CN106176711A - Pharmaceutical comprising flavonoid compound composition and use thereof - Google Patents
Pharmaceutical comprising flavonoid compound composition and use thereof Download PDFInfo
- Publication number
- CN106176711A CN106176711A CN201510289997.1A CN201510289997A CN106176711A CN 106176711 A CN106176711 A CN 106176711A CN 201510289997 A CN201510289997 A CN 201510289997A CN 106176711 A CN106176711 A CN 106176711A
- Authority
- CN
- China
- Prior art keywords
- formononetin
- flavonoid compound
- application according
- verbascoside
- flavonoid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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Abstract
Description
技术领域technical field
本发明属于制药领域,具体而言,涉及包含类黄酮化合物组合物的药物、以及类黄酮化合物组合物在制备用于治疗和/或预防癌症的药物中的应用。The present invention belongs to the field of pharmacy, and in particular relates to a medicine containing a flavonoid compound composition and an application of the flavonoid compound composition in preparing medicine for treating and/or preventing cancer.
背景技术Background technique
近年来,随着经济的快速增长、生存环境的恶化、以及饮食结构和生活方式的改变,癌症的发病率呈爆发式增长。目前常用的化疗药物不仅价格昂贵,而且会导致癌症患者出现严重的副作用,如化疗诱导性贫血、免疫功能、抗氧化功能下降等。因此开发一种价格低廉、毒副作用小的药物,对于减轻癌症病人的痛苦具有非常重要的意义。In recent years, with the rapid economic growth, the deterioration of the living environment, and the changes in diet and lifestyle, the incidence of cancer has exploded. Currently commonly used chemotherapy drugs are not only expensive, but also cause serious side effects in cancer patients, such as chemotherapy-induced anemia, decreased immune function, and antioxidant function. Therefore, it is of great significance to develop a drug with low price and little side effects for alleviating the pain of cancer patients.
作为纯天然植物药物,中药配方通常无毒副作用,可以长期服用。很多研究表明,植物药物中包含的许多天然成分具有抗癌作用,可以用于制备抗癌药物,例如类黄酮和生物类黄酮。(参见参考文献“Flavonoids and cancer prevention:a review of the evidence.D.F.Romagnolo&O.I.Selmin,Journal of Nutrition in Gerontology andGeriatrics,2013,31:206-238”和“Anti-cancer potential of flavonoids:recent trends and future perspectives.P.Batra&A.K.Sharma,3Biotech,2013,3:439-459”)。但是由于中药的成分复杂,通常有几十种甚至上百种的化合物组成,所以难以对其进行药理学研究和优化。中药的药材质量控制也是尤其重要,产地、气候、年份等因素都能影响中药材的质量,从而影响药物的有效性和稳定性。因此对中药进行优化,解决质量控制等难题对于中药的开发和推广具有重要的意义。As pure natural plant medicines, traditional Chinese medicine formulas usually have no toxic side effects and can be taken for a long time. Many studies have shown that many natural components contained in plant medicines have anticancer effects and can be used to prepare anticancer drugs, such as flavonoids and bioflavonoids. (See references "Flavonoids and cancer prevention: a review of the evidence. D.F. Romagnolo&O.I. Selmin, Journal of Nutrition in Gerontology and Geriatrics, 2013, 31:206-238" and "Anti-cancer potential of flavonoids: recent trends and future perspectives. P. Batra & A.K. Sharma, 3 Biotech, 2013, 3:439-459"). However, due to the complex composition of traditional Chinese medicine, usually consisting of dozens or even hundreds of compounds, it is difficult to conduct pharmacological research and optimization on it. The quality control of Chinese medicinal materials is also particularly important. Factors such as place of origin, climate, and year can affect the quality of Chinese medicinal materials, thereby affecting the effectiveness and stability of the drug. Therefore, optimizing traditional Chinese medicine and solving difficult problems such as quality control are of great significance for the development and promotion of traditional Chinese medicine.
目前对于类黄酮化合物用于抗癌药的研究集中于对单一类黄酮化合物或类黄酮化合物组合药物在治疗癌症或癌症副作用中的研究,如刺芒柄花素和毛蕊异黄酮单一使用时对乳腺癌具有一定的抑制和治疗作用(参见参考文献“Chen J,Lin C,Yong W,Ye Y,Huang Z.Calycosin and genistein induce apoptosis by inactivation ofHOTAIR/p-Akt signaling pathway in human breastcancer MCF-7cells.Cell Physiol Biochem.2015;35(2):722-8”;“J.Chen,J.Zeng,M.Xin,W.Huang,X.Chen.Formononetin Induces Cell Cycle Arrest of HumanBreast Cancer Cells via IGF1/PI3K/Akt Pathways In Vitro and In Vivo.Horm Metab Res 2011,43:681–686”;“Chen J,Zhao X,Ye Y,WangY,Tian J.Estrogen receptor beta-mediated proliferative inhibition andapoptosis in human breast cancer by calycosin and formononetin.CellPhysiol Biochem 2013;32(6):1790-7”;“Chen J,Zhao X,Ye Y,WangY,Tian J.Estrogen receptor beta-mediated proliferative inhibition andapoptosis in human breast cancer by calycosin and formononetin.CellPhysiol Biochem.2013;32(6):1790-7”)。然而,中药各组分对于癌症治疗的靶点各有差异,单一作用时其药效并不显著,更优化的方法为将多种组分作为组合药物使用,例如环磷酰胺、红景天苷和毛蕊异黄酮葡萄糖苷的组合药物,在特定比例的组合下,可以有效治疗乳腺癌,(徐鹏等,中国专利CN103933054(A),一种含有环磷酰胺的药物组合物及在治疗乳腺癌中的应用),然而在不同组分比例下其治疗效果良莠不齐。由于各药物作用于不同靶点,其协同作用能有效提高整体治疗效果。而由于中药组分的药理并不完全清晰,对组合药物配比进行优化需要进行大量的实验才能得到,目前少有使用中药组合药物作为癌症的治疗药物。At present, the research on flavonoid compounds used in anticancer drugs is focused on the study of single flavonoid compounds or flavonoid compound combination drugs in the treatment of cancer or cancer side effects, such as formononetin and calycosin in single use on breast cancer Has certain inhibitory and therapeutic effects (see reference "Chen J, Lin C, Yong W, Ye Y, Huang Z. Calycosin and genistein induce apoptosis by inactivation of HOTAIR/p-Akt signaling pathway in human breast cancer MCF-7cells. Cell Physiol Biochem.2015; 35(2):722-8"; "J. Chen, J. Zeng, M. Xin, W. Huang, X. Chen. Formononetin Induces Cell Cycle Arrest of Human Breast Cancer Cells via IGF1/PI3K/Akt Pathways In Vitro and In Vivo. Horm Metab Res 2011,43:681–686”; “Chen J, Zhao X, Ye Y, WangY, Tian J. Estrogen receptor beta-mediated proliferative inhibition and apoptosis in human breast cancer by calycosin and formononetin .CellPhysiol Biochem 2013; 32(6):1790-7"; "Chen J, Zhao X, Ye Y, WangY, Tian J. Estrogen receptor beta-mediated proliferative inhibition and apoptosis in human breast cancer by calycosin and formononetin. CellPhysiol Biochem. 2013;32(6):1790-7"). However, each component of traditional Chinese medicine has different targets for cancer treatment, and its efficacy is not significant when acting alone. A more optimal method is to use multiple components as a combination drug, such as cyclophosphamide, salidroside Combination medicine with calycosin glucoside, under the combination of specific ratio, can effectively treat breast cancer, (Xu Peng etc., Chinese patent CN103933054 (A), a kind of pharmaceutical composition containing cyclophosphamide and in the treatment of breast cancer application), however, its therapeutic effects vary under different component ratios. Since each drug acts on different targets, their synergistic effect can effectively improve the overall therapeutic effect. However, since the pharmacology of the components of traditional Chinese medicine is not completely clear, a large number of experiments are required to optimize the combination drug ratio. Currently, few Chinese medicine combination drugs are used as cancer treatment drugs.
黄芪的药用迄今已有2000多年的历史,具有补气生血的功效。黄芪含皂甙、蔗糖、多糖、多种氨基酸、叶酸及硒、锌、铜等多种微量元素,具有许多生物学和医学功效,如保肝、生血、抗氧化、抗高血压、增强免疫等。最近的研究表明,黄芪中的类黄酮成分能够有效刺激肾细胞中促红细胞生成素的表达,从而提高血液中的红细胞水平以改善和治疗贫血。其中主要的四种具有促进促红细胞生成素表达的类黄酮化合物为刺芒柄花素、芒柄花苷、毛蕊异黄酮和毛蕊异黄酮苷。The medicinal use of Astragalus has a history of more than 2,000 years, and it has the effect of nourishing qi and promoting blood. Astragalus contains saponins, sucrose, polysaccharides, various amino acids, folic acid, selenium, zinc, copper and other trace elements. Recent studies have shown that the flavonoids in Astragalus can effectively stimulate the expression of erythropoietin in kidney cells, thereby increasing the level of red blood cells in the blood to improve and treat anemia. Among them, the main four flavonoid compounds that can promote the expression of erythropoietin are formononetin, formononetin, acteosin and verbascoside.
