WO2022186608A1 - Anticancer use of extract from stichopus japonicus gonads or compounds derived therefrom - Google Patents
Anticancer use of extract from stichopus japonicus gonads or compounds derived therefrom Download PDFInfo
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- WO2022186608A1 WO2022186608A1 PCT/KR2022/002958 KR2022002958W WO2022186608A1 WO 2022186608 A1 WO2022186608 A1 WO 2022186608A1 KR 2022002958 W KR2022002958 W KR 2022002958W WO 2022186608 A1 WO2022186608 A1 WO 2022186608A1
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- cancer
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- sea cucumber
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Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/56—Materials from animals other than mammals
- A61K35/616—Echinodermata, e.g. starfish, sea cucumbers or sea urchins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention relates to the anticancer use of a sea cucumber gonad extract, or the anticancer use of a saponin compound isolated from a sea cucumber gonad extract.
- Sea cucumber ( Stichopus japonicus ) is a traditional seafood used as an important ingredient in Asian countries, especially China, Japan and Korea. There are many bioactive substances isolated from sea cucumber. In particular, collagen peptides and polysaccharides are well known to exhibit various biological activities. The ovaries of sea cucumbers are called sea cucumbers and are famous for their delicacies.
- Cancer is a disease in which the mortality rate continues to increase every year due to changes in the environment, an aging population, and changes in lifestyle. It is one of the five leading causes of death worldwide and is the leading cause of death in Korea. Cancer treatment is performed through surgery, radiation therapy, and drug therapy. In the case of drug therapy, starting with the first-generation chemotherapy, the second-generation targeted drug therapy has been developed and used the most, but it faces a major problem of anticancer drug resistance.
- the inventors of the present invention have completed the present invention as a result of conducting a study on anticancer activity through natural sea cucumber.
- the problem to be solved by the present invention is to provide an anticancer use of a sea cucumber extract, preferably a gonadal extract of sea cucumber.
- a sea cucumber extract preferably a gonadal extract of sea cucumber.
- saponin compound isolated from the sea cucumber extract preferably a gonadal extract of sea cucumber. It also provides a method of treating or preventing cancer in an individual in need thereof by treating the sea cucumber extract.
- the present invention is to provide an anticancer use of a sea cucumber extract, preferably a gonad extract of a sea cucumber, and more preferably an ovarian extract of a sea cucumber.
- An object of the present invention is to provide an anticancer composition comprising a gonad extract of sea cucumber.
- the present invention provides a composition for the treatment, improvement, or prevention of cancer or tumor comprising a gonadal extract of sea cucumber.
- the present invention provides a composition for killing cancer cells or tumor cells comprising the gonadal extract of sea cucumber.
- An object of the present invention is to provide a method for treating or preventing cancer in an individual in need thereof by treating a sea cucumber extract, preferably a sea cucumber gonad extract, more preferably a sea cucumber ovary extract.
- the present invention is intended to provide a method for killing cancer cells or tumor cells of an individual in need by treating the gonadal extract of sea cucumber.
- Cancer as referred to herein may be understood in a broad sense including tumors.
- a tumor refers to a cell mass that has grown abnormally by the autonomous overgrowth of body tissues, and can be divided into benign tumors and malignant tumors. While benign tumors have a relatively slow growth rate and do not metastasize, malignant tumors infiltrate into surrounding tissues, grow rapidly, and spread or metastasize to various parts of the body, endangering life. Therefore, diseases induced by tumors are collectively defined as cancer, and malignant tumors and cancer are used without special distinction.
- anticancer may mean inhibiting the proliferation of cancer cells or killing cancer cells.
- the composition may inhibit cancer proliferation and induce apoptosis, but is not limited thereto.
- treatment refers to alleviating, attenuating, or ameliorating one or more signs of a disease or condition, preventing additional signs, inhibiting the disease or symptom, e.g., treatment of a disease or condition. preventing the occurrence, alleviating the disease or symptom, causing regression of the disease or symptom, alleviating the symptoms caused by the disease or symptom, or prophylactically and/or therapeutically of the disease or symptom It can be used in a broad sense including stopping a symptom.
- Prevention means any action that inhibits or delays the onset of a disease by administration of the composition according to the present invention.
- the ovary extract of sea cucumber means that the ovary, which is the reproductive organ of sea cucumber, is extracted with a solvent.
- a solvent As the gonads of sea cucumbers mature, it is known that the testes turn milky white and the ovaries turn red.
- the solvent may be water, a C1 to C4 lower alcohol, or a mixed solvent thereof, preferably ethanol or an aqueous ethanol solution.
- the extract of the present invention may be prepared according to a method for preparing an extract for an extraction target of a conventional animal, and specifically may be a cold extraction method, a hot extraction method, or a heat extraction method, and a conventional extraction device, ultrasonic grinding extractor or fractionation. gear is available.
- the sea cucumber gonad extract preferably the ovary extract
- the sea cucumber ovary extract can be extracted with a 45 to 85% (V/V) aqueous ethanol solution as a solvent, and more preferably, the sea cucumber ovary with a 48 to 55% (V/V) aqueous ethanol solution as a solvent.
- V/V aqueous ethanol solution
- 75 to 83% (V/V) aqueous ethanol solution may be extracted as a solvent.
- the sea cucumber gonad may undergo a process of fractionating the extract, and the sea cucumber ovary fraction obtained therefrom may also be included in the scope of the present invention.
- the extract obtained by extracting sea cucumber ovaries with an aqueous ethanol solution may be fractionated, and preferably, the aqueous ethanol solution may be 45 to 85% (V/V) aqueous ethanol solution.
- the fraction may preferably be fractionated by using the sea cucumber ovary extract as a solvent butanol.
- the fraction can be obtained by suspending the sea cucumber ovary extract in distilled water, etc. and then using a separatory funnel, etc.
- the sea cucumber ovary extract can be fractionated with butanol.
- the fractionation may be carried out by a fractionation method commonly used in the art.
- the prepared extract or the fraction obtained by performing the fractionation process may then be filtered or concentrated or dried to remove the solvent, and both filtration, concentration and drying may be performed.
- the filtration may be performed using filter paper or a reduced pressure filter, and the concentration may be concentrated under reduced pressure using a reduced pressure concentrator, for example, a rotary evaporator, and the drying may be performed by, for example, a freeze-drying method.
- the extract or fraction is excellent in inhibiting cancer cells, killing, or inhibiting the generation of cancer cells, and preferably, the cancer cells may include pancreatic cancer and colorectal cancer.
- the extract or fraction may inhibit cancer cell proliferation in a cancer cell line, and the cancer cell line may include a pancreatic cancer cell line or a colon cancer cell line.
- the extract or fraction of the present invention provides a use for treating, preventing and/or improving pancreatic cancer or colorectal cancer.
- the extract or fraction of the present invention may provide a use for apoptosis of pancreatic neuroendocrine tumor, treatment, prevention and/or improvement of pancreatic neuroendocrine tumor.
- the sea cucumber gonadal, preferably ovarian extract is an anticancer composition comprising any one or more compounds selected from the group consisting of the following formulas S2, S3, S4, S5, S6, S8 and S9, preferably anticancer A pharmaceutical composition is provided.
- One embodiment of the present invention provides a composition for the treatment, improvement, or prevention of cancer or tumor comprising the gonad extract of sea cucumber.
- the use of the compound for anticancer, treatment, improvement, or prevention of cancer or tumor there is provided the use of the compound for anticancer, treatment, improvement, or prevention of cancer or tumor.
- an anti-cancer method a method for treating, improving or preventing cancer or tumor using the compound.
- the present invention provides a composition for killing cancer cells or tumor cells comprising a gonadal extract of sea cucumber, or the following compounds isolated from the extract.
- the compound may be derived from nature or may be synthesized by a chemical synthesis method, and the process for obtaining the compound is not particularly limited.
- the compound may be extracted or isolated from the gonads of sea cucumbers, preferably extracted or isolated from the ovaries of sea cucumbers.
- the cancer may preferably be a solid cancer, and the solid cancer may include pancreatic cancer, colorectal cancer, biliary tract cancer, ovarian cancer, breast cancer, and the like.
- One embodiment of the present invention provides a composition for treating, improving, or preventing pancreatic cancer.
- the composition may include any one or more of the compounds S2, S3, S4, S5, S6, S8, and S9.
- One embodiment of the present invention provides a composition for treating, improving, or preventing breast cancer.
- the composition may include any one or more of the compounds S3, S4, S5, S6, S8, and S9.
- One embodiment of the present invention provides a composition for treating, improving, or preventing colon cancer.
- the composition comprises the compound It may include any one or more of S3, S4, S5, S6, S8, and S9.
- One embodiment of the present invention provides a composition for treating, improving, or preventing biliary tract cancer and/or ovarian cancer, comprising any one or more of compounds S2, S3 and S9.
- the ovarian cancer may include ovarian mucinous cystic cancer
- the breast cancer may include triple negative breast cancer.
- Ovarian mucinous cystic cancer is classified as a rare cancer among ovarian cancer, and is known to have different histological characteristics from epithelial cell carcinoma, which accounts for the majority of ovarian cancer.
- Triple-negative breast cancer is the most aggressive carcinoma among breast cancers with the characteristics of highly differentiated, rapid progression, frequent recurrence, and low response rate to treatment, but it has been developed because there is no known target for treatment (e.g., HER2). It is classified as a representative intractable cancer for which there is no targeted anticancer agent.
- One embodiment of the present invention provides a compound having excellent anticancer effect on colorectal cancer, pancreatic cancer, and the like among solid cancers.
- the composition according to an embodiment of the present invention is a saponin compound derived from sea cucumber gonadal, preferably ovarian extract, or sea cucumber gonadal, preferably ovary of the present invention for the treatment, prevention, and/or improvement of cancer or tumor. It can be used without limitation as long as it is a field to which the novel use can be applied, and it may be preferably provided in the form of a pharmaceutical composition or a food composition. Preferably, the food composition may be provided as a health functional food composition.
- the composition according to an embodiment of the present invention may be provided in the form of a pharmaceutical composition for cancer treatment or a food composition.
- One embodiment of the present invention may be provided as a pharmaceutical composition for killing cancer cells comprising the sea cucumber gonad extract of the present invention, or a compound derived therefrom.
- the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier.
- Pharmaceutically acceptable carriers included in the pharmaceutical composition of the present invention are commonly used in formulation, and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, methyl cellulose, methylhydroxybenzoate, talc, magnesium stearate, and mineral oil.
