CN103417561A - Application of paeoniflorin compound in preparation of anti-tumor drug - Google Patents
Application of paeoniflorin compound in preparation of anti-tumor drug Download PDFInfo
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Abstract
The invention discloses application of a paeoniflorin compound or pharmaceutically acceptable salt, solvates, polymorphism, antipode or racemic mixture in preparation of drugs for preventing and/or curing tumors. Preferably, the paeoniflorin compound is chosen from albiflorin and/or paeoniflorin, and the tumors are solid tumors. Experiments in vitro and in vivo show that the paeoniflorin compound has exact anti-tumor activity, and a new anti-tumor drug is expected to be developed so as to provide new choices for clinical cancer treatment.
Description
Technical field
The invention belongs to field of antineoplastic medicaments, relate to the purposes of peoniflorin compounds in preparing antitumor drug, be specifically related to lactone glucoside of Radix Paeoniae and the peoniflorin purposes in preparing antitumor drug.
Background technology
Tumor be body under various carcinogenic factor effects, cell loses the normal regulation to its growth on gene level, causes its clonal abnormality hypertrophy and the neoplasm that forms, shows as lump.Tumor cell externally form, metabolism and function aspects is different from normal cell, presents persistence propagation more.According to valid data statistics, tumor is to threaten at present first of three large factors of whole world human life's health, so the research and development of antitumor drug become focus in recent years.
Traditional classification and progress according to antitumor drug, antitumor drug commonly used can be divided into to following several large class: one, cell toxicity medicament comprises the medicine (as cyclophosphamide, irinotecan) that destroys DNA structure and function, affects the medicine (as 5-fluorouracil, cytosine arabinoside, methotrexate) of Nucleic acid etc.; Two, affect the medicine of hormonal balance, comprise anti-estrogens medicine (as toremifene), anti-androgens medicine (as bicalutamide) and arimedex (as letrozole) etc.; Three, other and ancillary drug, comprise the medicines such as body's immunity regulator (as interleukin, interferon), biological response modifier (as erlotinib, gefitinib), cell-differentiation inducers (as retinoic acid, arsenious acid), folic acid resisting preparation (Alimta), monoclonal antibody (as Arastin) and auxiliary analgesia, emesis, leucocytosis.But, above medicine more or less exists side effect, can cause patient's the middle reaction of severe digestive system (as pernicious vomiting, stomatitis), bone marrow depression (as leukopenia, thrombocytopenia) and organ toxicity's (as neurotoxicity, Liver and kidney toxicity) as cell toxicity medicament, the hormonal balance interference medicament can cause that patient's light moderate gastrointestinal reaction, reproductive system damage even spirit depressing symptom, and most regulators and derivant etc. also can cause patient's dermoreaction and hepatic and renal function injure in various degree.For example irinotecan (Irinotecan Hydrochloride) treatment of Metastatic Colorectal Cancer that is usually used in being grown up, effect is more remarkable, but after medication, gastrointestinal side effect appears in 20% patient---severe diarrhea, neutrophilic granulocytopenia all appearred in 78.7% patient, of short duration serious cholinergic syndrome (.Science such as Bret Wallace, 330,2010. appear in 9% patient; Grandson's Yi etc. China Dispensary, 18 (35), 2007.; Wu Yuhong etc. Anhui medicine, 14 (10), 2010.); Alimta (Pemetrexed disodium, Alimta) be first anti-pleural mesothelium tumor medicine, it can cause patient's bone marrow depression, comprise neutrophilic granulocyte minimizing, thrombocytopenia, anemia or pancytopenia, liver, renal insufficiency person avoid use (Zheng Hang etc. treatment and prevention of tumour research, 34 (4), 2007.; Wang Jianying etc. the healthy digest in China and foreign countries, 12,2011.); Arastin (Bevacizumab, Avastin) is the monoclonal antibody of VEGF VEGF, by conjunction with VEGF and prevent it and the receptors bind of endothelial cell surface, has reduced microvascular generation and has suppressed the metastatic lesion progress.But its side effect clearly, comprise (the .Clinical Colorectal Cancer such as Eric O.Gamboa, 9 (1), 2010 such as gastric-intestinal perforation, wound cracking syndrome, hemorrhage, hypertensive crisis, nephrotic syndrome and congestive heart failure; The .British Journal of Cancer such as A Mailliez, 103,2010; The .Oncology such as Sanjaykumar Hapani, 79,2010).