刺芒柄花素也称为7-羟基-4’-甲氧基异黄酮、芒柄花黄素;英文名称为Formononetin、7-Hydroxy-3-(4-methoxyphenyl)chromone、7-Hydroxy-4'-methoxyisoflavone、或Dadein 4'-methyl ether;CAS编号为485-72-3;分子式为C16H12O4;分子量为268.26;刺芒柄花素的化学式由下式III表示:Formononetin is also known as 7-hydroxy-4'-methoxyisoflavone, formononetin; English name is Formononetin, 7-Hydroxy-3-(4-methoxyphenyl)chromone, 7-Hydroxy-4 '-methoxyisoflavone, or Dadein 4'-methyl ether; the CAS number is 485-72-3; the molecular formula is C 16 H 12 O 4 ; the molecular weight is 268.26; the chemical formula of formononetin is represented by the following formula III:
刺芒柄花素易溶于甲醇、乙酸乙酯、乙醚、稀碱溶液,难溶于水。可以从植物中提取刺芒柄花素,也可通过化学方法合成。例如,合成方法可参见参考文献:“J.Agric.Food Chem..EN;9.1994,42,1869-1871”。目前刺芒柄花素已知的药理作用如下:(1)抗癌作用:可防治乳腺癌、前列腺癌以及结肠癌;(2)雌激素作用:能增加小鼠等动物子宫的重量,但雌激素作用是很弱的,作用不及同类的异黄酮染料木素(金雀异黄素)、大豆黄素;(3)对Triton WR-1339引起的雄性白化病大鼠高血脂有降血脂作用;(4)临床用作利尿剂。Formononetin is easily soluble in methanol, ethyl acetate, ether, and dilute alkali solution, but hardly soluble in water. Formononetin can be extracted from plants or synthesized by chemical methods. For example, the synthesis method can be found in the reference: "J. Agric. Food Chem.. EN; 9.1994, 42, 1869-1871". At present, the known pharmacological effects of formononetin are as follows: (1) anticancer effect: it can prevent and treat breast cancer, prostate cancer and colon cancer; (2) estrogen effect: it can increase the weight of the uterus of mice and other animals, but estrogen The hormone effect is very weak, and the effect is not as good as the isoflavone genistein (genistein) and daidzein of the same kind; (3) there is a hypolipidemic effect on the hyperlipidemia of male albino rats caused by Triton WR-1339; ( 4) Clinically used as a diuretic.
芒柄花苷也称为刺芒柄花素-7-葡萄糖甙;英文名称为Ononin、或Formononetin-7-O-beta-D-glucopyranoside;CAS号为486-62-4;分子式为C22H22O9;分子量为430.40;芒柄花苷的化学式由下式IV表示:Formononetin is also known as formononetin-7-glucoside; the English name is Ononin, or Formononetin-7-O-beta-D-glucopyranoside; the CAS number is 486-62-4; the molecular formula is C 22 H 22 O 9 ; the molecular weight is 430.40; the chemical formula of formononetin is represented by the following formula IV:
毛蕊异黄酮的英文名称为Calycosin或7,3'-dihydroxy-4'-methoxyisoflavone;分子式为C16H12O5;分子量为284.26348;毛蕊异黄酮的化学式由下式II表示:The English name of calycosin is Calycosin or 7,3'-dihydroxy-4'-methoxyisoflavone; the molecular formula is C 16 H 12 O 5 ; the molecular weight is 284.26348; the chemical formula of calycosin is represented by the following formula II:
目前毛蕊异黄酮已知的药理作用如下:(1)提高免疫功能;(2)增强抗氧化、抗辐射和抗癌作用;(3)保护心脑血管、肝脏、肾脏和肺脏作用;(4)保护脑细胞、提高记忆力;(5)抗菌及抑制病毒作用;(6)降血脂、降血糖、减少糖尿病并发症等。At present, the known pharmacological effects of calycosin are as follows: (1) improve immune function; (2) enhance anti-oxidation, anti-radiation and anti-cancer effects; (3) protect cardiovascular and cerebrovascular, liver, kidney and lung effects; (4) protect Brain cells, improve memory; (5) Antibacterial and antiviral effects; (6) Lower blood fat, lower blood sugar, reduce diabetes complications, etc.
毛蕊异黄酮苷也称为毛蕊异黄酮葡萄糖苷、毛蕊异黄酮-7-O-β-D葡萄糖苷;英文名为Calycosin-7-glucoside、Calycosin-7-O-β-D-glucoside、3',7-Dihydroxy-4'-methoxyisoflavone-7-beta-D-glucopyranoside、Calycosin 7-O-beta-D-glucoside、Calycosin7-beta-D-glucopyranoside、或Calycosin-7-O-beta-D-glucopyranoside;分子量为446.40;CAS号为20633-67-4,毛蕊异黄酮苷的化学式由下式V表示:Actascoside is also known as acteosin glucoside, acteosin-7-O-β-D glucoside; English name is Calycosin-7-glucoside, Calycosin-7-O-β-D-glucoside, 3',7- Dihydroxy-4'-methoxyisoflavone-7-beta-D-glucopyranoside, Calycosin 7-O-beta-D-glucoside, Calycosin7-beta-D-glucopyranoside, or Calycosin-7-O-beta-D-glucopyranoside; molecular weight 446.40 The CAS number is 20633-67-4, and the chemical formula of verbascoside is represented by the following formula V:
最近的研究表明,几种从黄芪中分离的类黄酮化合物在单独使用时能够预防和治疗癌症(参见参考文献“Formononetin induces cellcycle arrest of human breast cancer cells via IGF1/PI3K/Akt pathways invitro and in vivo.C.J.Zeng et al.,Hormone and Metabolic Research2011,43:681-686”和“Formononetin-induced apoptosis of humanprostate cancer cells through ERK1/2mitogen-activated protein kinaseinactivation.Y.Ye et al.,Hormone and Metabolic Research,2012,44:263-267”、以及专利文献“芒柄花黄素在制备抗乳腺癌药物中的应用”,专利号CN103393638 A)。但是上述研究均单独使用一种类黄酮化合物,而目前的各种类黄酮化合物在单独使用时存在药效有限且使用剂量较大的缺陷。Recent studies have shown that several flavonoid compounds isolated from Astragalus membranaceus can prevent and treat cancer when used alone (see reference "Formononetin induces cellcycle arrest of human breast cancer cells via IGF1/PI3K/Akt pathways invitro and in vivo. C.J.Zeng et al., Hormone and Metabolic Research2011,43:681-686" and "Formononetin-induced apoptosis of humanprostate cancer cells through ERK1/2mitogen-activated protein kinaseinactivation. Y.Ye et al., Hormone and Metabolic Research, 2012, 44:263-267", and the patent document "Application of formononetin in the preparation of anti-breast cancer drugs", patent number CN103393638 A). However, the above studies all use one flavonoid compound alone, and the current various flavonoid compounds have the disadvantages of limited efficacy and large dosage when used alone.
发明内容Contents of the invention
为解决上述现有技术中所存在的问题,本发明提供了包含类黄酮化合物组合物的药物以及类黄酮化合物组合物在制备用于治疗和/或预防癌症的药物中的应用。In order to solve the above-mentioned problems in the prior art, the present invention provides a medicament containing a flavonoid compound composition and an application of the flavonoid compound composition in preparing a medicament for treating and/or preventing cancer.
具体而言,本发明提供了:Specifically, the present invention provides:
(1)类黄酮化合物组合物在制备用于治疗和/或预防癌症的药物中的应用,其中所述类黄酮化合物组合物包含至少两种由式I表示的类黄酮化合物作为活性成分:(1) Use of a flavonoid compound composition in the preparation of a medicament for treating and/or preventing cancer, wherein the flavonoid compound composition comprises at least two flavonoid compounds represented by formula I as active ingredients:
其中,R1为羟基或并且Wherein, R 1 is hydroxyl or and
R2为H或羟基。 R2 is H or hydroxyl.
(2)根据(1)所述的应用,其中,基于所述类黄酮化合物组合物的总量,所述由式I表示的类黄酮化合物的总量占1-100重量%。(2) The use according to (1), wherein, based on the total amount of the flavonoid compound composition, the total amount of the flavonoid compound represented by formula I is 1-100% by weight.
(3)根据(1)所述的应用,其中,所述类黄酮化合物组合物包含刺芒柄花素,并且还包含选自毛蕊异黄酮、芒柄花苷和毛蕊异黄酮苷中的至少一种。(3) The use according to (1), wherein the flavonoid compound composition contains formonetin, and further contains at least one selected from the group consisting of calycosin, formononetin and verbascoside.
(4)根据(3)所述的应用,其中,所述类黄酮化合物组合物包含刺芒柄花素和毛蕊异黄酮。(4) The use according to (3), wherein the flavonoid compound composition contains formonetin and calycosin.
(5)根据(4)所述的应用,其中,所述的刺芒柄花素和毛蕊异黄酮的摩尔比为(0.5-100):(0.5-100)。(5) The application according to (4), wherein the molar ratio of formononetin to calycosin is (0.5-100):(0.5-100).
(6)根据(3)所述的应用,其中,所述类黄酮化合物组合物包含刺芒柄花素和毛蕊异黄酮苷。(6) The use according to (3), wherein the flavonoid compound composition contains formonetin and verbascoside.
(7)根据(6)所述的应用,其中,所述的刺芒柄花素和毛蕊异黄酮苷的摩尔比为(0.5-100):(0.5-100)。(7) The application according to (6), wherein the molar ratio of formononetin to verbascoside is (0.5-100):(0.5-100).