- the pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, and the like, in addition to the above components.
- the pharmaceutical carrier is a non-limiting example and is not limited to the above type.
- the pharmaceutical composition of the present invention may further include a known anticancer agent as an active ingredient, and may be used in combination with other known treatments for the treatment of a desired cancer.
- Other treatments include, but are not limited to, chemotherapy, radiation therapy, hormone therapy, bone marrow transplantation, stem-cell replacement therapy, other biological therapies, immunotherapy, and the like.
- anticancer agents examples include anticancer antibiotics such as dactinomycin (actinomycin D), doxorubicin (adriamycin), daunorubicin, idarubicin, mitok mitoxantrone, plicamycin, mitomycin C and bleomycin; and plant alkaloids vincristine, vinblastine, paclitaxel, docetaxel, etoposide, teniposide, topotecan and iridotecan, but is not limited thereto.
- anticancer antibiotics such as dactinomycin (actinomycin D), doxorubicin (adriamycin), daunorubicin, idarubicin, mitok mitoxantrone, plicamycin, mitomycin C and bleomycin
- the pharmaceutical composition of the present invention may be administered orally or parenterally, and is preferably applied by oral administration.
- a suitable dosage of the pharmaceutical composition of the present invention is variously prescribed depending on factors such as formulation method, administration method, age, weight, sex, pathological condition, food, administration time, administration route, excretion rate and reaction sensitivity of the patient.
- a preferred dosage of the pharmaceutical composition of the present invention may be in the range of 0.001-100 mg/kg, 0.005-90 mg/kg, 0.01-80 mg/kg based on an adult, and the dosage is conventional, such as administration method, administration purpose, etc. It can be controlled by factors considered as
- the pharmaceutical composition of the present invention is prepared in unit dosage form by formulating using a pharmaceutically acceptable carrier and/or excipient according to a method that can be easily carried out by a person of ordinary skill in the art to which the present invention pertains. or may be prepared by incorporation into a multi-dose container.
- the formulation may be in the form of a solution, suspension, syrup, or emulsion in oil or aqueous medium, or may be in the form of an extract, powder, powder, granule, tablet or capsule, and may additionally include a dispersant or stabilizer.
- the composition of the present invention when prepared as a food composition, it includes ingredients commonly added during food production, for example, proteins, carbohydrates, fats, nutrients, seasonings and flavoring agents.
- the above-mentioned carbohydrates include monosaccharides such as glucose, fructose and the like; disaccharides such as maltose, sucrose, oligosaccharides and the like; and polysaccharides, for example, conventional sugars such as dextrin, cyclodextrin, and the like, and sugar alcohols such as xylitol, sorbitol, and erythritol.
- a natural flavoring agent such as stevia extract or a synthetic flavoring agent such as saccharin may be used.
- An embodiment of the present invention provides a method of improving the cancer prevention, improvement or therapeutic effect of a sea cucumber gonadal extract by increasing any one or more saponin compounds selected from the group consisting of Formulas S2, S3, S4, S5, S6, S8 and S9. to provide.
- the sea cucumber gonad extract may include a sea cucumber ovary extract.
- One embodiment of the present invention provides a method for cancer prevention, improvement or treatment of a gonadal extract of sea cucumber, or a method for treating cancer in an individual in need thereof by treating the gonadal extract of sea cucumber, or a method for killing cancer cells.
- Another embodiment of the present invention provides a pharmaceutical for the treatment of cancer or a method for preparing the same, wherein the pharmaceutical includes a gonadal extract of sea cucumber.
- the cancer may include any one or more selected from the group consisting of pancreatic cancer, colorectal cancer, biliary tract cancer, ovarian cancer, breast cancer, pancreatic neuroendocrine tumor and colorectal cancer, preferably consisting of pancreatic cancer, pancreatic neuroendocrine tumor and colorectal cancer It may include any one or more cancers selected from the group.
- the gonad extract may include an ethanol extract of sea cucumber ovary, and preferably, the gonad extract may include 45 to 85% ethanol extract of sea cucumber ovary.
- One embodiment of the present invention is for cancer prevention, improvement or treatment use of any one or more compounds selected from the group consisting of the following formulas S2, S3, S4, S5, S6, S8 and S9, or treating the compound and requiring it
- a method for treating cancer in a subject, or a method for killing cancer cells is provided.
- Another embodiment of the present invention provides a pharmaceutical for the treatment of cancer or a method for preparing the same, wherein the pharmaceutical comprises any one or more compounds selected from the group consisting of Formulas S2, S3, S4, S5, S6, S8 and S9 mentioned herein.
- the cancer may include any one or more selected from the group consisting of pancreatic cancer, colorectal cancer, biliary tract cancer, ovarian cancer, breast cancer, pancreatic neuroendocrine tumor and colorectal cancer, preferably pancreatic cancer, colorectal cancer, biliary tract cancer, It may include any one or more selected from the group consisting of ovarian cancer, and breast cancer.
- the "subject" of the present invention means any animal, including humans, that has or can develop a target disease, and by administering the pharmaceutical composition of the present invention to an individual having or suspected of having a cancer-related disease, the individual is efficiently treated Or it can be prevented.
- the pharmaceutical composition of the present invention is not particularly limited as long as it is an individual for the purpose of cancer treatment or cancer cell death prevention or treatment, and can be applied to any individual.
- any animal such as monkey, dog, cat, rabbit, guinea pig, rat, mouse, cow, sheep, pig, goat, birds and fish may be used.
- administering means introducing a predetermined substance into a patient by any suitable method, and the administration route may be administered through any general route as long as it can reach a target tissue.
- Intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, intrapulmonary administration, rectal administration, etc. may be, but are not limited thereto.
- the anticancer pharmaceutical composition comprising the sea cucumber gonadal extract or a saponin compound derived therefrom according to the present invention has excellent apoptosis effect on cancer cells, so that it can treat pancreatic cancer, pancreatic neuroendocrine tumor, colorectal cancer, biliary tract cancer, ovarian cancer, breast cancer, etc. It can be usefully used for the treatment, prevention, or improvement of solid cancer.
- 1 is a result showing the results of confirming the apoptosis effect in pancreatic cancer and pancreatic neurocytoma with extracts obtained using different parts of sea cucumber.
- Figure 2 is the result of confirming the effect of colon cancer apoptosis with extracts obtained using different parts of sea cucumber.
- 3A to 3I are results confirming the apoptosis effect of compounds isolated from sea cucumber ovary extracts on pancreatic cancer and breast cancer cell lines.
- Figure 4a is the result of confirming the apoptosis effect of each compound on the MSS type colorectal cancer cell line
- Figure 4b is the result of confirming the apoptosis effect of each compound on the MSI-h type colorectal cancer cell line.
- sample number extraction part extraction solvent stock conc. (mg/ml) One Body 100% DW 25 2 Body 80% EtOH 25 3 Intestine 80% EtOH 25 4 Intestine 50% EtOH 25 5 Ovary 80% EtOH 25 6 Ovary 50% EtOH 25
- Samples 1-6 were obtained by extracting the body, intestine, and ovary of sea cucumber with solvents of the indicated concentrations, respectively.
- pancreatic cancer cell lines Two types of pancreatic cancer cell lines (CFPAC-1 and HPAC) and a pancreatic neuroendocrine tumor BON-1 cell line were tested for cytotoxicity of the sample.
- CFPAC-1 and HPAC Two types of pancreatic cancer cell lines
- a pancreatic neuroendocrine tumor BON-1 cell line were tested for cytotoxicity of the sample.
- 3 ⁇ 6 x 10 3 cells/well of each cell was seeded in a 96-well plate and cultured overnight at 37°C, 5% CO 2 in an incubator.
- each sample was dilution in each culture medium to 100ug/ml, and the cells were treated and cultured for 3 days. After 3 days, the survival rate of each cell was calculated by MTT assay.
- the experiment was repeated twice as a triplication.
- the ovarian extract of sea cucumber has a particularly superior cancer cell killing effect on pancreatic cancer cell lines, two types (CFPAC-1 and HPAC) and pancreatic neuroendocrine tumors compared to other sites.
- cytotoxicity tests were performed by seeding cells 1X10 3 cells/well into 96-well plates, and the following experimental protocols were all the same as for pancreatic cancer cell lines.
- Eicosapentaenoic acid and 8 types of compounds were prepared as follows.
- pancreatic cancer cell lines (CFPAC-1, HPAC, PANC-1 and BxPC-3), 1 pancreatic neuroendocrine tumor cell line (BON-1), 2 biliary tract cancer cell lines (Huct-1 and SNU1196), 2 ovarian cancer cell lines
- the species (Sk-OV3, and YDOV-151) and the breast cancer cell line MCF-7 were purchased from the laboratory of Professor Si-Young Song at Yonsei Medical Center, and the breast cancer cell lines MDA-MB-231 and BT-474 and the MSS colorectal cancer cell line SW620 and MSI-H
- the colorectal cancer cell line, HCT116 was purchased from a Korean cell line bank.
- CFPAC-1 is IMDM (containing 10% (v/v) fetal bovine serum (FBS) and 1% (v/v) antibiotics)
- HPAC and BON-1 are DMEM/F12 (containing 10% (v/v) FBS) and 1% (v/v) antibiotics)
- PANC-1 YDOV-151, SW620 and HCT116 in DMEM (containing 10% (v/v) FBS and 1% (v/v) antibiotics)
- RPMI1640 It was cultured in a culture medium containing 10% (v/v) FBS and 1% (v/v) antibiotics).
- each cell was seeded in a 96-well plate at 1 ⁇ 2 x 10 3 cells/well, and the remaining cells were seeded in a 96-well plate at 3 ⁇ 7 x 10 3 cells/well the day before the experiment. Then, it was cultured in an incubator at 37° C. 5% CO 2 overnight. On the day of the experiment, each sample was treated and cultured in cells for 3 days. After 3 days, the survival rate of each cell was calculated by MTT assay (Sigma Aldrich). The experiment was repeated two or more times as a triplication, and was analyzed with GraphPad Prism 8. The experimental results for colorectal cancer cell lines were statistically analyzed using SPSS statistics version 20.0.
- E1 was generally resistant to pancreatic cancer and breast cancer cell line MCF-7, and the S1 compound showed no apoptotic effect in all cancer cell lines tested.
- the S2 compound showed an apoptotic effect in the pancreatic cancer cell line, but was resistant to the breast cancer cell line MCF-7. Therefore, it was confirmed that the S2 compound was particularly effective in apoptosis of the pancreatic cancer cell line.