By contrast, anti-tumor Chinese medicine is less to the infringement of body, and the mechanism of action of anti-tumor Chinese medicine relates generally to cytotoxicity, improves immunity of organisms, inducing apoptosis of tumour cell and the aspects such as differentiation and inhibition neonate tumour blood vessel.According to effect and the effect characteristics of Chinese medicine, anti-tumor Chinese medicine can be divided into to following several large class: one, antipyretic and antidotal type, as Radix Scutellariae, Folium Isatidis; Two, blood-activating stasis-removing kind, as Radix Et Rhizoma Rhei, Radix Salviae Miltiorrhizae; Three, the body resistance strengthening and constitution consolidating class, as Radix Ginseng, the Radix Astragali, Radix Asparagi; Four, dissipating phlegm and resolving masses class, as the Rhizoma Pinelliae, Fructus Trichosanthis, Rhizoma Arisaematis; Five, promoting diuresis to clear away damp pathogen class, as Poria, Semen Plantaginis, Herba Dianthi; Six, external type medicine, as Realgar, Semen Strychni.Part effective ingredient in above-mentioned anti-tumor Chinese medicine, often studied for antitumor by people as the paclitaxel (taxol) in Ramulus et folium taxi cuspidatae (Taxus brevifolia), and obtained preferably curative effect (the sunshine Tang Dynasty etc. Chinese Clinical rehabilitation, 27,2006.; Jiang Zhiwu etc. Heilungkiang scientific and technological information, 7,2010; Pluznik, the .Cancer Research such as DH, 54 (15), 1994).Therefore, the further investigation about the anti-tumor Chinese medicine effective ingredient has important theoretical significance and Clinical significance of MG.
Yet, due to the compound complicated component in most of Chinese medicine, the separating-purifying difficulty, the limited and drug effect of quality control and the mechanism of action are still unintelligible, magnanimity screening antineoplastic effective composition is very difficult, so many deficiencies and limitation about the research ubiquity of anti-tumor Chinese medicine effective ingredient.The paclitaxel for example extracted from Ramulus et folium taxi cuspidatae is the specificity stabilizing agent of microtubule, can promote the assembling of microtubule and keep microtubule stable, the various functions of cell have been disturbed in the accumulation of these microtubules, particularly make cell division stop at mitotic phase, thereby blocked the proper splitting of cell, brought into play anticancer effect.But paclitaxel is larger to patient's side effect, common adverse reactions has anaphylaxis (incidence rate is up to 39%), bone marrow depression, and (serious neutrophilic granulocyte incidence rate is 47%, serious blood platelet reduction incidence rate is 5%), neurotoxicity (the peripheral neuropathy incidence rate is 62%), Cardiovascular Toxicity (incidence rate is 55%), gastrointestinal reaction (feel sick, vomiting, diarrhoea and mucositis incidence rate are respectively 59%, 43% and 39%) and alopecia (incidence rate is up to more than 80%) etc. (Ye Dongmei etc. China Dispensary, 29,2011.; Ma Lianshun etc. the medical world, 3,2009; Derry, the .Cancer Research such as WB, 58 (6), 1998.).
Therefore, the study of pharmacy personnel still are being devoted to develop new anti-tumor Chinese medicine effective ingredient.