(8)根据(3)所述的应用,其中,所述类黄酮化合物组合物包含刺芒柄花素、芒柄花苷和毛蕊异黄酮。(8) The use according to (3), wherein the flavonoid compound composition contains formononetin, formononetin, and calycosin.
(9)根据(8)所述的应用,其中,所述的刺芒柄花素、芒柄花苷和毛蕊异黄酮的摩尔比为(0.5-100):(0.5-100):(0.5-100)。(9) The application according to (8), wherein the molar ratio of the formononetin, formononetin and acteosin is (0.5-100):(0.5-100):(0.5-100 ).
(10)根据(9)所述的应用,其中,所述的刺芒柄花素、芒柄花苷和毛蕊异黄酮的摩尔比为2:25:1。(10) The application according to (9), wherein the molar ratio of formononetin, formononetin and verbascoisoflavone is 2:25:1.
(11)根据(3)所述的应用,其中,所述类黄酮化合物组合物包含刺芒柄花素、芒柄花苷和毛蕊异黄酮苷。(11) The use according to (3), wherein the flavonoid compound composition contains formononetin, formononetin, and verbascoside.
(12)根据(11)所述的应用,其中,所述的刺芒柄花素、芒柄花苷和毛蕊异黄酮苷的摩尔比为(0.5-100):(0.5-100):(0.5-100)。(12) The application according to (11), wherein the molar ratio of formononetin, formononetin and verbascoside is (0.5-100):(0.5-100):(0.5- 100).
(13)根据(3)所述的应用,其中,所述类黄酮化合物组合物包含刺芒柄花素、毛蕊异黄酮和毛蕊异黄酮苷。(13) The use according to (3), wherein the flavonoid compound composition comprises formonetin, actecoisoflavone, and verbascoside.
(14)根据(13)所述的应用,其中,所述的刺芒柄花素、毛蕊异黄酮和毛蕊异黄酮苷的摩尔比为(0.5-100):(0.5-100):(0.5-100)。(14) The application according to (13), wherein the molar ratio of formononetin, acteosin and verbascoside is (0.5-100):(0.5-100):(0.5-100) .
(15)根据(13)所述的应用,其中,所述类黄酮化合物组合物包含刺芒柄花素、芒柄花苷、毛蕊异黄酮和毛蕊异黄酮苷。(15) The use according to (13), wherein the flavonoid compound composition comprises formononetin, formononetin, acteosin and verbascoside.
(16)根据(15)所述的应用,其中,所述的刺芒柄花素、芒柄花苷、毛蕊异黄酮和毛蕊异黄酮苷的摩尔比为(0.5-100):(0.5-100):(0.5-100):(0.5-100)。(16) The application according to (15), wherein the molar ratio of the formononetin, formononetin, acteosin and verbascoside is (0.5-100):(0.5-100): (0.5-100): (0.5-100).
(17)根据(15)所述的应用,其中,所述的刺芒柄花素、芒柄花苷、毛蕊异黄酮和毛蕊异黄酮苷的摩尔比为1:1:5:1。(17) The application according to (15), wherein the molar ratio of formononetin, formononetin, acteosin and verbascoside is 1:1:5:1.
(18)根据(1)所述的应用,其中,所述药物还包含与所述类黄酮化合物组合物配混的其他抗癌药物,并且所述类黄酮化合物组合物的总摩尔量与所述其他抗癌药物的总摩尔量之比为(1-400):(1-20)。(18) The application according to (1), wherein the drug further comprises other anticancer drugs compounded with the flavonoid compound composition, and the total molar amount of the flavonoid compound composition is the same as that of the flavonoid compound composition. The total molar ratio of other anticancer drugs is (1-400):(1-20).
(19)根据(1)所述的应用,其中,所述药物还具有改善免疫功能和/或抗氧化功能的作用。(19) The application according to (1), wherein the drug also has the effect of improving immune function and/or antioxidant function.
(20)一种用于治疗和/或预防癌症的药物组合物,包含作为活性成分的类黄酮化合物、以及药学可接受的辅料,其中所述类黄酮化合物为至少两种由式I表示的类黄酮化合物:(20) A pharmaceutical composition for treating and/or preventing cancer, comprising a flavonoid compound as an active ingredient, and pharmaceutically acceptable excipients, wherein the flavonoid compound is at least two types represented by formula I Flavonoids:
其中,R1为羟基或并且Wherein, R 1 is hydroxyl or and
R2为H或羟基。 R2 is H or hydroxyl.
(21)根据(20)所述的药物组合物,其中,所述药物组合物还包含与所述类黄酮化合物配混的其他抗癌药物,并且所述类黄酮化合物的总摩尔量与所述其他抗癌药物的总摩尔量之比为(1-400):(1-20)。(21) The pharmaceutical composition according to (20), wherein the pharmaceutical composition further comprises other anticancer drugs compounded with the flavonoid compound, and the total molar amount of the flavonoid compound is the same as that of the flavonoid compound The total molar ratio of other anticancer drugs is (1-400):(1-20).
(22)根据(20)所述的药物组合物,其中,基于所述药物组合物的总量,所述类黄酮化合物的总量占1-100重量%。(22) The pharmaceutical composition according to (20), wherein the total amount of the flavonoid compound accounts for 1 to 100% by weight based on the total amount of the pharmaceutical composition.
(23)根据(20)所述的药物组合物,其中,所述药物组合物的剂型为口服液或注射剂。(23) The pharmaceutical composition according to (20), wherein the dosage form of the pharmaceutical composition is oral liquid or injection.
本发明与现有技术相比具有以下优点和积极效果:Compared with the prior art, the present invention has the following advantages and positive effects:
本发明的类黄酮化合物组合物能够有效地改善抗癌功能,可抑制癌细胞增殖,从而可用于预防和治疗癌症。本发明的类黄酮化合物组合物中的各活性成分具有良好的协同效果,并且显著地降低了各活性成分的用量,价格低廉且毒副作用小。The flavonoid compound composition of the invention can effectively improve the anti-cancer function and inhibit the proliferation of cancer cells, so it can be used for preventing and treating cancer. Each active component in the flavonoid compound composition of the present invention has good synergistic effect, and the usage amount of each active component is significantly reduced, and the price is low and the toxic and side effects are small.
此外,本发明的类黄酮化合物组合物还能够改善免疫功能和抗氧化功能,能够减轻和治疗放疗和/或化疗引起的免疫功能下降和/或抗氧化功能下降等副作用。In addition, the flavonoid compound composition of the present invention can also improve immune function and antioxidant function, and can alleviate and treat side effects such as decreased immune function and/or decreased antioxidant function caused by radiotherapy and/or chemotherapy.
附图说明Description of drawings
图1示出在实施例1中,两种类黄酮化合物的组合物对癌细胞的抑制率的结果。FIG. 1 shows the results of the inhibition rate of cancer cells by the composition of two flavonoid compounds in Example 1.
图2示出在实施例1中,三种类黄酮化合物的组合物对癌细胞的抑制率的结果。FIG. 2 shows the results of the inhibitory rate of the composition of the three flavonoid compounds on cancer cells in Example 1. FIG.
图3示出在实施例1中,制备例5的类黄酮化合物组合物对癌细胞的抑制率的结果。Fig. 3 shows the results of the inhibition rate of the flavonoid compound composition of Preparation Example 5 on cancer cells in Example 1.
图4示出在实施例1中,制备例6的类黄酮化合物组合物对癌细胞的抑制率的结果。FIG. 4 shows the results of the inhibition rate of cancer cells by the flavonoid compound composition of Preparation Example 6 in Example 1. FIG.
图5示出在实施例2中,制备例7的类黄酮化合物组合物对癌细胞的抑制率的结果。FIG. 5 shows the results of the inhibition rate of the flavonoid compound composition of Preparation Example 7 on cancer cells in Example 2. FIG.
图6示出在对比例1中,单一类黄酮化合物药物对癌细胞的抑制率的结果。FIG. 6 shows the results of the inhibitory rate of a single flavonoid compound drug on cancer cells in Comparative Example 1.
图7示出单一类黄酮化合物和本发明的类黄酮化合物组合物对癌细胞抑制率的最优结果对比情况。Fig. 7 shows the comparison of the optimal results of the inhibition rate of cancer cells by a single flavonoid compound and the flavonoid compound composition of the present invention.
图8示出在实施例3中,检测红细胞数(RBC)、白细胞数(WBC)、血细胞比容(Ht)、血红蛋白(Hb)的结果。Fig. 8 shows the results of detection of red blood cell count (RBC), white blood cell count (WBC), hematocrit (Ht), and hemoglobin (Hb) in Example 3.
图9示出在实施例3中,检测超氧化物歧化酶(SOD)、总抗氧化能力(T-AOC)、丙二醛(MDA)的结果。FIG. 9 shows the results of detecting superoxide dismutase (SOD), total antioxidant capacity (T-AOC), and malondialdehyde (MDA) in Example 3.
图10示出在实施例3中,检测白细胞介素-2(IL-2)的结果。Fig. 10 shows the results of detecting interleukin-2 (IL-2) in Example 3.