- the compounds S3, S4, S5, S6, S8, and S9 had an apoptotic effect on both breast cancer cell lines and pancreatic cancer cell lines.
- MTT assay was performed to obtain cytotoxic IC50 values for three single compounds S2, S3 and S9.
- apoptosis effects were also confirmed in biliary tract cancer, ovarian cancer and breast cancer cell lines.
- Table 3 the results shown in Table 3 below were obtained.
- S2, S3, and S9 all have an apoptosis effect on pancreatic cancer, biliary tract cancer, ovarian cancer and breast cancer at a certain concentration or more, so it is used for treatment, improvement of pancreatic cancer, biliary tract cancer, ovarian cancer or breast cancer it can be seen that
- S2, S3 and S9 all showed relatively high sensitivity to YDOV151, especially among ovarian cancer cell lines.
- the YDOV151 cell line is an ovarian mucinous cystadenocarcinoma cell line constructed in the Obstetrics and Gynecology laboratory of Severance Hospital. It is known to have different histological characteristics.
- the S2, S3 and S9 showed high sensitivity to the ovarian mucinous cyst cancer cell line.
- triple-negative breast cancer type MDA-BM-231 cell line showed high sensitivity to S2, S3 and S9.
- Triple-negative breast cancer is the most aggressive carcinoma among breast cancers with the characteristics of high differentiation, rapid progression, frequent recurrence, and low response rate to treatment. classified as cancer. Therefore, the single extract of sea cucumber ovary shows a specific sensitive effect in ovarian mucinous cystic cancer and triple-negative breast cancer, which are representative intractable cancers among ovarian cancer and breast cancer. It is considered
Abstract
The present invention provides an anti-cancer use of an extract from the gonads of Stichopus Japonicus, preferably, an extract from the ovaries thereof. The present invention provides an anti-cancer use of compounds isolated from an extract from the gonads of Stichopus Japonicus, preferably, an extract from the ovaries thereof. In addition, provided is a method, which processes an extract of Stichopus Japonicus to treat cancer or prevent cancer of an individual requiring same.
Description
본 출원은 2021년 3월 2일에 출원된 한국특허출원 제10-2021-0027739호에 기초한 우선권을 주장하며, 해당 출원의 명세서 및 도면에 개시된 모든 내용은 본 출원에 원용된다. 본 발명은 해삼 생식선 추출물의 항암 용도, 또는 해삼 생식선 추출물로부터 분리된 사포닌 화합물의 항암 용도에 관한 것이다.This application claims priority based on Korean Patent Application No. 10-2021-0027739 filed on March 2, 2021, and all contents disclosed in the specification and drawings of the application are incorporated herein by reference. The present invention relates to the anticancer use of a sea cucumber gonad extract, or the anticancer use of a saponin compound isolated from a sea cucumber gonad extract.
해삼(sea cucumber, 학명 Stichopus japonicus)은 아시아 국가, 특히 중국, 일본 및 한국에서 중요한 식재료로 사용되는 전통 해산물이다. 해삼에서 분리된 많은 생리 활성 물질이 있다. 특히 콜라겐 펩타이드, 다당류 등은 다양한 생물학적 활성을 나타내는 것으로 잘 알려져 있다. 해삼의 난소는 해서자라고 하여 진미로 유명하다. Sea cucumber ( Stichopus japonicus ) is a traditional seafood used as an important ingredient in Asian countries, especially China, Japan and Korea. There are many bioactive substances isolated from sea cucumber. In particular, collagen peptides and polysaccharides are well known to exhibit various biological activities. The ovaries of sea cucumbers are called sea cucumbers and are famous for their delicacies.
암은 환경의 변화, 인구 고령화 및 생활양식의 변화 등으로 인해 사망률이 매년 지속해서 증가하는 질병이다. 전 세계적으로 5대 사망원인 중 하나이며 우리나라에서도 높은 사망원인을 차지하는 질병이다. 암의 치료는 외과적 수술, 방사선 치료, 약물 요법으로 시행되고 있다. 약물 요법의 경우 1세대 화학항암제(chemotherapy)를 시작으로 2세대 표적항암제 (targeted drugs therapy)가 개발되어 현재까지 가장 많이 사용되고 있지만, 항암제 내성이라는 큰 문제에 직면해있다. 항암제 내성을 극복하기 위해 3세대 면역항암제(immunotherapy)의 개발, 기존 약물의 문제점을 보완한 차세대 치료제(next generation drug)의 개발, 기존의 약물과의 병용요법(combination therapy), 병의 유무를 구분하거나 치료 반응을 예측할 수 있는 표시자인 바이오마커(biomarker)의 개발, 천연물 유래의 새로운 항암 물질 개발, 치료 효능의 극대화를 위하여 새로운 약물전달시스템을 개발하는 등의 다양한 접근방식이 진행 중이다.Cancer is a disease in which the mortality rate continues to increase every year due to changes in the environment, an aging population, and changes in lifestyle. It is one of the five leading causes of death worldwide and is the leading cause of death in Korea. Cancer treatment is performed through surgery, radiation therapy, and drug therapy. In the case of drug therapy, starting with the first-generation chemotherapy, the second-generation targeted drug therapy has been developed and used the most, but it faces a major problem of anticancer drug resistance. Development of third-generation immunotherapy to overcome anticancer drug resistance, development of next-generation drugs that supplement the problems of existing drugs, combination therapy with existing drugs, and classification of disease Various approaches are underway, such as the development of biomarkers, which are markers that can predict treatment response, the development of new anticancer substances derived from natural products, and the development of new drug delivery systems to maximize therapeutic efficacy.
본 발명의 발명자들은 천연물 해삼을 통한 항암 활성 연구를 수행한 결과 본 발명을 완성하기에 이르렀다. The inventors of the present invention have completed the present invention as a result of conducting a study on anticancer activity through natural sea cucumber.
따라서 본 발명이 해결하고자 하는 과제는 해삼 추출물, 바람직하게 해삼의 생식선 추출물의 항암 용도를 제공하고자 한다. 또한 해삼 추출물로부터 분리된 사포닌 화합물의 신규한 용도를 제공하고자 한다. 또한 해삼 추출물을 처리하여 이를 필요로 하는 개체의 암을 치료하거나, 암을 예방하는 방법을 제공한다. Therefore, the problem to be solved by the present invention is to provide an anticancer use of a sea cucumber extract, preferably a gonadal extract of sea cucumber. In addition, it is intended to provide a novel use of the saponin compound isolated from the sea cucumber extract. It also provides a method of treating or preventing cancer in an individual in need thereof by treating the sea cucumber extract.
상기 과제를 해결하기 위하여 본 발명은 해삼의 추출물, 바람직하게 해삼의 생식선 추출물, 더 바람직하게 해삼의 난소 추출물의 항암 용도를 제공하고자 한다. 본 발명은 해삼의 생식선 추출물을 포함하는 항암용 조성물을 제공하고자 한다. 본 발명은 해삼의 생식선 추출물을 포함하는 암 또는 종양의 치료, 개선, 또는 예방용 조성물을 제공한다. 또한 본 발명은 해삼의 생식선 추출물을 포함하는 암세포 또는 종양세포 사멸용 조성물을 제공한다. 본 발명은 해삼의 추출물, 바람직하게 해삼의 생식선 추출물, 더 바람직하게 해삼의 난소 추출물을 처리하여 이를 필요로 하는 개체의 암을 치료하거나, 암을 예방하는 방법을 제공하고자 한다. 또한 본 발명은 해삼의 생식선 추출물을 처리하여 이를 필요로 하는 개체의 암세포 또는 종양세포 사멸 방법을 제공하고자 한다.In order to solve the above problems, the present invention is to provide an anticancer use of a sea cucumber extract, preferably a gonad extract of a sea cucumber, and more preferably an ovarian extract of a sea cucumber. An object of the present invention is to provide an anticancer composition comprising a gonad extract of sea cucumber. The present invention provides a composition for the treatment, improvement, or prevention of cancer or tumor comprising a gonadal extract of sea cucumber. In addition, the present invention provides a composition for killing cancer cells or tumor cells comprising the gonadal extract of sea cucumber. An object of the present invention is to provide a method for treating or preventing cancer in an individual in need thereof by treating a sea cucumber extract, preferably a sea cucumber gonad extract, more preferably a sea cucumber ovary extract. In addition, the present invention is intended to provide a method for killing cancer cells or tumor cells of an individual in need by treating the gonadal extract of sea cucumber.
본 명세서에서 언급된 암은 종양도 포함되는 넓은 의미로 이해될 수 있다. 종양(tumor)은 신체조직의 자율적인 과잉 성장에 의해 비정상적으로 자라난 세포덩어리를 의미하며, 양성종양(benign tumor)과 악성종양(malignant tumor)으로 구분할 수 있다. 양성종양이 비교적 성장 속도가 느리고 전이되지 않는 것에 반해 악성종양은 주위 조직에 침윤하면서 빠르게 성장하고 신체 각 부위에 확산되거나 전이되어 생명을 위협하게 된다. 따라서 종양에 의해 유발된 질병을 통칭하여 암(cancer)이라 정의하고 있으며, 악성종양과 암은 특별히 구분하지 않고 사용되고 있다. 본 발명에서 항암이란 암세포의 증식을 억제하거나 암세포를 죽이는 것을 의미할 수 있다. 본 발명의 일 구현 예에 따른 항암용 약학 조성물에 있어서, 상기 조성물은 암의 증식을 억제하고, 세포사멸을 유도할 수 있으나, 이에 제한되지 않는다. 본 발명에 사용되는 "치료"란 용어는, 질환 또는 증상의 하나 이상의 징후를 경감하거나 약화하거나 개선하는 것, 추가적인 징후를 예방하는 것, 질환 또는 증상을 억제하는 것, 예를 들어 질환 또는 증상의 발생을 막는 것, 질환 또는 증상을 완화시키는 것, 질환 또는 증상의 퇴행을 야기하는 것, 질환 또는 증상에 의해 야기되는 증상을 완화시키는 것, 또는 예방적으로 및/또는 치료적으로 질환 또는 증상의 징후를 중단시키는 것을 포함하는 넓은 의미로 사용될 수 있다. "예방"은 본 발명에 따른 조성물의 투여에 의해 질환의 발병을 억제 또는 지연시키는 모든 행위를 의미한다.Cancer as referred to herein may be understood in a broad sense including tumors. A tumor refers to a cell mass that has grown abnormally by the autonomous overgrowth of body tissues, and can be divided into benign tumors and malignant tumors. While benign tumors have a relatively slow growth rate and do not metastasize, malignant tumors infiltrate into surrounding tissues, grow rapidly, and spread or metastasize to various parts of the body, endangering life. Therefore, diseases induced by tumors are collectively defined as cancer, and malignant tumors and cancer are used without special distinction. In the present invention, anticancer may mean inhibiting the proliferation of cancer cells or killing cancer cells. In the anticancer pharmaceutical composition according to an embodiment of the present invention, the composition may inhibit cancer proliferation and induce apoptosis, but is not limited thereto. As used herein, the term "treatment" refers to alleviating, attenuating, or ameliorating one or more signs of a disease or condition, preventing additional signs, inhibiting the disease or symptom, e.g., treatment of a disease or condition. preventing the occurrence, alleviating the disease or symptom, causing regression of the disease or symptom, alleviating the symptoms caused by the disease or symptom, or prophylactically and/or therapeutically of the disease or symptom It can be used in a broad sense including stopping a symptom. "Prevention" means any action that inhibits or delays the onset of a disease by administration of the composition according to the present invention.