The root that the Radix Paeoniae Alba is ranunculaceae plant Radix Paeoniae (Paeonia albiflora Pall), known pharmacological action comprises analgesia, calmness, convulsion, antiinflammatory, resisting pathogenic microbes and hepatoprotective, also immune system, smooth muscle are had to effect, can be applicable to clinically epilepsy, analgesia, treating narcotic addiction, only dizzy, treatment rheumatoid arthritis, bacillary dysentery and enteritis, viral hepatitis and Senile disease, also have the flocculation of sulfuric-resisting barium and mucolytics effect.One of active component of the Radix Paeoniae Alba is the peoniflorin compounds, with lactone glucoside of Radix Paeoniae (English Albiflorin by name; English another name Paeonilactone C; Be called for short AL) and peoniflorin (English Paeoniflorin by name) be representative.The object of the present invention is to provide the new therapeutic uses of peoniflorin compounds, for prevention and the treatment of clinical tumor provides new selection.
Summary of the invention
The object of the present invention is to provide a class new type antineoplastic medicine---peoniflorin compounds, this compounds derives from Chinese medicine, can be used for preventing and/or treating of kinds of tumors clinically.
In order to realize the foregoing invention purpose, the present invention has adopted following technical scheme:
Peoniflorin compounds or its pharmaceutically acceptable salt, solvate, polymorphs body, enantiomer or racemic mixture prevent and/or treat the purposes in the medicine of tumor in preparation.
Preferably, described peoniflorin compounds is selected from the lactone glucoside of Radix Paeoniae of structural formula 1 and/or the peoniflorin of structural formula 2:
In purposes of the present invention, described tumor is entity tumor.
Preferably, described tumor is selected from one or more in intestinal cancer, pulmonary carcinoma, hepatocarcinoma, neuroblastoma, cerebroma, breast carcinoma, cervical cancer, rhabdomyosarcoma, nasopharyngeal carcinoma, cancer of pancreas, laryngeal carcinoma, carcinoma of prostate, renal carcinoma, adrenocortical tumor, skin carcinoma, melanoma, ovarian cancer, bladder cancer, lymphatic cancer and gastric cancer.
Preferred, described tumor is selected from one or more in intestinal cancer, pulmonary carcinoma, neuroblastoma, breast carcinoma, cervical cancer, rhabdomyosarcoma, nasopharyngeal carcinoma, cancer of pancreas, laryngeal carcinoma, carcinoma of prostate, renal carcinoma and adrenocortical tumor.
In purposes of the present invention, a kind of preferred scheme is: described peoniflorin compounds is lactone glucoside of Radix Paeoniae, and described tumor is selected from one or more in intestinal cancer, cancer of pancreas, laryngeal carcinoma, cervical cancer, breast carcinoma and carcinoma of prostate.
In purposes of the present invention, another kind of preferred scheme is: described peoniflorin compounds is peoniflorin, and described tumor is selected from one or more in laryngeal carcinoma, cervical cancer, nasopharyngeal carcinoma and cancer of pancreas.
In purposes of the present invention, described intestinal cancer is selected from one or more in colon and rectum carcinoma, colorectal cancer.
In purposes of the present invention, described prophylaxis of tumours refers to the treatment precancerous lesion.Preferably, described prophylaxis of tumours refers to treatment intestinal cancer precancerous lesion, and prevention serious symptom enteritis changes intestinal cancer into.
In purposes of the present invention, described medicine is acceptable arbitrary dosage form clinically.Preferably, described dosage form comprises through gastrointestinal administration preparation and non-through the gastrointestinal administration preparation.Preferred, describedly through the gastrointestinal administration preparation, be selected from powder, tablet, granule, capsule, drop pill, Emulsion or suspensoid; Describedly non-ly through the gastrointestinal administration preparation, be selected from injection, spray, suppository, filling agent, patch or ointment.
In purposes of the present invention, lactone glucoside of Radix Paeoniae and peoniflorin can be respectively as the described unique active component that prevents and/or treats tumour medicine, also can be jointly as the described active component that prevents and/or treats tumour medicine; Can also be respectively or jointly together with other material, prepare the described tumour medicine that prevents and/or treats.