具体实施方式detailed description
以下通过具体实施方式的描述并参照附图对本发明作进一步说明,但这并非是对本发明的限制,本领域技术人员根据本发明的基本思想,可以做出各种修改或改进,但是只要不脱离本发明的基本思想,均在本发明的范围之内。The present invention will be further described below by the description of specific embodiment and with reference to accompanying drawing, but this is not limitation of the present invention, those skilled in the art can make various modifications or improvements according to the basic idea of the present invention, but as long as not departing from The basic idea of the present invention is within the scope of the present invention.
如本文所用,术语“治疗”是指为了使有生命的人体或者动物体恢复或获得健康或减少痛苦,进行阻断、缓解(或改善)或者消除病因或病灶的过程。As used herein, the term "treatment" refers to the process of blocking, relieving (or improving) or eliminating the cause or focus of a living human or animal body to restore or obtain health or reduce pain.
如本文所用,术语“药物”包括用于人类和动物应用的人用药物和兽用药物。此外,本文所用的术语“药物”是指可提供预防、治疗和/或有益效果的任何物质。本文所用的术语“药物”不必要被限制为需要上市许可证的物质。As used herein, the term "pharmaceutical" includes human and veterinary drugs for human and animal applications. Furthermore, the term "drug" as used herein refers to any substance that can provide prophylactic, therapeutic and/or beneficial effects. The term "drug" as used herein is not necessarily limited to substances requiring a marketing authorization.
在本文中,术语“纯化的形式”是指药学上纯的形式。如本文所用,术语“药学上纯的”是指基本上不含其它化合物。As used herein, the term "purified form" refers to a pharmaceutically pure form. As used herein, the term "pharmaceutically pure" means substantially free of other compounds.
本发明提供了类黄酮化合物组合物在制备用于治疗和/或预防癌症的药物中的应用。The invention provides the application of the flavonoid compound composition in the preparation of medicines for treating and/or preventing cancer.
本发明的发明人通过实验发现:当将毛蕊异黄酮、刺芒柄花素、芒柄花苷和毛蕊异黄酮苷中的两种或多种进行组合时,所得到的组合物的各组分显示出了出人意料的协同作用,所得到的组合物在改善抗癌功能方面具有显著的效果,能够有效预防和治疗癌症。在此发现的基础上,发明人进一步得到了本发明的技术方案。The inventors of the present invention have found through experiments that when two or more of actecosin, formononetin, formononetin and verbascoside are combined, each component of the resulting composition shows Due to the unexpected synergistic effect, the obtained composition has a remarkable effect in improving the anti-cancer function, and can effectively prevent and treat cancer. On the basis of this discovery, the inventor further obtained the technical solution of the present invention.
具体而言,本发明提供了类黄酮化合物组合物在制备用于治疗和/或预防癌症的药物中的应用,其中所述类黄酮化合物组合物包含至少两种由式I表示的类黄酮化合物作为活性成分:Specifically, the present invention provides the use of a flavonoid compound composition in the preparation of a medicament for treating and/or preventing cancer, wherein the flavonoid compound composition comprises at least two flavonoid compounds represented by formula I as Active ingredient:
其中,R1为羟基或并且Wherein, R 1 is hydroxyl or and
R2为H或羟基。 R2 is H or hydroxyl.
优选地,在制备所述类黄酮化合物组合物时,所述的类黄酮化合物是以纯化的形式使用的。Preferably, when preparing the flavonoid compound composition, the flavonoid compound is used in a purified form.
所述类黄酮化合物的纯化的形式可商购得到(例如可得自四川维克奇生物技术有限公司),也可使用本领域已知的纯化方法进行制备。Purified forms of the flavonoid compounds are commercially available (for example, from Sichuan Weikeqi Biotechnology Co., Ltd.), and can also be prepared using purification methods known in the art.
其中,需要说明的是,在式I中,当R1为羟基,R2为H时,所述的类黄酮化合物为刺芒柄花素。Wherein, it should be noted that in formula I, when R 1 is hydroxyl and R 2 is H, the flavonoid compound is formonetin.
式I中,当R1为羟基,R2为羟基时,所述的类黄酮化合物为毛蕊异黄酮。In formula I, when R 1 is hydroxyl and R 2 is hydroxyl, the flavonoid compound is calycosin.
式I中,当R1为R2为H时,所述的类黄酮化合物为芒柄花苷。In formula I, when R 1 is When R 2 is H, the flavonoid compound is formononetin.
式I中,当R1为R2为羟基时,所述的类黄酮化合物为毛蕊异黄酮苷。In formula I, when R 1 is When R 2 is a hydroxyl group, the flavonoid compound is verbascoside.
优选地,基于所述类黄酮化合物组合物的总量,所述由式I表示的类黄酮化合物的总量占1-100重量%,更优选占50-100重量%,特别优选占90-100重量%。例如,基于所述类黄酮化合物组合物的总量,所述由式I表示的类黄酮化合物的总量可以占1、2、3、4、5、6、7、8、9、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90或95重量%。Preferably, based on the total amount of the flavonoid compound composition, the total amount of the flavonoid compound represented by formula I accounts for 1-100% by weight, more preferably 50-100% by weight, particularly preferably 90-100% by weight weight%. For example, based on the total amount of the flavonoid compound composition, the total amount of the flavonoid compounds represented by formula I may account for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 , 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95% by weight.
优选的是,本发明所述的类黄酮化合物组合物包含刺芒柄花素,并且还包含选自毛蕊异黄酮、芒柄花苷和毛蕊异黄酮苷中的至少一种。Preferably, the flavonoid compound composition of the present invention contains formononetin, and further contains at least one selected from acteosin, formononetin and verbascoside.
还优选的是,本发明所述的类黄酮化合物组合物包含刺芒柄花素和毛蕊异黄酮。其中,刺芒柄花素和毛蕊异黄酮的摩尔比优选为(0.5-100):(0.5-100),更优选为(1-40):(0.5-100),特别优选为(20):(5-40)。Also preferably, the flavonoid compound composition of the present invention comprises formonetin and calycosin. Wherein, the mol ratio of formononetin and calycosin is preferably (0.5-100):(0.5-100), more preferably (1-40):(0.5-100), particularly preferably (20):( 5-40).
还优选的是,本发明所述的类黄酮化合物组合物包含刺芒柄花素和毛蕊异黄酮苷。其中,刺芒柄花素和毛蕊异黄酮苷的摩尔比为(0.5-100):(0.5-100),更优选为(1-40):(0.5-100),特别优选为(20):(0.5-5)。Still preferably, the flavonoid compound composition of the present invention comprises formonetin and verbascoside. Wherein, the mol ratio of formononetin and verbascoside is (0.5-100):(0.5-100), more preferably (1-40):(0.5-100), especially preferably (20):( 0.5-5).
还优选的是,本发明所述的类黄酮化合物组合物包含刺芒柄花素、芒柄花苷和毛蕊异黄酮。其中,刺芒柄花素、芒柄花苷和毛蕊异黄酮的摩尔比为(0.5-100):(0.5-100):(0.5-100),更优选为(1-40):(0.5-100):(0.5-100),特别优选为2:25:1。Also preferably, the flavonoid compound composition of the present invention comprises formononetin, formononetin and verbascoisoflavone. Wherein, the mol ratio of formononetin, formononetin and calycosin is (0.5-100):(0.5-100):(0.5-100), more preferably (1-40):(0.5-100 ):(0.5-100), particularly preferably 2:25:1.
还优选的是,本发明所述的类黄酮化合物组合物包含刺芒柄花素、芒柄花苷和毛蕊异黄酮苷。其中,刺芒柄花素、芒柄花苷和毛蕊异黄酮苷的摩尔比为(0.5-100):(0.5-100):(0.5-100),更优选为(1-40):(0.5-100):(0.5-100),特别优选为20:40:40。Still preferably, the flavonoid compound composition of the present invention comprises formononetin, formononetin and verbascoside. Wherein, the mol ratio of formononetin, formononetin and verbascoside is (0.5-100):(0.5-100):(0.5-100), more preferably (1-40):(0.5- 100):(0.5-100), particularly preferably 20:40:40.
还优选的是,本发明所述的类黄酮化合物组合物包含刺芒柄花素、毛蕊异黄酮和毛蕊异黄酮苷。其中,刺芒柄花素、毛蕊异黄酮和毛蕊异黄酮苷的摩尔比为(0.5-100):(0.5-100):(0.5-100),更优选为(1-40):(0.5-100):(0.5-100),特别优选为20:5:5。Still preferably, the flavonoid compound composition of the present invention comprises formonetin, acteosin and acteoisoflavone. Wherein, the molar ratio of formononetin, acteosin and verbascoside is (0.5-100):(0.5-100):(0.5-100), more preferably (1-40):(0.5-100) :(0.5-100), particularly preferably 20:5:5.
还优选的是,本发明所述的类黄酮化合物组合物包含刺芒柄花素、芒柄花苷、毛蕊异黄酮和毛蕊异黄酮苷。其中,刺芒柄花素、芒柄花苷、毛蕊异黄酮和毛蕊异黄酮苷的摩尔比为(0.5-100):(0.5-100):(0.5-100):(0.5-100),特别优选为(1-40):(0.5-100):(0.5-100):(0.5-100),最优选为1:1:5:1。Still preferably, the flavonoid compound composition of the present invention comprises formononetin, formononetin, actecoisoflavone and verbascoside. Wherein, the molar ratio of formononetin, formononetin, acteosin and verbascoside is (0.5-100):(0.5-100):(0.5-100):(0.5-100), especially preferably (1-40):(0.5-100):(0.5-100):(0.5-100), most preferably 1:1:5:1.