상기 해삼의 난소 추출물은 해삼의 생식기인 난소를 용매로 추출한 것을 의미한다. 해삼의 생식선은 성숙함에 따라 정소는 유백색으로 난소는 홍색으로 변하는 것으로 알려져 있다. 본 발명은 해삼의 생식선 중 바람직하게 난소 추출물을 이용할 수 있다. 상기 용매는 물, C1~C4의 저급알코올, 또는 이들의 혼합용매를 사용할 수 있으며, 바람직하게, 에탄올 또는 에탄올 수용액을 사용하는 것이 바람직하다. 본 발명의 추출물은 통상의 동물을 추출대상으로 한 추출물의 제조방법에 따라 제조된 것일 수 있으며, 구체적으로는 냉침추출법, 온침추출법 또는 열 추출법 등일 수 있으며, 통상의 추출기기, 초음파 분쇄 추출기 또는 분획기를 이용할 수 있다. 바람직하게 상기 해삼 생식선 추출물, 바람직하게 난소 추출물은 45 내지 85%(V/V) 에탄올 수용액을 용매로 추출할 수 있으며 더 바람직하게 상기 해삼 난소를 48 내지 55%(V/V) 에탄올 수용액을 용매로, 또는 75 내지 83%(V/V) 에탄올 수용액을 용매로 추출할 수 있다. The ovary extract of sea cucumber means that the ovary, which is the reproductive organ of sea cucumber, is extracted with a solvent. As the gonads of sea cucumbers mature, it is known that the testes turn milky white and the ovaries turn red. In the present invention, it is possible to preferably use an ovarian extract from the gonads of sea cucumbers. The solvent may be water, a C1 to C4 lower alcohol, or a mixed solvent thereof, preferably ethanol or an aqueous ethanol solution. The extract of the present invention may be prepared according to a method for preparing an extract for an extraction target of a conventional animal, and specifically may be a cold extraction method, a hot extraction method, or a heat extraction method, and a conventional extraction device, ultrasonic grinding extractor or fractionation. gear is available. Preferably, the sea cucumber gonad extract, preferably the ovary extract, can be extracted with a 45 to 85% (V/V) aqueous ethanol solution as a solvent, and more preferably, the sea cucumber ovary with a 48 to 55% (V/V) aqueous ethanol solution as a solvent. Alternatively, 75 to 83% (V/V) aqueous ethanol solution may be extracted as a solvent.
또 다른 실시예에서 상기 해삼 생식선, 바람직하게 난소는 추출물을 분획하는 과정을 거칠 수 있으며, 이로부터 수득된 해삼 난소 분획물도 본 발명의 범위에 포함될 수 있다. 바람직하게 해삼 난소를 에탄올 수용액으로 추출한 추출물을 분획할 수 있으며, 바람직하게 상기 에탄올 수용액은 45 내지 85%(V/V) 에탄올 수용액일 수 있다. 상기 분획물은 바람직하게 해삼 난소 추출물을 부탄올을 용매로 하여 분획할 수 있다. 상기 분획물은 해삼 난소 추출물을 증류수 등에 현탁시킨 후 분별 깔때기 등을 사용하여 헥산, 메틸렌클로라이드, 에틸아세테이트, 부탄올, 물 또는 이들의 조합에 의해 얻을 수 있으며, 바람직하게 본 발명의 목적상 상기 해삼 난소 추출물은 부탄올로 분획할 수 있다. 상기 분획화는 당업계에서 통상적으로 이용되는 분획화 방법으로 실시할 수 있다. In another embodiment, the sea cucumber gonad, preferably the ovary, may undergo a process of fractionating the extract, and the sea cucumber ovary fraction obtained therefrom may also be included in the scope of the present invention. Preferably, the extract obtained by extracting sea cucumber ovaries with an aqueous ethanol solution may be fractionated, and preferably, the aqueous ethanol solution may be 45 to 85% (V/V) aqueous ethanol solution. The fraction may preferably be fractionated by using the sea cucumber ovary extract as a solvent butanol. The fraction can be obtained by suspending the sea cucumber ovary extract in distilled water, etc. and then using a separatory funnel, etc. to obtain hexane, methylene chloride, ethyl acetate, butanol, water, or a combination thereof. Preferably, for the purpose of the present invention, the sea cucumber ovary extract can be fractionated with butanol. The fractionation may be carried out by a fractionation method commonly used in the art.
상기 제조된 추출물 또는 상기 분획과정을 수행하여 수득한 분획물은 이후 여과하거나 농축 또는 건조과정을 수행하여 용매를 제거할 수 있으며, 여과, 농축 및 건조를 모두 수행할 수 있다. 구체적으로 상기 여과는 여과지를 이용하거나 감압여과기를 이용할 수 있으며, 상기 농축은 감압 농축기, 일예로 회전 증발기를 이용하여 감압농축할 수 있으며, 상기 건조는 일예로 동결건조법으로 수행할 수 있다. The prepared extract or the fraction obtained by performing the fractionation process may then be filtered or concentrated or dried to remove the solvent, and both filtration, concentration and drying may be performed. Specifically, the filtration may be performed using filter paper or a reduced pressure filter, and the concentration may be concentrated under reduced pressure using a reduced pressure concentrator, for example, a rotary evaporator, and the drying may be performed by, for example, a freeze-drying method.
상기 추출물 또는 분획물은 암세포 억제, 사멸 또는 암세포 생성 억제 효과가 우수하며, 바람직하게 상기 암세포는 췌장암 및 대장암을 포함할 수 있다. 상기 추출물 또는 분획물은 암세포주에서 암세포 증식을 억제할 수 있으며, 상기 암세포주는 췌장암 세포주 또는 대장암 세포주를 포함할 수 있다. 일 실시예에서 본 발명의 추출물 또는 분획물은 췌장암 또는 대장암 치료, 예방 및/또는 개선 용도를 제공한다. 일 실시예에서 본 발명의 추출물 또는 분획물은 췌장신경내분비종양의 세포 사멸, 췌장신경내분비종양 치료, 예방 및/또는 개선 용도를 제공할 수 있다. The extract or fraction is excellent in inhibiting cancer cells, killing, or inhibiting the generation of cancer cells, and preferably, the cancer cells may include pancreatic cancer and colorectal cancer. The extract or fraction may inhibit cancer cell proliferation in a cancer cell line, and the cancer cell line may include a pancreatic cancer cell line or a colon cancer cell line. In one embodiment, the extract or fraction of the present invention provides a use for treating, preventing and/or improving pancreatic cancer or colorectal cancer. In one embodiment, the extract or fraction of the present invention may provide a use for apoptosis of pancreatic neuroendocrine tumor, treatment, prevention and/or improvement of pancreatic neuroendocrine tumor.
본 발명의 일 실시예서, 상기 해삼 생식선, 바람직하게 난소 추출물은 하기 화학식 S2, S3, S4, S5, S6, S8 및 S9로 이루어진 군에서 선택된 어느 하나 이상의 화합물을 포함하는 항암용 조성물, 바람직하게 항암용 약학 조성물을 제공한다. 본 발명의 일 실시예는 해삼의 생식선 추출물을 포함하는 암 또는 종양의 치료, 개선, 또는 예방용 조성물을 제공한다. 본 발명의 일 실시예에서 상기 화합물의 항암 용도, 암 또는 종양의 치료, 개선, 또는 예방 용도를 제공한다. 본 발명의 일 실시예에서 상기 화합물을 이용한 항암 방법, 암 또는 종양의 치료, 개선 또는 예방 방법을 제공한다. 또한 본 발명은 해삼의 생식선 추출물, 또는 상기 추출물로부터 분리된 하기 화합물들을 포함하는 암세포 또는 종양세포 사멸용 조성물을 제공한다. In one embodiment of the present invention, the sea cucumber gonadal, preferably ovarian extract is an anticancer composition comprising any one or more compounds selected from the group consisting of the following formulas S2, S3, S4, S5, S6, S8 and S9, preferably anticancer A pharmaceutical composition is provided. One embodiment of the present invention provides a composition for the treatment, improvement, or prevention of cancer or tumor comprising the gonad extract of sea cucumber. In one embodiment of the present invention, there is provided the use of the compound for anticancer, treatment, improvement, or prevention of cancer or tumor. In one embodiment of the present invention provides an anti-cancer method, a method for treating, improving or preventing cancer or tumor using the compound. In addition, the present invention provides a composition for killing cancer cells or tumor cells comprising a gonadal extract of sea cucumber, or the following compounds isolated from the extract.
상기 화합물은 자연에서 유래될 수도 있고, 화학적 합성방법으로 합성될 수도 있으며, 상기 화합물은 얻는 과정은 특별히 제한되지 않는다. 본 발명의 일 실시예에서 상기 화합물은 해삼의 생식선으로부터 추출 또는 분리할 수 있으며, 바람직하게 해삼의 난소로부터 추출 또는 분리할 수 있다. The compound may be derived from nature or may be synthesized by a chemical synthesis method, and the process for obtaining the compound is not particularly limited. In one embodiment of the present invention, the compound may be extracted or isolated from the gonads of sea cucumbers, preferably extracted or isolated from the ovaries of sea cucumbers.
상기 암은 바람직하게 고형암일 수 있으며, 상기 고형암은 췌장암, 대장암, 담도암, 난소암, 유방암 등을 포함할 수 있다. The cancer may preferably be a solid cancer, and the solid cancer may include pancreatic cancer, colorectal cancer, biliary tract cancer, ovarian cancer, breast cancer, and the like.
