. 본 발명의 범위는 전술한 설명이 아니라 특허청구범위에 나타나 있으며, 그와 동등한 범위 내에 있는 모든 차이점은 본 발명에 포함된 것으로 해석되어야 할 것이다.So far, the present invention has been examined focusing on its preferred embodiments. A person skilled in the art to which the present invention pertains will understand that the present invention may be implemented in a modified form without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments should be considered from an illustrative rather than a restrictive perspective. The scope of the present invention is indicated in the claims rather than the foregoing description, and all differences within the equivalent scope should be construed as being included in the present invention.
Claims (10)
A composition that induces apoptosis of pancreatic cancer cells in vitro, containing myrrh extract as an active ingredient.
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