在本发明所述的药物或药物组合物中,还可包含与所述类黄酮化合物配混的其他抗癌药物或活性成分。所述类黄酮化合物的总摩尔量与所述其他抗癌药物或活性成分的总摩尔量之比为(1-400):(1-20),优选20:1。这些其他的抗癌药物或活性成分例如为顺铂、维生素C等。在顺铂的情况中,顺铂与本发明所述的类黄酮化合物的总量的摩尔比例如为(1-400):(1-20),优选20:1。In the medicament or pharmaceutical composition of the present invention, other anticancer drugs or active ingredients compounded with the flavonoid compound may also be included. The ratio of the total molar weight of the flavonoid compound to the total molar weight of the other anticancer drugs or active ingredients is (1-400):(1-20), preferably 20:1. These other anticancer drugs or active ingredients are, for example, cisplatin, vitamin C, and the like. In the case of cisplatin, the molar ratio of cisplatin to the total amount of flavonoid compounds of the present invention is, for example, (1-400):(1-20), preferably 20:1.
本发明所述的类黄酮化合物组合物可以有效地改善抗癌功能,抑制癌细胞增殖,可用于预防和治疗癌症。因此,本发明所述的类黄酮化合物组合物可用于制备用于治疗和/或预防癌症的药物。The flavonoid compound composition of the invention can effectively improve the anti-cancer function, inhibit the proliferation of cancer cells, and can be used for preventing and treating cancer. Therefore, the flavonoid compound composition of the present invention can be used to prepare medicines for treating and/or preventing cancer.
此外,本发明的类黄酮化合物组合物还能够改善免疫功能和抗氧化功能,能够减轻和治疗放疗和/或化疗引起的免疫功能下降和/或抗氧化功能下降等副作用。因此,优选的是,所述治疗和/或预防癌症的药物还具有改善免疫功能和/或抗氧化功能的作用。In addition, the flavonoid compound composition of the present invention can also improve immune function and antioxidant function, and can alleviate and treat side effects such as decreased immune function and/or decreased antioxidant function caused by radiotherapy and/or chemotherapy. Therefore, preferably, the drug for treating and/or preventing cancer also has the effect of improving immune function and/or anti-oxidation function.
优选地,本发明所述的类黄酮化合物组合物用于治疗和/或预防癌症的有效量可以为0.05μM-100mM,更优选为0.5μM-1mM,特别优选为20-60μM。当本发明的类黄酮化合物组合物用于治疗应用时,其治疗有效量可以为0.05μM-100mM,更优选为20-60μM;当本发明的类黄酮化合物组合物用于预防应用时,其预防有效量可以为0.05μM-100mM,更优选为20-60μM。Preferably, the effective amount of the flavonoid compound composition of the present invention for treating and/or preventing cancer may be 0.05 μM-100 mM, more preferably 0.5 μM-1 mM, particularly preferably 20-60 μM. When the flavonoid compound composition of the present invention is used for therapeutic application, its therapeutically effective amount can be 0.05 μM-100 mM, more preferably 20-60 μM; when the flavonoid compound composition of the present invention is used for preventive application, its preventive The effective amount may be 0.05 μM-100 mM, more preferably 20-60 μM.
本发明还提供了一种用于治疗和/或预防癌症的药物组合物,包含作为活性成分的本发明所述的类黄酮化合物、以及药学可接受的辅料。具体而言,所述类黄酮化合物为至少两种由式I表示的类黄酮化合物:The present invention also provides a pharmaceutical composition for treating and/or preventing cancer, comprising the flavonoid compound described in the present invention as an active ingredient, and pharmaceutically acceptable excipients. Specifically, the flavonoid compound is at least two flavonoid compounds represented by formula I:
其中,R1为羟基或并且Wherein, R 1 is hydroxyl or and
R2为H或羟基。 R2 is H or hydroxyl.
优选地,基于所述药物组合物的总重量,所述类黄酮化合物的总量占1-100重量%,更优选占50-100重量%。例如,基于所述药物组合物的总量,所述类黄酮化合物的总量可以占1、2、3、4、5、6、7、8、9、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90或95重量%。Preferably, based on the total weight of the pharmaceutical composition, the total amount of the flavonoid compound accounts for 1-100% by weight, more preferably 50-100% by weight. For example, based on the total amount of the pharmaceutical composition, the total amount of the flavonoid compound can account for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95% by weight.
优选的是,所述药物组合物包含刺芒柄花素,并且还包含选自毛蕊异黄酮、芒柄花苷和毛蕊异黄酮苷中的至少一种。以上针对类黄酮化合物组合物所述的类黄酮化合物的各种组合以及相应的比例也适用于所述药物组合物。Preferably, the pharmaceutical composition comprises formonetin, and further comprises at least one selected from acteosin, formononetin and verbascoside. Various combinations and corresponding ratios of flavonoid compounds described above for the flavonoid compound composition are also applicable to the pharmaceutical composition.
本领域技术人员可以根据需要(例如给药途径和标准药学实践)对药学可接受的辅料的种类和用量进行选择,以制成所需的药物。本发明的组合物中可采用本领域公知的药用辅料,包括但不限于(例如)参考文献:“《药剂学》(第四版),毕殿洲主编,人民卫生出版社2001年出版”中所披露的药用辅料。Those skilled in the art can select the type and amount of pharmaceutically acceptable excipients according to needs (such as administration route and standard pharmaceutical practice), so as to prepare the desired drug. Pharmaceutical excipients known in the art can be used in the composition of the present invention, including but not limited to (for example) references: "" Pharmaceutics" (Fourth Edition), edited by Bi Dianzhou, published by People's Health Publishing House in 2001" Disclosed pharmaceutical excipients.
所述的药学可接受的辅料包括本领域已知的可药用载体,例如聚乙二醇类、聚维酮类、表面活性剂类(如泊洛沙姆188)、有机酸类(如酒石酸、琥珀酸等)、糖类(如右旋糖、半乳糖、蔗糖等)与醇类(甘露醇、山梨醇、木糖醇等)、纤维素(如乙基纤维素、羧甲乙纤维素等)、聚丙烯酸树脂类等。所述的药学可接受的辅料还包括可药用稀释剂,其例子包括乙醇、甘油和水等。所述药物组合物还可以包含任何合适的粘结剂、润滑剂、悬浮剂、包衣剂、增溶剂等。The pharmaceutically acceptable adjuvant includes pharmaceutically acceptable carriers known in the art, such as polyethylene glycols, povidones, surfactants (such as poloxamer 188), organic acids (such as tartaric acid , succinic acid, etc.), sugars (such as dextrose, galactose, sucrose, etc.) and alcohols (mannitol, sorbitol, xylitol, etc.), cellulose (such as ethyl cellulose, carboxymethyl ethyl cellulose, etc. ), polyacrylic resins, etc. The pharmaceutically acceptable auxiliary materials also include pharmaceutically acceptable diluents, examples of which include ethanol, glycerin and water. The pharmaceutical composition may also contain any suitable binders, lubricants, suspending agents, coating agents, solubilizers and the like.
本发明的药物组合物可以以口服或者非口服的形式施用。口服施用时可采用固体、液体等形式,非口服施用时可采用注射剂等形式。The pharmaceutical composition of the present invention can be administered orally or parenterally. Forms such as solids and liquids can be used for oral administration, and forms such as injections can be used for parenteral administration.
用于口服的固体形式可包括片剂、丸剂、胶囊剂、散剂、颗粒剂等,本领域技术人员可以根据需要选择采用下述辅料进行制备:填充剂(如淀粉、糊精、乳糖、甘露醇、微晶纤维素等)、吸收剂(如硫酸钙、磷酸氢钙等)、湿润剂(如水、乙醇等)、粘合剂(如羟甲基纤维素、聚维酮、淀粉浆等)、崩解剂(如交联羧甲基纤维素钠、交联聚维酮等)、润滑剂(如硬脂酸、滑石粉、聚乙二醇、微粉硅胶等)、矫味剂(如甜味剂(如蔗糖、甜菊甙、阿斯帕坦等)、芳香剂(如香料和香精等)、着色剂(如甜菜红、焦糖、柠檬黄等)等。Solid forms for oral administration can include tablets, pills, capsules, powders, granules, etc. Those skilled in the art can choose to prepare by using the following auxiliary materials as needed: fillers (such as starch, dextrin, lactose, mannitol, etc.) , microcrystalline cellulose, etc.), absorbents (such as calcium sulfate, calcium hydrogen phosphate, etc.), wetting agents (such as water, ethanol, etc.), binders (such as hydroxymethyl cellulose, povidone, starch slurry, etc.), Disintegrants (such as croscarmellose sodium, crospovidone, etc.), lubricants (such as stearic acid, talc, polyethylene glycol, micronized silica gel, etc.), flavoring agents (such as sweet Agents (such as sucrose, stevioside, aspartame, etc.), flavoring agents (such as spices and essences, etc.), coloring agents (such as beet red, caramel, lemon yellow, etc.), etc.