본 발명의 일 구현예는 췌장암 치료, 개선, 또는 예방용 조성물을 제공한다. 상기 조성물은 상기 화합물 S2, S3, S4, S5, S6, S8, 및 S9 중 어느 하나 이상을 포함할 수 있다. 본 발명의 일 구현예는 유방암 치료, 개선, 또는 예방용 조성물을 제공한다. 상기 조성물은 상기 화합물 S3, S4, S5, S6, S8, 및 S9 중 어느 하나 이상을 포함할 수 있다. 본 발명의 일 구현예는 대장암 치료, 개선, 또는 예방용 조성물을 제공한다. 상기 조성물은 상기 화합물 S3, S4, S5, S6, S8, 및 S9 중 어느 하나 이상을 포함할 수 있다. 본 발명의 일 구현예는 화합물 S2, S3 및 S9 중 어느 하나 이상을 포함하는 담도암 및/또는 난소암 치료, 개선, 또는 예방용 조성물을 제공한다. One embodiment of the present invention provides a composition for treating, improving, or preventing pancreatic cancer. The composition may include any one or more of the compounds S2, S3, S4, S5, S6, S8, and S9. One embodiment of the present invention provides a composition for treating, improving, or preventing breast cancer. The composition may include any one or more of the compounds S3, S4, S5, S6, S8, and S9. One embodiment of the present invention provides a composition for treating, improving, or preventing colon cancer. The composition comprises the compound It may include any one or more of S3, S4, S5, S6, S8, and S9. One embodiment of the present invention provides a composition for treating, improving, or preventing biliary tract cancer and/or ovarian cancer, comprising any one or more of compounds S2, S3 and S9.
특히 상기 난소암은 난소 점액성 낭포암을 포함할 수 있고, 상기 유방암은 삼중음성유방암을 포함할 수 있다. 난소 점액성 낭포암은 난소암 중에서도 희귀암으로 분류되는 암으로, 대다수 난소암을 차지하는 상피세포암과는 다른 조직학적 특성을 갖는 것으로 알려져 있다. 삼중음성유방암(Triple-negative breast cancer)은 유방암 중 고분화, 빠른 진행, 빈번한 재발, 치료에 대한 낮은 반응율의 특성을 가진 가장 공격적인 암종이지만, 치료를 위한 알려진 타겟(예를 들어 HER2)이 없어 개발된 표적항암제도 전무한 대표적인 난치암으로 분류된다. 본 발명의 일 실시예는 고형암 중 대장암, 췌장암 등에 대한 항암 효과가 우수한 화합물을 제공한다. In particular, the ovarian cancer may include ovarian mucinous cystic cancer, and the breast cancer may include triple negative breast cancer. Ovarian mucinous cystic cancer is classified as a rare cancer among ovarian cancer, and is known to have different histological characteristics from epithelial cell carcinoma, which accounts for the majority of ovarian cancer. Triple-negative breast cancer is the most aggressive carcinoma among breast cancers with the characteristics of highly differentiated, rapid progression, frequent recurrence, and low response rate to treatment, but it has been developed because there is no known target for treatment (e.g., HER2). It is classified as a representative intractable cancer for which there is no targeted anticancer agent. One embodiment of the present invention provides a compound having excellent anticancer effect on colorectal cancer, pancreatic cancer, and the like among solid cancers.
본 발명의 일 실시예에 따른 상기 조성물은 본 발명의 해삼 생식선, 바람직하게 난소 추출물, 또는 해삼 생식선, 바람직하게 난소로부터 유래된 사포닌 화합물의 암 또는 종양의 치료, 예방, 및/또는 개선 등을 위한 신규 용도가 적용될 수 있는 분야이면 제한없이 사용될 수 있으며, 바람직하게 약학적 조성물, 또는 식품 조성물 형태로 제공될 수 있다. 바람직하게 상기 식품 조성물은 건강 기능 식품 조성물로 제공될 수 있다. 본 발명의 일 실시예에 따른 상기 조성물은 암 치료용 약학적 조성물, 또는 식품 조성물 형태로 제공될 수 있다. 본 발명의 일 구현예는 본 발명의 해삼 생식선 추출물, 또는 이로부터 유래된 화합물을 포함하는 암 세포 사멸용 약학적 조성물로 제공될 수 있다. The composition according to an embodiment of the present invention is a saponin compound derived from sea cucumber gonadal, preferably ovarian extract, or sea cucumber gonadal, preferably ovary of the present invention for the treatment, prevention, and/or improvement of cancer or tumor. It can be used without limitation as long as it is a field to which the novel use can be applied, and it may be preferably provided in the form of a pharmaceutical composition or a food composition. Preferably, the food composition may be provided as a health functional food composition. The composition according to an embodiment of the present invention may be provided in the form of a pharmaceutical composition for cancer treatment or a food composition. One embodiment of the present invention may be provided as a pharmaceutical composition for killing cancer cells comprising the sea cucumber gonad extract of the present invention, or a compound derived therefrom.
본 발명의 조성물이 약학적 조성물로 제조되는 경우, 본 발명의 약학적 조성물은 약학적으로 허용되는 담체를 포함한다. 본 발명의 약학적 조성물에 포함되는 약학적으로 허용되는 담체는 제제시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아 고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세결정성 셀룰로스, 폴리비닐피롤리돈, 셀룰로스, 물, 메틸 셀룰로스, 메틸히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일 등을 포함하나, 이에 한정되는 것은 아니다. 본 발명의 약학적 조성물은 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있다. 상기 약학적 담체는 비제한적인 예시이며, 상기 종류로 한정되지 않는다. When the composition of the present invention is prepared as a pharmaceutical composition, the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers included in the pharmaceutical composition of the present invention are commonly used in formulation, and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, methyl cellulose, methylhydroxybenzoate, talc, magnesium stearate, and mineral oil. The pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, and the like, in addition to the above components. The pharmaceutical carrier is a non-limiting example and is not limited to the above type.
본 발명의 약학적 조성물은 유효성분으로서 공지된 항암제를 추가로 포함할 수 있고, 목적하는 암의 치료를 위해 공지된 다른 치료와 병용될 수 있다. 다른 치료에는 화학요법, 방사선치료, 호르몬 치료, 골수 이식, 줄기-세포 대체치료, 다른 생물학적 치료, 면역치료 등이 포함되지만, 이에 제한되는 것은 아니다. 본 발명의 약학적 조성물에 포함될 수 있는 항암제의 예시에는 항암 항생제로 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 있으나, 이에 제한되는 것은 아니다.The pharmaceutical composition of the present invention may further include a known anticancer agent as an active ingredient, and may be used in combination with other known treatments for the treatment of a desired cancer. Other treatments include, but are not limited to, chemotherapy, radiation therapy, hormone therapy, bone marrow transplantation, stem-cell replacement therapy, other biological therapies, immunotherapy, and the like. Examples of anticancer agents that may be included in the pharmaceutical composition of the present invention include anticancer antibiotics such as dactinomycin (actinomycin D), doxorubicin (adriamycin), daunorubicin, idarubicin, mitok mitoxantrone, plicamycin, mitomycin C and bleomycin; and plant alkaloids vincristine, vinblastine, paclitaxel, docetaxel, etoposide, teniposide, topotecan and iridotecan, but is not limited thereto.
본 발명의 약학적 조성물은 경구 또는 비경구 투여할 수 있으며, 바람직하게는 경구 투여 방식으로 적용된다. 본 발명의 약학적 조성물의 적합한 투여량은 제제화 방법, 투여 방식, 환자의 연령, 체중, 성, 병적 상태, 음식, 투여 시간, 투여 경로, 배설 속도 및 반응 감응성과 같은 요인들에 의해 다양하게 처방될 수 있다. 본 발명의 약학적 조성물의 바람직한 투여량은 성인 기준으로 0.001-100 ㎎/kg, 0.005-90 ㎎/kg, 0.01-80㎎/kg 범위일 수 있으며, 상기 투여량은 투여 방법, 투여 목적 등 통상적으로 고려되는 요인들에 의해 조절될 수 있으며, 본 발명의 효과를 달성할 수 있는 범위 내에서 적절히 조절될 수 있다. The pharmaceutical composition of the present invention may be administered orally or parenterally, and is preferably applied by oral administration. A suitable dosage of the pharmaceutical composition of the present invention is variously prescribed depending on factors such as formulation method, administration method, age, weight, sex, pathological condition, food, administration time, administration route, excretion rate and reaction sensitivity of the patient. can be A preferred dosage of the pharmaceutical composition of the present invention may be in the range of 0.001-100 mg/kg, 0.005-90 mg/kg, 0.01-80 mg/kg based on an adult, and the dosage is conventional, such as administration method, administration purpose, etc. It can be controlled by factors considered as
본 발명의 약학적 조성물은 당해 발명이 속하는 기술분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있는 방법에 따라, 약학적으로 허용되는 담체 및/또는 부형제를 이용하여 제제화함으로써 단위 용량 형태로 제조되거나 또는 다용량 용기 내에 내입시켜 제조될 수 있다. 이때 제형은 오일 또는 수성 매질중의 용액, 현탁액, 시럽제 또는 유화액 형태이거나 엑스제, 산제, 분말제, 과립제, 정제 또는 캅셀제 형태일 수도 있으며, 분산제 또는 안정화제를 추가적으로 포함할 수 있다. The pharmaceutical composition of the present invention is prepared in unit dosage form by formulating using a pharmaceutically acceptable carrier and/or excipient according to a method that can be easily carried out by a person of ordinary skill in the art to which the present invention pertains. or may be prepared by incorporation into a multi-dose container. In this case, the formulation may be in the form of a solution, suspension, syrup, or emulsion in oil or aqueous medium, or may be in the form of an extract, powder, powder, granule, tablet or capsule, and may additionally include a dispersant or stabilizer.
본 발명의 조성물이 식품 조성물로 제조되는 경우, 식품 제조 시에 통상적으로 첨가되는 성분을 포함하며, 예를 들어, 단백질, 탄수화물, 지방, 영양소, 조미제 및 향미제를 포함한다. 상술한 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스, 올리고당 등; 및 폴리사카라이드, 예를 들어 덱스트린, 사이클로덱스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 향미제로서 스테비아 추출물과 같은 천연 향미제, 또는 사카린 등의 합성 향미제를 사용할 수 있다.When the composition of the present invention is prepared as a food composition, it includes ingredients commonly added during food production, for example, proteins, carbohydrates, fats, nutrients, seasonings and flavoring agents. Examples of the above-mentioned carbohydrates include monosaccharides such as glucose, fructose and the like; disaccharides such as maltose, sucrose, oligosaccharides and the like; and polysaccharides, for example, conventional sugars such as dextrin, cyclodextrin, and the like, and sugar alcohols such as xylitol, sorbitol, and erythritol. As the flavoring agent, a natural flavoring agent such as stevia extract or a synthetic flavoring agent such as saccharin may be used.