用于口服的液体形式(口服液)包括溶液剂、乳剂、混悬剂、糖浆剂等,本领域技术人员可以根据需要选择采用下述辅料进行制备:溶剂(如水、甘油、二甲基亚砜(DMSO)、乙醇、丙二醇、聚乙二醇、脂肪油、液体石蜡、醋酸乙酯等)、矫味剂(如甜味剂(如蔗糖、甜菊甙、阿斯帕坦等)、芳香剂(如香料和香精)等)、着色剂(如甜菜红、焦糖、柠檬黄等)、防腐剂(尼泊金类、苯甲酸与苯甲酸钠、山梨酸等)、润湿剂(如聚山梨酯类、聚氧乙烯脂肪醇醚类等)、助悬剂(如甘油、胶树类、纤维素类、硅藻土等)、乳化剂(如表面活性剂类等)等。The liquid form (oral solution) used for oral administration includes solutions, emulsions, suspensions, syrups, etc. Those skilled in the art can choose to use the following auxiliary materials for preparation as required: solvents (such as water, glycerin, dimethyl sulfoxide, etc.) (DMSO), ethanol, propylene glycol, polyethylene glycol, fatty oil, liquid paraffin, ethyl acetate, etc.), flavoring agents (such as sweeteners (such as sucrose, stevioside, aspartame, etc.), aromatics ( Such as spices and flavors), coloring agents (such as beet red, caramel, lemon yellow, etc.), preservatives (parabens, benzoic acid and sodium benzoate, sorbic acid, etc.), wetting agents (such as polysorbate Classes, polyoxyethylene fatty alcohol ethers, etc.), suspending agents (such as glycerin, gum trees, celluloses, diatomaceous earth, etc.), emulsifiers (such as surfactants, etc.), etc.
优选的是,本发明的药物组合物的剂型为口服液。Preferably, the dosage form of the pharmaceutical composition of the present invention is oral liquid.
以下通过例子的方式进一步解释或说明本发明的内容,但这些例子不应被理解为对本发明保护范围的限制。The content of the present invention is further explained or illustrated by way of examples below, but these examples should not be construed as limiting the protection scope of the present invention.
在以下例子中,毛蕊异黄酮、刺芒柄花素、芒柄花苷、毛蕊异黄酮苷均可购自四川维克奇生物技术有限公司。In the following examples, acteosin, formononetin, formononetin and acteocoside can all be purchased from Sichuan Weikeqi Biotechnology Co., Ltd.
胎牛血清(FBS)购自life technologies公司。Fetal bovine serum (FBS) was purchased from life technologies company.
青霉素购自Sigma公司。Penicillin was purchased from Sigma.
链霉素购自Sigma公司。Streptomycin was purchased from Sigma.
顺铂购自Sigma公司。Cisplatin was purchased from Sigma Company.
MTT试剂购自Sigma公司。MTT reagent was purchased from Sigma Company.
试验例1:构建癌细胞增殖抑制的离体研究模型Test Example 1: Construction of an in vitro research model of cancer cell proliferation inhibition
本试验例采用MCF-7乳腺癌细胞系、Hela子宫颈癌细胞系(购自Sigma公司)以及多药耐药性A549-DDP肺癌细胞系(购于中国医学科学院肿瘤细胞库)作为癌细胞增殖抑制的研究模型。将上述细胞接种于96孔培养板,每个孔中细胞数为4000个,每孔加入200微升细胞培养液(DMEM培养基,其中含有10%(v/v)的胎牛血清(FBS)、100U/ml的青霉素以及100U/ml的链霉素),放入37℃恒温培养箱,控制二氧化碳浓度在5%(v/v),培养24小时。In this test example, the MCF-7 breast cancer cell line, the Hela cervical cancer cell line (purchased from Sigma Company) and the multidrug-resistant A549-DDP lung cancer cell line (purchased from the Chinese Academy of Medical Sciences Tumor Cell Bank) were used as cancer cell proliferation cells. Inhibition research model. The above cells were seeded in a 96-well culture plate, the number of cells in each well was 4000, and 200 microliters of cell culture medium (DMEM medium containing 10% (v/v) fetal bovine serum (FBS) was added to each well. , 100U/ml of penicillin and 100U/ml of streptomycin), put into a 37°C constant temperature incubator, control the carbon dioxide concentration at 5% (v/v), and cultivate for 24 hours.
制备例1:制备含有两种活性成分的类黄酮化合物组合物:刺芒柄花素(F)+(芒柄花苷(O)、毛蕊异黄酮(C)和毛蕊异黄酮苷(CG)中的一种)Preparation Example 1: Preparation of a flavonoid compound composition containing two active ingredients: one of formononetin (F)+(formononetin (O), actecosin (C) and actecoside (CG) kind)
将刺芒柄花素、芒柄花苷、毛蕊异黄酮和毛蕊异黄酮苷分别用DMSO溶解,配制成各自的DMSO母液(每种母液分别为3个浓度:50μM、500μM、5mM,用来配制不同的终浓度,以提高实验精度)。按照不同活性成分的终浓度计算并量取所需体积的DMSO母液,合并,并用试验例1所述的细胞培养液稀释至300微升。各活性成分的终浓度分别为:刺芒柄花素20μM,芒柄花苷、毛蕊异黄酮和毛蕊异黄酮苷各自分别为0.5、1、5、10、20、40、70、100μM。Dissolve formononetin, formononetin, verbascoisoflavone and verbascoside in DMSO respectively, and prepare respective DMSO mother solutions (each mother solution has 3 concentrations: 50 μM, 500 μM, 5 mM, used to prepare different final concentration to improve experimental precision). Calculate and measure the required volume of DMSO mother solution according to the final concentration of different active ingredients, combine, and dilute to 300 microliters with the cell culture solution described in Test Example 1. The final concentrations of the active ingredients were: formononetin 20 μM, and formononetin, acteosin and verbascoside respectively 0.5, 1, 5, 10, 20, 40, 70 and 100 μM.
制备例2-7按照制备例1的方法进行,但是使得活性成分的终浓度如下:Preparation examples 2-7 are carried out according to the method of preparation example 1, but make the final concentration of active ingredient as follows:
制备例2:制备含有两种活性成分的类黄酮化合物组合物:F+(O、C和CG中的一种)Preparation Example 2: Preparation of a flavonoid compound composition containing two active ingredients: F+ (one of O, C and CG)
刺芒柄花素40μM,芒柄花苷、毛蕊异黄酮和毛蕊异黄酮苷各自分别为0.5、1、5、10、20、40、70、100μM。Formononetin 40 μM, formononetin, verbascoisoflavone and verbascoside were 0.5, 1, 5, 10, 20, 40, 70, 100 μM respectively.
制备例3:制备含有三种活性成分的类黄酮化合物组合物:F+(O、C和CG中的两种)Preparation Example 3: Preparation of a flavonoid compound composition containing three active ingredients: F+ (two of O, C and CG)
刺芒柄花素20μM,芒柄花苷、毛蕊异黄酮和毛蕊异黄酮苷各自分别为0.5、1、5、10、20、40、70、100μM。Formononetin 20 μM, formononetin, verbascoisoflavone and verbascoside were 0.5, 1, 5, 10, 20, 40, 70, 100 μM respectively.
制备例4:制备含有三种活性成分的类黄酮化合物组合物:F+(O、C和CG中的两种)Preparation Example 4: Preparation of a flavonoid compound composition containing three active ingredients: F+ (two of O, C and CG)
刺芒柄花素40μM,芒柄花苷、毛蕊异黄酮和毛蕊异黄酮苷各自分别为0.5、1、5、10、20、40、70、100μM。Formononetin 40 μM, formononetin, verbascoisoflavone and verbascoside were 0.5, 1, 5, 10, 20, 40, 70, 100 μM respectively.
制备例5:制备含有四种活性成分的类黄酮化合物组合物:F+O+C+CGPreparation Example 5: Preparation of a flavonoid compound composition containing four active ingredients: F+O+C+CG
刺芒柄花素0.08μM、芒柄花苷0.08μM、毛蕊异黄酮0.4μM和毛蕊异黄酮苷0.08μM。另外,在此浓度基础上,再配制包含不同浓度的这四种活性成分的类黄酮化合物组合物,其中每种活性成分的浓度为5倍、10倍、15倍、25倍、40倍、60倍、80倍、90倍、100倍、125倍、300倍、500倍、800倍、以及1000倍于所述的各自的浓度。Formononetin 0.08μM, formononetin 0.08μM, actecoisoflavone 0.4μM and verbascoside 0.08μM. In addition, on the basis of this concentration, flavonoid compound compositions containing these four active ingredients in different concentrations are formulated, wherein the concentration of each active ingredient is 5 times, 10 times, 15 times, 25 times, 40 times, 60 times times, 80 times, 90 times, 100 times, 125 times, 300 times, 500 times, 800 times, and 1000 times the respective concentration.
制备例6:制备含有三种活性成分的类黄酮化合物组合物:F+O+CPreparation Example 6: Preparation of a flavonoid compound composition containing three active ingredients: F+O+C
刺芒柄花素0.016μM、芒柄花苷0.4μM和毛蕊异黄酮0.08μM。另外,在此浓度基础上,再配制包含不同浓度的这三种活性成分的类黄酮化合物组合物,其中每种活性成分的浓度为5倍、10倍、15倍、25倍、40倍、60倍、80倍、90倍、100倍、125倍、300倍、500倍、800倍、以及1000倍于所述的各自的浓度。Formononetin 0.016 μM, formononetin 0.4 μM and calycosin 0.08 μM. In addition, on the basis of this concentration, flavonoid compound compositions containing these three active ingredients in different concentrations are formulated, wherein the concentration of each active ingredient is 5 times, 10 times, 15 times, 25 times, 40 times, 60 times times, 80 times, 90 times, 100 times, 125 times, 300 times, 500 times, 800 times, and 1000 times the respective concentration.
制备例7:制备含有五种活性成分的类黄酮化合物组合物:F+O+C+CG+顺铂Preparation Example 7: Preparation of a flavonoid compound composition containing five active ingredients: F+O+C+CG+cisplatin
按刺芒柄花素:芒柄花苷:毛蕊异黄酮:毛蕊异黄酮苷的比例为1:1:5:1进行配制,使得这四种类黄酮化合物的总浓度为12.5μM、25μM、50μM、100μM、200μM和400μM,在上述六种浓度的溶液中,每种溶液均分别加入顺铂0、1.25μM、2.5μM、5μM、10μM和20μM,共配制成36种浓度的溶液。According to formononetin: formononetin: acteosin: acteoisoflavone glucoside ratio is 1:1:5:1 to prepare, so that the total concentration of these four flavonoid compounds is 12.5 μ M, 25 μ M, 50 μ M, 100 μ M, 200 μM and 400 μM, in the above six concentrations of solutions, each solution was added with cisplatin 0, 1.25 μM, 2.5 μM, 5 μM, 10 μM and 20 μM, and a total of 36 concentrations of solutions were prepared.
实施例1:类黄酮化合物组合物抑制癌细胞增殖的效果Example 1: Effect of flavonoid compound composition on inhibiting cancer cell proliferation
试验例1中的MCF-7乳腺癌细胞和HeLa子宫颈癌细胞在培养24小时后,分为药物组和对照组。向药物组MCF-7细胞中分别加入制备例2、4、5和6的药物组合物200微升;向药物组HeLa细胞中分别加入制备例1、3、5和6的药物组合物200微升;向对照组中加入培养基+10%v/vDMSO,200微升。继续培养48小时后,分别加入3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT试剂,最终浓度0.5mg/mL)。继续培养一小时后,去除培养液并加入100微升DMSO。检测每个孔在570nm波长下的OD值,从而确定癌细胞的存活率。细胞响应通过对照组OD值标准化。The MCF-7 breast cancer cells and HeLa cervical cancer cells in Test Example 1 were divided into a drug group and a control group after being cultured for 24 hours. Add respectively 200 microliters of the pharmaceutical composition of Preparation Examples 2, 4, 5 and 6 to the drug group MCF-7 cells; add respectively 200 microliters of the pharmaceutical composition of Preparation Examples 1, 3, 5 and 6 to the drug group HeLa cells liter; add culture medium+10% v/vDMSO to the control group, 200 microliters. After continuing to culture for 48 hours, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT reagent, final concentration 0.5 mg/mL) was added respectively. After culturing was continued for one hour, the medium was removed and 100 microliters of DMSO was added. Detect the OD value of each well at a wavelength of 570nm to determine the survival rate of cancer cells. Cellular responses were normalized by the OD value of the control group.
用含有两种类黄酮化合物的组合物处理的癌细胞的存活率参见图1,其中F的浓度为20μM(HeLa细胞)和40μM(MCF-7细胞),C和CG的浓度各自分别为0.5、1、5、10、20、40、70、100μM。See Figure 1 for the survival rate of cancer cells treated with a composition containing two flavonoid compounds, where the concentrations of F are 20 μM (HeLa cells) and 40 μM (MCF-7 cells), and the concentrations of C and CG are 0.5, 1 , 5, 10, 20, 40, 70, 100 μM.
用含有三种类黄酮化合物的组合物处理的癌细胞的存活率参见图2,其中F的浓度为20μM(HeLa细胞)和40μM(MCF-7细胞),另外两种类黄酮化合物的总浓度各自分别为0.5、1、5、10、20、40、70、100μM。See Figure 2 for the survival rate of cancer cells treated with a composition containing three flavonoid compounds, where the concentration of F is 20 μM (HeLa cells) and 40 μM (MCF-7 cells), and the total concentrations of the other two flavonoid compounds are respectively 0.5, 1, 5, 10, 20, 40, 70, 100 μM.
用制备例5的类黄酮化合物组合物处理的癌细胞的存活率参见图3。The survival rate of cancer cells treated with the flavonoid compound composition of Preparation Example 5 is shown in FIG. 3 .
用制备例6的类黄酮化合物组合物处理的癌细胞的存活率参见图4。See Figure 4 for the survival rate of cancer cells treated with the flavonoid compound composition of Preparation Example 6.
实施例2:优化过的类黄酮化合物组合物能够增强顺铂的抗癌效果Example 2: The optimized flavonoid compound composition can enhance the anticancer effect of cisplatin
试验例1中的多药耐药性A549-DDP肺癌细胞在培养24小时后,分为药物组和对照组。向药物组分别加入制备例7的药物组合物200微升;向对照组加入培养基+顺铂药物,200微升。继续培养48小时后,分别加入3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐(3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide,即MTT试剂,最终浓度0.5mg/mL)。继续培养一小时后,去除培养液并加入100微升DMSO。检测每个孔在570nm波长下的OD值,从而确定癌细胞的存活率。细胞响应通过对照组OD值标准化。The multidrug-resistant A549-DDP lung cancer cells in Test Example 1 were divided into a drug group and a control group after being cultured for 24 hours. Add 200 microliters of the pharmaceutical composition of Preparation Example 7 to the drug group; add 200 microliters of culture medium + cisplatin to the control group. After continuing to cultivate for 48 hours, 3-(4,5-dimethylthiazol-2)-2,5-diphenyltetrazolium bromide (3-(4,5-dimethyl-thiazol-2-yl )-2,5-diphenyltetrazolium bromide, namely MTT reagent, the final concentration is 0.5mg/mL). After culturing was continued for one hour, the medium was removed and 100 microliters of DMSO was added. Detect the OD value of each well at a wavelength of 570nm to determine the survival rate of cancer cells. Cellular responses were normalized by the OD value of the control group.
结果参见图5,可以看出本发明的药物组合物可以大幅提高顺铂的癌症治疗效果,并有效降低其所需剂量,从而减少化疗所引起的副作用。Referring to Fig. 5 for the results, it can be seen that the pharmaceutical composition of the present invention can greatly improve the cancer treatment effect of cisplatin, and effectively reduce its required dose, thereby reducing the side effects caused by chemotherapy.
对比例1:单一类黄酮化合物的抗癌作用Comparative Example 1: Anticancer effect of a single flavonoid compound
将四种单一类黄酮化合物的浓度各自分别配制为0.05、0.1、0.15、0.20、0.30、0.50、1.0、3、10、20、40、80和100μM,按实施例1相同的步骤,分别加入试验例1的细胞后检测OD值。The concentrations of the four single flavonoid compounds were respectively prepared to be 0.05, 0.1, 0.15, 0.20, 0.30, 0.50, 1.0, 3, 10, 20, 40, 80 and 100 μM, and were added to the test according to the same steps as in Example 1. The OD value of the cells in Example 1 was detected later.
用刺芒柄花素(F)处理的癌细胞的存活率参见图6。See Figure 6 for the survival rate of cancer cells treated with formononetin (F).
图7显示了单一类黄酮化合物和本发明的类黄酮化合物组合药物的最优结果对比(图7中各类黄酮化合物的浓度如下面的表4所示)。可以看出,对于HeLa子宫颈癌细胞和MCF-7乳腺癌细胞,使用本发明的组合药物能够得到更好的癌细胞抑制率。因此,本发明显示出出乎意料的协同作用。Figure 7 shows a comparison of the optimal results of a single flavonoid compound and the combination of flavonoid compounds of the present invention (concentrations of each type of flavonoid compound in Figure 7 are shown in Table 4 below). It can be seen that for HeLa cervical cancer cells and MCF-7 breast cancer cells, better cancer cell inhibition rate can be obtained by using the combination drug of the present invention. Thus, the present invention shows an unexpected synergy.
以上细胞实验的数据如下表1-4所示。The data of the above cell experiments are shown in Tables 1-4 below.
表1:用刺芒柄花素处理HeLa和MCF-7细胞Table 1: Treatment of HeLa and MCF-7 cells with formonetin
表2:两种类黄酮化合物的组合效果Table 2: Combined effect of two flavonoid compounds
其中,刺芒柄花素为每孔20μM(HeLa细胞)或40μM(MCF-7细胞),其他类黄酮化合物组分的浓度如表中左起第二栏所示Among them, formononetin is 20 μM (HeLa cells) or 40 μM (MCF-7 cells) per well, and the concentration of other flavonoid components is shown in the second column from the left in the table
由表2可知,对于两种细胞系,F+C和F+CG的效果最好。It can be seen from Table 2 that for the two cell lines, F+C and F+CG have the best effects.
表3:三种类黄酮化合物的组合效果Table 3: Combination effects of three flavonoid compounds
其中,刺芒柄花素为每孔20μM(HeLa细胞)或40μM(MCF-7细胞),其他每种类黄酮化合物组分的浓度相同,如表中左起第二栏所示(例如,对于HeLa细胞,20μM F+70μM C+70μM CG)Among them, formononetin is 20 μM (HeLa cells) or 40 μM (MCF-7 cells) per well, and the concentration of each other flavonoid compound components is the same, as shown in the second column from the left in the table (for example, for HeLa cells, 20μM F+70μM C+70μM CG)
由表3可知,包含F和CG的组合物具有最好的效果。It can be seen from Table 3 that the composition containing F and CG has the best effect.