본 발명의 일 실시예는 화학식 S2, S3, S4, S5, S6, S8 및 S9로 이루어진 군에서 선택된 어느 하나 이상의 사포닌 화합물을 증가시켜 해삼 생식선 추출물의 암 예방, 개선 또는 치료 효과를 개선하는 방법을 제공한다. 바람직하게 상기 해삼 생식선 추출물은 해삼 난소 추출물을 포함할 수 있다. An embodiment of the present invention provides a method of improving the cancer prevention, improvement or therapeutic effect of a sea cucumber gonadal extract by increasing any one or more saponin compounds selected from the group consisting of Formulas S2, S3, S4, S5, S6, S8 and S9. to provide. Preferably, the sea cucumber gonad extract may include a sea cucumber ovary extract.
본 발명의 일 구현예는 해삼의 생식선 추출물의 암 예방, 개선 또는 치료 용도 또는 해삼의 생식선 추출물을 처리하여 이를 필요로 하는 개체의 암 치료 방법, 또는 암세포 사멸방법을 제공한다. 본 발명의 다른 구현예는 암 치료용 의약품 또는 이의 제조 방법을 제공하며, 상기 의약품은 해삼의 생식선 추출물을 포함한다. 상기 암은 췌장암, 대장암, 담도암, 난소암, 유방암, 췌장 신경내분비종양 및 대장암으로 이루어진 군에서 선택된 어느 하나 이상을 포함할 수 있으며, 바람직하게 췌장암, 췌장 신경내분비종양 및 대장암으로 이루어진 군에서 선택된 어느 하나 이상의 암을 포함할 수 있다. 상기 생식선 추출물은 해삼 난소의 에탄올 추출물을 포함하며, 바람직하게 상기 생식선 추출물은 해삼 난소의 45 내지 85% 에탄올 추출물을 포함할 수 있다. One embodiment of the present invention provides a method for cancer prevention, improvement or treatment of a gonadal extract of sea cucumber, or a method for treating cancer in an individual in need thereof by treating the gonadal extract of sea cucumber, or a method for killing cancer cells. Another embodiment of the present invention provides a pharmaceutical for the treatment of cancer or a method for preparing the same, wherein the pharmaceutical includes a gonadal extract of sea cucumber. The cancer may include any one or more selected from the group consisting of pancreatic cancer, colorectal cancer, biliary tract cancer, ovarian cancer, breast cancer, pancreatic neuroendocrine tumor and colorectal cancer, preferably consisting of pancreatic cancer, pancreatic neuroendocrine tumor and colorectal cancer It may include any one or more cancers selected from the group. The gonad extract may include an ethanol extract of sea cucumber ovary, and preferably, the gonad extract may include 45 to 85% ethanol extract of sea cucumber ovary.
본 발명의 일 구현예는 하기 화학식 S2, S3, S4, S5, S6, S8 및 S9로 이루어진 군에서 선택된 어느 하나 이상의 화합물의 암 예방, 개선 또는 치료 용도, 또는 상기 화합물을 처리하여 이를 필요로 하는 개체의 암 치료 방법, 또는 암세포 사멸방법을 제공한다. 본 발명의 다른 구현예는 암 치료용 의약품 또는 이의 제조 방법을 제공하며, 상기 의약품은 본원에 언급된 화학식 S2, S3, S4, S5, S6, S8 및 S9로 이루어진 군에서 선택된 어느 하나 이상의 화합물을 포함한다. 상기 암은 상기 암은 췌장암, 대장암, 담도암, 난소암, 유방암, 췌장 신경내분비종양 및 대장암으로 이루어진 군에서 선택된 어느 하나 이상을 포함할 수 있으며, 바람직하게 췌장암, 대장암, 담도암, 난소암, 및 유방암으로 이루어진 군에서 선택된 어느 하나 이상을 포함할 수 있다. One embodiment of the present invention is for cancer prevention, improvement or treatment use of any one or more compounds selected from the group consisting of the following formulas S2, S3, S4, S5, S6, S8 and S9, or treating the compound and requiring it A method for treating cancer in a subject, or a method for killing cancer cells is provided. Another embodiment of the present invention provides a pharmaceutical for the treatment of cancer or a method for preparing the same, wherein the pharmaceutical comprises any one or more compounds selected from the group consisting of Formulas S2, S3, S4, S5, S6, S8 and S9 mentioned herein. include The cancer may include any one or more selected from the group consisting of pancreatic cancer, colorectal cancer, biliary tract cancer, ovarian cancer, breast cancer, pancreatic neuroendocrine tumor and colorectal cancer, preferably pancreatic cancer, colorectal cancer, biliary tract cancer, It may include any one or more selected from the group consisting of ovarian cancer, and breast cancer.
본 발명의 "개체"는 대상 질환이 발병하였거나 발병할 수 있는 인간을 포함한 모든 동물을 의미하며, 본 발명의 약학적 조성물을 암 관련 질환을 갖는 개체 또는 의심 개체에 투여함으로써, 개체를 효율적으로 치료 또는 예방할 수 있다. 본 발명의 약학적 조성물은 암치료, 또는 암세포 사멸을 예방 또는 치료 목적으로 하는 개체이면 특별히 한정되지 않고, 어떠한 개체에든 적용 가능하다. 예를 들면, 원숭이, 개, 고양이, 토끼, 모르모트, 랫트, 마우스, 소, 양, 돼지, 염소 등과 같은 동물, 조류 및 어류 등 어느 것이나 사용할 수 있다.The "subject" of the present invention means any animal, including humans, that has or can develop a target disease, and by administering the pharmaceutical composition of the present invention to an individual having or suspected of having a cancer-related disease, the individual is efficiently treated Or it can be prevented. The pharmaceutical composition of the present invention is not particularly limited as long as it is an individual for the purpose of cancer treatment or cancer cell death prevention or treatment, and can be applied to any individual. For example, any animal such as monkey, dog, cat, rabbit, guinea pig, rat, mouse, cow, sheep, pig, goat, birds and fish may be used.
본 발명의 "투여"는, 어떠한 적절한 방법으로 환자에게 소정의 물질을 도입하는 것을 의미하며, 투여 경로는 목적 조직에 도달할 수 있는 한 어떠한 일반적인 경로를 통하여 투여될 수 있다. 복강내 투여, 정맥내 투여, 근육내 투여, 피하 투여, 피내 투여, 경구 투여, 국소 투여, 비내 투여, 폐내 투여, 직장 내 투여 등이 될 수 있으나, 이에 제한되지는 않는다. "Administration" of the present invention means introducing a predetermined substance into a patient by any suitable method, and the administration route may be administered through any general route as long as it can reach a target tissue. Intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, intrapulmonary administration, rectal administration, etc. may be, but are not limited thereto.
본 발명에 따른 해삼 생식선 추출물 또는 이로부터 유래된 사포닌 화합물을 포함하는 항암용 약학 조성물은 암세포에 대한 사멸 효과가 우수하여, 췌장암, 췌장신경내분비종양, 대장암, 담도암, 난소암, 유방암 등의 고형암 치료, 예방, 또는 개선에 유용하게 이용될 수 있다. The anticancer pharmaceutical composition comprising the sea cucumber gonadal extract or a saponin compound derived therefrom according to the present invention has excellent apoptosis effect on cancer cells, so that it can treat pancreatic cancer, pancreatic neuroendocrine tumor, colorectal cancer, biliary tract cancer, ovarian cancer, breast cancer, etc. It can be usefully used for the treatment, prevention, or improvement of solid cancer.
본 명세서에 첨부되는 다음의 도면들은 본 발명의 바람직한 실시예를 예시하는 것이며, 전술한 발명의 내용과 함께 본 발명의 기술사상을 더욱 이해시키는 역할을 하는 것이므로, 본 발명은 그러한 도면에 기재된 사항에만 한정되어 해석되어서는 아니 된다.The following drawings attached to the present specification illustrate preferred embodiments of the present invention, and serve to further understand the technical idea of the present invention together with the above-described contents of the present invention, so the present invention is limited to the matters described in such drawings It should not be construed as being limited.
도 1은 해삼의 서로 다른 부위를 이용하여 얻은 추출물로 췌장암 및 췌장신경세포종에서의 세포 사멸 효과를 확인한 결과를 나타낸 결과이다. 1 is a result showing the results of confirming the apoptosis effect in pancreatic cancer and pancreatic neurocytoma with extracts obtained using different parts of sea cucumber.
도 2는 해삼의 서로 다른 부위를 이용하여 얻은 추출물로 대장암 세포 사멸 효과를 확인한 결과이다. Figure 2 is the result of confirming the effect of colon cancer apoptosis with extracts obtained using different parts of sea cucumber.
도 3a 내지 도 3i는 해삼 난소 추출물에서 분리한 화합물들이 췌장암 및 유방암 세포주에 대해 갖는 세포 사멸 효과를 확인한 결과이다. 3A to 3I are results confirming the apoptosis effect of compounds isolated from sea cucumber ovary extracts on pancreatic cancer and breast cancer cell lines.
도 4a는 MSS type 대장암 세포주에 대한 각 화합물별 세포 사멸 효과를 확인한 결과이고, 도 4b는 MSI-h type 대장암 세포주에 대한 각 화합물별 세포 사멸 효과를 확인한 결과이다. Figure 4a is the result of confirming the apoptosis effect of each compound on the MSS type colorectal cancer cell line, Figure 4b is the result of confirming the apoptosis effect of each compound on the MSI-h type colorectal cancer cell line.
이하, 본 발명의 이해를 돕기 위하여 실시예 등을 들어 상세하게 설명하기로 한다. 그러나, 본 발명에 따른 실시예들은 여러 가지 다른 형태로 변형될 수 있으며, 본 발명의 범위가 하기 실시예들에 한정되는 것으로 해석되어서는 안 된다. 본 발명의 실시예들은 본 발명이 속한 분야에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다.Hereinafter, examples and the like will be described in detail to help the understanding of the present invention. However, the embodiments according to the present invention may be modified in various other forms, and the scope of the present invention should not be construed as being limited to the following examples. The embodiments of the present invention are provided to more completely explain the present invention to those of ordinary skill in the art to which the present invention pertains.
Ⅰ. 해삼 난소 추출물의 항암 효과 확인I. Confirmation of anticancer effect of sea cucumber ovary extract
1.One.
추출 부위 및 용매 농도Extraction site and solvent concentration
| 시료번호sample number | 추출부위extraction part | 추출용매extraction solvent | stock conc. (mg/ml)stock conc. (mg/ml) |
| 1One |
Body |
100% DW100% DW | 2525 |
| 22 |
Body |
80% EtOH80% EtOH | 2525 |
| 33 |
Intestine |
80% EtOH80% EtOH | 2525 |
| 44 |
Intestine |
50% EtOH50% EtOH | 2525 |
| 55 | Ovary Ovary | 80% EtOH80% EtOH | 2525 |
| 66 | Ovary Ovary | 50% EtOH50% EtOH | 2525 |
해삼의 본체(body), 내장 (intestine), 및 난소 (ovary)를 각각 제시된 농도의 용매로 추출하여 시료 1-6을 얻었다. Samples 1-6 were obtained by extracting the body, intestine, and ovary of sea cucumber with solvents of the indicated concentrations, respectively.
2. 해삼 추출물의 암세포 억제 효과 확인2. Confirmation of cancer cell suppression effect of sea cucumber extract
(1) 췌장암 세포 사멸 효과 (1) Pancreatic cancer cell death effect
췌장암 세포주 2종(CFPAC-1 및 HPAC) 및 췌장신경내분비종양 세포주(pancreatic neuroendocrine tumor) BON-1 세포주에 대해 해당 시료의 cytotoxicity test를 진행하였다. 실험 전날 각 세포를 3~6 x 103 cells/well씩 96well plate에 seeding 후 하룻밤동안 37℃, 5% CO2 incubator에서 배양하였다. 실험 당일 각 시료를 100ug/ml가 되도록 각 배양액에 dilution 한 뒤 세포에 3일 동안 처리, 배양하였다. 3일 후 MTT assay를 통해 각 세포의 survival rate를 계산하였다. 실험은 triplication으로 2회 반복 실험 진행하였다.Two types of pancreatic cancer cell lines (CFPAC-1 and HPAC) and a pancreatic neuroendocrine tumor BON-1 cell line were tested for cytotoxicity of the sample. The day before the experiment, 3~6 x 10 3 cells/well of each cell was seeded in a 96-well plate and cultured overnight at 37°C, 5% CO 2 in an incubator. On the day of the experiment, each sample was dilution in each culture medium to 100ug/ml, and the cells were treated and cultured for 3 days. After 3 days, the survival rate of each cell was calculated by MTT assay. The experiment was repeated twice as a triplication.
도 1에서 확인할 수 있듯이, 해삼의 난소 추출물은 췌장암 세포주, 2종(CFPAC-1 및 HPAC) 및 췌장신경내분비종양에 대해 다른 부위에 비해 특히 우수한 암세포 사멸 효과가 있음을 알 수 있었다. As can be seen in FIG. 1 , it was found that the ovarian extract of sea cucumber has a particularly superior cancer cell killing effect on pancreatic cancer cell lines, two types (CFPAC-1 and HPAC) and pancreatic neuroendocrine tumors compared to other sites.
(2) 대장암 세포 사멸 효과(2) colon cancer apoptosis effect
대장암 세포주 SW480, 및 SW620에 대해서도 세포를 1X103 cells/well씩 96well plate에 seeding 하여 cytotoxicity test를 진행하였으며, 이후의 실험 프로토콜은 모두 췌장암 세포주의 실험방법과 동일하다.For colorectal cancer cell lines SW480 and SW620, cytotoxicity tests were performed by seeding cells 1X10 3 cells/well into 96-well plates, and the following experimental protocols were all the same as for pancreatic cancer cell lines.
도 2에서 확인할 수 있듯이, 해삼의 난소 추출물(시료번호 5 및 6)은 대장암 세포주에 대해서도 해삼의 다른 부위에 비해 특히 우수한 암세포 사멸 효과가 있음을 알 수 있었다. As can be seen in FIG. 2 , it was found that the ovarian extracts of sea cucumber (Sample Nos. 5 and 6) had a particularly superior cancer cell killing effect on colon cancer cell lines compared to other parts of the sea cucumber.
Ⅱ. 해삼 난소 유래 화합물의 항암 효능 확인II. Confirmation of anticancer efficacy of sea cucumber ovary-derived compounds
1. 실험 재료 및 방법1. Experimental Materials and Methods
하기와 같이, Eicosapentaenoic acid 및 8종의 화합물을 준비하였다. Eicosapentaenoic acid and 8 types of compounds were prepared as follows.
9종의 화합물 (30mg/ml in DMSO)을 -20℃에 보관한 뒤 in vitro assay에 사용하였다. 세포배양 배지는 Hyclone, Gibco 및 Invitrogen에서 구매하였고, DMSO 및 MTT powder는 Sigma aldrich에서 구매하였다. 췌장암 세포주 4종(CFPAC-1, HPAC, PANC-1 및 BxPC-3), 췌장 신경내분비 종양 세포주 1종 (BON-1), 담도암 세포주 2종 (Hucct-1 및 SNU1196), 난소암 세포주 2종 (Sk-OV3, 및 YDOV-151)및 유방암 세포주 MCF-7는 연세의료원 송시영 교수님 연구실에서 분양 받았고, 유방암 세포주 MDA-MB-231, BT-474 와 MSS 대장암 세포주인 SW620 세포주와 MSI-H 대장암 세포주인 HCT116는 한국 세포주 은행에서 분양 받았다. Nine compounds (30mg/ml in DMSO) were stored at -20°C and used for in vitro assays. Cell culture medium was purchased from Hyclone, Gibco, and Invitrogen, and DMSO and MTT powder were purchased from Sigma aldrich. 4 pancreatic cancer cell lines (CFPAC-1, HPAC, PANC-1 and BxPC-3), 1 pancreatic neuroendocrine tumor cell line (BON-1), 2 biliary tract cancer cell lines (Huct-1 and SNU1196), 2 ovarian cancer cell lines The species (Sk-OV3, and YDOV-151) and the breast cancer cell line MCF-7 were purchased from the laboratory of Professor Si-Young Song at Yonsei Medical Center, and the breast cancer cell lines MDA-MB-231 and BT-474 and the MSS colorectal cancer cell line SW620 and MSI-H The colorectal cancer cell line, HCT116, was purchased from a Korean cell line bank.
CFPAC-1은 IMDM(containing 10%(v/v) fetal bovine serum(FBS) and 1%(v/v) antibiotics), HPAC 및 BON-1은 DMEM/F12(containing 10%(v/v) FBS and 1%(v/v) antibiotics), PANC-1, YDOV-151, SW620 및 HCT116은 DMEM(containing 10%(v/v) FBS and 1%(v/v) antibiotics), 나머지 세포주들은 RPMI1640(containing 10%(v/v) FBS and 1%(v/v) antibiotics) 배양액에서 배양하였다.CFPAC-1 is IMDM (containing 10% (v/v) fetal bovine serum (FBS) and 1% (v/v) antibiotics), HPAC and BON-1 are DMEM/F12 (containing 10% (v/v) FBS) and 1% (v/v) antibiotics), PANC-1, YDOV-151, SW620 and HCT116 in DMEM (containing 10% (v/v) FBS and 1% (v/v) antibiotics), and RPMI1640 ( It was cultured in a culture medium containing 10% (v/v) FBS and 1% (v/v) antibiotics).
대장암 세포주인 SW620 및 HCT116은 각 세포를 1~2 x 103 cells/well씩 96 well plate에 seeding 하였고, 나머지 세포는 실험 전날 각 세포를 3~7 x 103 cells/well씩 96well plate에 seeding 후 하룻밤 동안 37℃ 5% CO2 incubator에서 배양하였다. 실험 당일 각 시료를 세포에 3일 동안 처리, 배양하였다. 3일 후 MTT assay (Sigma Aldrich)를 통해 각 세포의 survival rate를 계산하였다. 실험은 triplication으로 2회 이상 반복하여 진행하였고, GraphPad Prism 8로 분석하였다. 대장암 세포주에 대한 실험결과는 SPSS statistics version 20.0으로 통계 분석하였다.For colorectal cancer cell lines SW620 and HCT116, each cell was seeded in a 96-well plate at 1~2 x 10 3 cells/well, and the remaining cells were seeded in a 96-well plate at 3~7 x 10 3 cells/well the day before the experiment. Then, it was cultured in an incubator at 37° C. 5% CO 2 overnight. On the day of the experiment, each sample was treated and cultured in cells for 3 days. After 3 days, the survival rate of each cell was calculated by MTT assay (Sigma Aldrich). The experiment was repeated two or more times as a triplication, and was analyzed with GraphPad Prism 8. The experimental results for colorectal cancer cell lines were statistically analyzed using SPSS statistics version 20.0.
2. 췌장암 및 유방암 세포 사멸능 확인2. Confirmation of apoptosis in pancreatic cancer and breast cancer
총 9종의 해삼 난소 단일 화합물에 대해 30, 10, 3, 및 1 ug/ml 의 농도로 3일동안 다양한 암세포주에 처리한 결과, 다음과 같은 결과를 얻었다. 도 3a 내지 도 3i에 각 화합물별 암세포주에 대한 세포 사멸능을 평가하였다. As a result of treatment with various cancer cell lines for 3 days at concentrations of 30, 10, 3, and 1 ug/ml for a total of 9 types of sea cucumber ovary single compounds, the following results were obtained. 3A to 3I, the cell killing ability of each compound for each cancer cell line was evaluated.
그 결과, E1은 전반적으로 췌장암 및 유방암 세포주 MCF-7에서 내성을 보였고, S1 화합물은 테스트했던 모든 암세포주에서 세포사멸 효과를 보이지 않았다. S2 화합물은 췌장암 세포주에서는 세포사멸 효과를 보였으나, 유방암 세포주인 MCF-7 에서는 내성을 보였으며, 따라서, S2 화합물은 췌장암 세포 사멸에 특히 효과적임을 확인하였다. S3, S4, S5, S6, S8, 및 S9 화합물은 유방암 세포주 및 췌장암 세포주 모두에 대해 세포 사멸 효과가 확인되었다. As a result, E1 was generally resistant to pancreatic cancer and breast cancer cell line MCF-7, and the S1 compound showed no apoptotic effect in all cancer cell lines tested. The S2 compound showed an apoptotic effect in the pancreatic cancer cell line, but was resistant to the breast cancer cell line MCF-7. Therefore, it was confirmed that the S2 compound was particularly effective in apoptosis of the pancreatic cancer cell line. The compounds S3, S4, S5, S6, S8, and S9 had an apoptotic effect on both breast cancer cell lines and pancreatic cancer cell lines.