表4:不同类黄酮化合物组合物的结果比较Table 4: Comparison of results for different flavonoid compound compositions
其中,细胞活性为与对照孔(无药物处理,细胞活性为1)的比较值Wherein, the cell activity is the comparison value with the control well (without drug treatment, the cell activity is 1)
由以上数据可知,与使用单独一种类黄酮化合物相比,当上述类黄酮化合物组合使用时,仅需对细胞系使用较低的浓度。From the above data, it can be seen that when the above flavonoid compounds are used in combination, only lower concentrations need to be used in the cell line than when the flavonoid compounds are used alone.
试验例2:构建模拟化疗副作用的动物研究模型Test Example 2: Constructing an Animal Research Model to Simulate the Side Effects of Chemotherapy
本试验例采用的是雄性Sprague-Dawley大鼠(4周,180-220g,中国药科大学实验动物中心,南京)作为动物研究模型。大鼠培养在恒温(25±2℃)环境下,供以标准食物和水,并提供12/12小时的日夜循环。通过注射3天40mg/kg/天的抗肿瘤药物环磷酰胺(Cyclophosphamide,CYP)诱发贫血、免疫功能下降、氧化应激等。In this test example, male Sprague-Dawley rats (4 weeks, 180-220 g, Experimental Animal Center, China Pharmaceutical University, Nanjing) were used as animal research models. Rats were maintained at a constant temperature (25±2° C.), provided with standard food and water, and provided with a 12/12-hour day-night cycle. Anemia, decreased immune function, and oxidative stress were induced by injecting 40 mg/kg/day of the antineoplastic drug cyclophosphamide (CYP) for 3 days.
实施例3Example 3
将40只雄性Sprague-Dawley大鼠(4周,180-220g,中国药科大学实验动物中心,南京)分为3组,每组8只。其中对普通组提供正常的水和盐;对照组和药物组首先按照试验例所述方法进行CYP处理模拟化疗副作用,然后,给对照组提供正常的水和盐;对药物组提供毛蕊异黄酮、刺芒柄花素、芒柄花苷和毛蕊异黄酮苷的混合物(按照制备例1的方法制备),其摩尔比为20:4:4:4,并且分为低剂量组(FH)和高剂量组(FL)两组,低剂量为1.4、1.4、7、1.4μmol/kg,高剂量为4、4、20、4μmol/kg,方式为口服。以上3组大鼠按相应方式分别喂养14天,然后分别从视孔取各组大鼠的血液样品。Forty male Sprague-Dawley rats (4 weeks, 180-220 g, Experimental Animal Center, China Pharmaceutical University, Nanjing) were divided into 3 groups, 8 rats in each group. Wherein, normal water and salt are provided to the normal group; the control group and the drug group first carry out CYP treatment according to the method described in the test example to simulate the side effects of chemotherapy, and then provide normal water and salt to the control group; The mixture of formononetin, formononetin and verbascoside (prepared according to the method of Preparation Example 1), its molar ratio is 20:4:4:4, and is divided into low-dose group (FH) and high-dose group (FL) Two groups, the low doses are 1.4, 1.4, 7, 1.4 μmol/kg, the high doses are 4, 4, 20, 4 μmol/kg, the way is oral. The rats in the above three groups were fed for 14 days in corresponding ways, and then the blood samples of the rats in each group were collected from the sight holes.
血液样品取得后,利用自动生化分析仪(中大医院生化分析中心,南京)检测红细胞数(RBC),白细胞数(WBC),血细胞比容(Ht)、血红蛋白(Hb)的水平(结果参见图8)。对血液样品进行离心处理(3,000×g,15分钟,4℃),取得上层血清进行免疫学检测和氧化功能试验,包括检测超氧化物歧化酶(SOD)、总抗氧化能力(T-AOC)、丙二醛(MDA)和白细胞介素-2(IL-2)的水平(结果参见图9和10)。IL-2由T淋巴细胞分泌,是重要的免疫功能参数,通过ELISA商用套件(南京建成生物工程研究所,南京)检测(以上检测方法可参见参考文献“Bernadette F.Rodak,George A.Fritsma,Kathryn Doig,Hematology:Clinical Principles and Applications,Elsevier Health Sciences,2007”)。After the blood samples were obtained, the red blood cell count (RBC), white blood cell count (WBC), hematocrit (Ht), and hemoglobin (Hb) levels were detected by an automatic biochemical analyzer (Biochemical Analysis Center, Zhongda Hospital, Nanjing) (results are shown in Fig. 8). The blood sample was centrifuged (3,000×g, 15 minutes, 4°C), and the upper serum was obtained for immunological detection and oxidation function test, including detection of superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) , malondialdehyde (MDA) and interleukin-2 (IL-2) levels (see Figures 9 and 10 for results). IL-2 is secreted by T lymphocytes and is an important immune function parameter. It is detected by ELISA commercial kit (Nanjing Jiancheng Bioengineering Institute, Nanjing) (for the above detection methods, please refer to the reference "Bernadette F. Rodak, George A. Fritsma, Kathryn Doig, Hematology: Clinical Principles and Applications, Elsevier Health Sciences, 2007").
具体结果见表5。The specific results are shown in Table 5.
表5.药物作用下大鼠血液的造血功能、免疫功能及抗氧化功能参数Table 5. Hematopoietic function, immune function and antioxidant function parameters of rat blood under drug action
从表5可以看出,对照组的大鼠经过CYP作用后,相比普通组健康大鼠,血液中的红细胞数、白细胞数、血细胞比容、血红蛋白水平显著降低,显示出典型的化疗导致的功能性贫血症状。药物组大鼠的各项参数与普通组健康大鼠非常接近,表明本发明的药物能有效提高造血功能,治疗化疗导致的贫血副作用。同时,对照组的大鼠免疫功能参数IL-2相比普通组明显降低,表现出化疗导致的免疫功能降低症状。药物组大鼠的IL-2参数则相比对照组有显著提高,甚至高于普通组,表现出极大的增强免疫效果,表明本发明的药物能治疗化疗导致的免疫功能降低的副作用。同样的,在抗氧化功能方面,药物组能够有效治疗和改善化疗引起的T-AOC和SOD参数降低,以及MDA升高的不良副作用。It can be seen from Table 5 that after the rats in the control group were treated with CYP, compared with the healthy rats in the normal group, the number of red blood cells, white blood cells, hematocrit, and hemoglobin levels in the blood were significantly reduced, showing a typical chemotherapeutic effect. Symptoms of functional anemia. The parameters of the rats in the drug group are very close to those of the healthy rats in the normal group, indicating that the drug of the present invention can effectively improve hematopoietic function and treat anemia side effects caused by chemotherapy. At the same time, the immune function parameter IL-2 of the rats in the control group was significantly lower than that in the normal group, showing symptoms of decreased immune function caused by chemotherapy. Compared with the control group, the IL-2 parameter of the rats in the drug group was significantly improved, even higher than that of the normal group, showing a great immune-enhancing effect, indicating that the drug of the present invention can treat the side effects of decreased immune function caused by chemotherapy. Similarly, in terms of antioxidant function, the drug group can effectively treat and improve the decrease of T-AOC and SOD parameters caused by chemotherapy, as well as the adverse side effects of MDA increase.
对比例2Comparative example 2
在前述实施例3中,同时进行EPO组的检测,在CYP处理后对大鼠每天注射75IU/kg的EPO,14天后取血样进行前述参数的检测。将普通组、对照组、药物组及EPO组进行对比,结果见图8至图10。从图8可以看出,本发明的药物与EPO在治疗化疗引起的功能性贫血方面具有相近的效果,甚至在WBC、Hb、Ht等参数方面,本发明的药物更优于EPO。同样的,图9和图10表明,本发明的药物在增强抗氧化功能方面与EPO的效果相当,在增强免疫功能方面更优于EPO。In the aforementioned Example 3, the detection of the EPO group was carried out at the same time. After the CYP treatment, the rats were injected with 75 IU/kg of EPO every day, and blood samples were taken 14 days later for the detection of the aforementioned parameters. The normal group, the control group, the drug group and the EPO group were compared, and the results are shown in Fig. 8 to Fig. 10 . As can be seen from Figure 8, the drug of the present invention and EPO have similar effects in the treatment of functional anemia caused by chemotherapy, and even in parameters such as WBC, Hb, Ht, the drug of the present invention is better than EPO. Similarly, Fig. 9 and Fig. 10 show that the drug of the present invention has the same effect as EPO in enhancing antioxidant function, and is better than EPO in enhancing immune function.
综上所述,由上述实施例和比较例的结果可以看出,本发明的类黄酮化合物组合物对抑制癌细胞增殖具有非常好的协同效果,并且显著地降低了各活性组分的用量,同时能减轻由化疗引起的抗氧化功能降低、免疫功能降低等副作用。In summary, it can be seen from the results of the above examples and comparative examples that the flavonoid compound composition of the present invention has a very good synergistic effect on inhibiting cancer cell proliferation, and significantly reduces the dosage of each active component, At the same time, it can alleviate side effects such as decreased antioxidant function and immune function caused by chemotherapy.
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