상기와 같은 결과를 통해, S2, S3, S4, S5, S6, S8, 및 S9 화합물은 췌장암 치료, 또는 개선 효과가 있음을 알 수 있었으며, S3, S4, S5, S6, S8, 및 S9 화합물은 유방암 치료, 또는 개선 효과가 있음을 알 수 있었다. Through the above results, it can be seen that the compounds S2, S3, S4, S5, S6, S8, and S9 have an effect of treating or improving pancreatic cancer, and the S3, S4, S5, S6, S8, and S9 compounds are It was found that there was an effect of treating or improving breast cancer.
3. 대장암 세포 사멸능 확인3. Confirmation of colorectal cancer cell killing ability
총 9종의 해삼 난소 단일 화합물에 대해 30, 20, 및 10 ug/ml 의 농도로 3일동안 대장암 암세포주 2종에 처리한 결과, 다음과 같은 결과를 얻었다. 도 4a 및 도 4b에 각 화합물별 암세포주에 대한 세포 사멸능을 평가하였다. 도 4a 및 도 4b에서 확인할 수 있듯이, 해삼 난소 유래 화합물들의 대장암 세포주 SW620 및 HCT116에 대한 세포 생존능을 확인한 결과를 보여준다. 화합물 S3, S4, S5, S6, S8 및 S9는 현미부수체(microsatellite) 불안정성 MSI-high (MSI- H) 타입과 불안정성이 없는 MSS 타입 모두에서 대장암 세포주 사멸 효과가 뛰어났다. 이와 달리, E1, S1, 및 S2 화합물은 대장암 세포주 2종 모두에서 사멸 효과가 유의미하게 나타나지 않았다. 이러한 결과를 통해 해삼 난소 추출물에서 분리된 화합물의 종류에 따라 서로 다른 효과를 가질 수 있음을 알 수 있었다. As a result of treating two types of colorectal cancer cancer cell lines for 3 days at concentrations of 30, 20, and 10 ug/ml for a total of 9 types of sea cucumber ovary single compounds, the following results were obtained. In Figures 4a and 4b, the cell killing ability of each compound was evaluated for each cancer cell line. As can be seen in Figures 4a and 4b, it shows the results of confirming the cell viability of the sea cucumber ovary-derived compounds against colorectal cancer cell lines SW620 and HCT116. Compounds S3, S4, S5, S6, S8 and S9 were excellent in killing colon cancer cell lines in both the microsatellite unstable MSI-high (MSI-H) type and the MSS type without instability. In contrast, the compounds E1, S1, and S2 did not show a significant killing effect in both colorectal cancer cell lines. Through these results, it can be seen that different effects can be obtained depending on the type of compound isolated from the sea cucumber ovary extract.
4. S2, S3 및 S9 의 암종에 따른 Cytotoxic IC50 확인 4. Confirmation of Cytotoxic IC50 according to S2, S3 and S9 carcinomas
S2, S3 및 S9 세가지 단일 화합물에 대해 cytotoxic IC50 값을 구하기 위해 MTT assay 실험을 진행하였다. 췌장암 세포주 외 담도암, 난소암 및 유방암 세포주에서의 세포사멸 효과도 확인하였다. 그 결과 다음 표 3과 같은 결과를 얻었다. MTT assay was performed to obtain cytotoxic IC50 values for three single compounds S2, S3 and S9. In addition to pancreatic cancer cell lines, apoptosis effects were also confirmed in biliary tract cancer, ovarian cancer and breast cancer cell lines. As a result, the results shown in Table 3 below were obtained.
상기 표 3에서 확인할 수 있듯이, S2, S3, 및 S9는 모두 일정 농도 이상에서 췌장암, 담도암, 난소암 및 유방암 세포 사멸 효과를 가지므로, 췌장암, 담도암, 난소암 또는 유방암 치료, 개선에 이용될 수 있음을 알 수 있다. As can be seen in Table 3 above, S2, S3, and S9 all have an apoptosis effect on pancreatic cancer, biliary tract cancer, ovarian cancer and breast cancer at a certain concentration or more, so it is used for treatment, improvement of pancreatic cancer, biliary tract cancer, ovarian cancer or breast cancer it can be seen that
한편, S2, S3 와 S9은 모두 난소암 세포주 중에서는 특히 YDOV151에 대해 비교적 높은 감수성을 나타내었다. YDOV151 세포주는 세브란스 병원 산부인과 연구실에서 구축한 ovarian mucinous cystadenocarcinoma (난소 점액성 낭포암) 세포주로, 난소 점액성 낭포암은 난소암 중에서도 희귀암으로 분류되는 암으로, 대다수 난소암을 차지하는 상피세포암과는 다른 조직학적 특성을 갖는 것으로 알려져 있다. 상기 S2, S3 와 S9은 난소 점액성 낭포암 세포주에 대해 높은 감수성을 보였다. On the other hand, S2, S3 and S9 all showed relatively high sensitivity to YDOV151, especially among ovarian cancer cell lines. The YDOV151 cell line is an ovarian mucinous cystadenocarcinoma cell line constructed in the Obstetrics and Gynecology laboratory of Severance Hospital. It is known to have different histological characteristics. The S2, S3 and S9 showed high sensitivity to the ovarian mucinous cyst cancer cell line.
삼중음성유방암(Triple-negative breast cancer) 타입의 MDA-BM-231 세포주는 S2, S3 와 S9에 대해 높은 감수성을 나타내었다. 삼중음성유방암은 유방암 중 고분화, 빠른 진행, 빈번한 재발, 치료에 대한 낮은 반응율의 특성을 가진 가장 공격적인 암종이지만, 치료를 위한 알려진 타겟(예를 들어 HER2)이 없어 개발된 표적항암제도 전무한 대표적인 난치암으로 분류된다. 따라서 해삼난소 단일추출물이 난소암과 유방암 중에서도 대표적 난치암인 난소 점액성 낭포암과 삼중음성유방암에서 특이적으로 민감한 효과를 보이는 바, 상기 S2, S3 또는 S9 화합물은 암치료 용도로 이용되기 충분하다고 여겨진다.The triple-negative breast cancer type MDA-BM-231 cell line showed high sensitivity to S2, S3 and S9. Triple-negative breast cancer is the most aggressive carcinoma among breast cancers with the characteristics of high differentiation, rapid progression, frequent recurrence, and low response rate to treatment. classified as cancer. Therefore, the single extract of sea cucumber ovary shows a specific sensitive effect in ovarian mucinous cystic cancer and triple-negative breast cancer, which are representative intractable cancers among ovarian cancer and breast cancer. It is considered
Claims (10)
- 해삼의 생식선 추출물을 포함하는 암 예방, 개선 또는 치료용 조성물. A composition for preventing, improving or treating cancer, comprising the gonad extract of sea cucumber.
- 제1항에 있어서, 상기 생식선 추출물은 해삼 난소의 에탄올 추출물인 것을 특징으로 하는 암 예방, 개선, 또는 치료용 조성물. The composition for preventing, improving, or treating cancer according to claim 1, wherein the gonad extract is an ethanol extract of sea cucumber ovary.
- 제1항에 있어서, 상기 생식선 추출물은 해삼 난소의 45 내지 85% 에탄올 추출물인 것을 특징으로 하는 암 예방, 개선, 또는 치료용 조성물. The composition for preventing, improving, or treating cancer according to claim 1, wherein the gonad extract is a 45 to 85% ethanol extract of sea cucumber ovary.
- 제1항에 있어서, 상기 암은 췌장암, 췌장 신경내분비종양 및 대장암으로 이루어진 군에서 선택된 어느 하나 이상의 암인 것을 특징으로 하는 암 예방, 개선, 또는 치료용 조성물. The composition for preventing, improving, or treating cancer according to claim 1, wherein the cancer is at least one cancer selected from the group consisting of pancreatic cancer, pancreatic neuroendocrine tumor and colorectal cancer.
- 하기 화학식 S2, S3, S4, S5, S6, S8 및 S9로 이루어진 군에서 선택된 어느 하나 이상의 화합물을 포함하는 암 예방, 개선, 또는 치료용 조성물.A composition for preventing, improving, or treating cancer comprising at least one compound selected from the group consisting of Formula S2, S3, S4, S5, S6, S8 and S9.
- 제5항에 있어서, 상기 암은 췌장암, 대장암, 담도암, 난소암, 및 유방암으로 이루어진 군에서 선택된 어느 하나 이상인 것을 특징으로 하는 암 예방, 개선, 또는 치료용 조성물.The composition for preventing, improving, or treating cancer according to claim 5, wherein the cancer is at least one selected from the group consisting of pancreatic cancer, colorectal cancer, biliary tract cancer, ovarian cancer, and breast cancer.
- 제6항에 있어서, 상기 난소암은 난소 점액성 낭포암인 것을 특징으로 하는 암 예방, 개선, 또는 치료용 조성물.The composition for preventing, improving, or treating cancer according to claim 6, wherein the ovarian cancer is ovarian mucinous cystic cancer.
- 제6항에 있어서, 상기 유방암은 삼중음성유방암인 것을 특징으로 하는 암 예방, 개선, 또는 치료용 조성물.The composition for preventing, improving, or treating cancer according to claim 6, wherein the breast cancer is triple negative breast cancer.
- 하기 화학식 S2, S3, S4, S5, S6, S8 및 S9로 이루어진 군에서 선택된 어느 하나 이상의 사포닌 화합물을 증가시키는 것을 특징으로 하는, 해삼 생식선 추출물의 암 예방, 개선 또는 치료 효과를 개선하는 방법.A method of improving the cancer prevention, improvement or therapeutic effect of a sea cucumber gonadal extract, characterized in that it increases any one or more saponin compounds selected from the group consisting of the following formulas S2, S3, S4, S5, S6, S8 and S9.
- 제9항에 있어서, 상기 해삼 생식선 추출물은 해삼 난소 추출물인 것을 특징으로 하는 해삼 생식선 추출물의 암 예방, 개선 또는 치료 효과를 개선하는 방법. The method of claim 9, wherein the sea cucumber gonad extract is a sea cucumber ovary extract.
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