Experiment in vivo and vitro shows, peoniflorin compounds of the present invention can significantly suppress the kinds of tumors such as intestinal cancer, breast carcinoma, cervical cancer, rhabdomyosarcoma, nasopharyngeal carcinoma, cancer of pancreas, laryngeal carcinoma, carcinoma of prostate, pulmonary carcinoma, neuroblastoma, renal carcinoma and adrenocortical tumor, has the anti-tumor function of wide spectrum; The peoniflorin compounds can also be treated precancerous lesion, effectively blocks the conversion of hyperenteritis to intestinal cancer, to the incidence rate for the treatment of intestinal cancer precancerous lesion, reduction intestinal cancer, significant.And the advantage antitumor spectra of peoniflorin and lactone glucoside of Radix Paeoniae there is some difference, lactone glucoside of Radix Paeoniae especially can significantly suppress intestinal cancer, cancer of pancreas, laryngeal carcinoma, cervical cancer, breast carcinoma and carcinoma of prostate, and peoniflorin especially can significantly suppress laryngeal carcinoma, cervical cancer, nasopharyngeal carcinoma and cancer of pancreas.Specifically,
1, peoniflorin constituents inhibition tumor cell proliferation experiment
The demonstration of MTT testing result, lactone glucoside of Radix Paeoniae has remarkable inhibitory action to the propagation of colon-cancer cell HT29, colon-cancer cell CT26, human rhabdomyosarcoma cells A204, nasopharyngeal carcinoma cell CNE-2Z, laryngeal cancer cell Hep2, pancreatic cancer cell PANC1, prostate gland cancer cell DU145, cervical cancer cell Hela, breast cancer cell MDA231, breast cancer cell T47D and breast cancer cell MCF7.Wherein, colon-cancer cell HT29, pancreatic cancer cell PANC1, laryngeal cancer cell Hep2, cervical cancer cell Hela, breast cancer cell MDA231 and prostate gland cancer cell DU145 are especially responsive to lactone glucoside of Radix Paeoniae.
The demonstration of mtt assay testing result, peoniflorin has remarkable inhibitory action to the propagation of nasopharyngeal carcinoma cell CNE-2Z, laryngeal cancer cell Hep2, pancreatic cancer cell PANC1 and the kinds of tumor cells such as cervical cancer cell Hela and human rhabdomyosarcoma cells A204.Wherein, nasopharyngeal carcinoma cells CNE-2 Z, laryngeal carcinoma Hep2 cell, cancer of pancreas PANC1 cell and s are especially responsive to peoniflorin.
2, peoniflorin constituents inhibition tumor cell migration experiment
The demonstration of tumor cell migration test experience result, lactone glucoside of Radix Paeoniae has remarkable inhibitory action to the migration of colon-cancer cell CT26, cervical cancer cell Hela, neuroblastoma cell SY5Y, breast cancer cell MDA231, breast cancer cell T47D, breast cancer cell MCF7, human rhabdomyosarcoma cells A204, renal carcinoma Wilms cell G401, nasopharyngeal carcinoma cell CNE2Z, prostate gland cancer cell DU145, laryngeal cancer cell Hep2, lung cell A549, lung carcinoma cell LLC, pancreatic cancer cell PANC1 and adrenal cortex oncocyte SW13 etc.Wherein, lactone glucoside of Radix Paeoniae is especially remarkable to the inhibitory action of cervical cancer cell Hela, colon-cancer cell CT26, breast cancer cell MDA231, nasopharyngeal carcinoma cell CNE2Z and pancreatic cancer cell PANC1 migration.
The demonstration of tumor cell migration test experience result, peoniflorin has remarkable inhibitory action to the migration of human rhabdomyosarcoma cells A204, nasopharyngeal carcinoma cell CNE-2Z, colon-cancer cell CT26, prostate gland cancer cell DU145, laryngeal cancer cell Hep2, pancreatic cancer cell PANC1 and adrenal cortex oncocyte SW13 etc.Wherein, peoniflorin is especially remarkable to the inhibitory action of colon-cancer cell CT26, nasopharyngeal carcinoma cell CNE2Z, laryngeal cancer cell Hep2 and adrenal cortex oncocyte SW13.
3, anti-tumor in vivo effect
In the body of nude mice model, experimental result shows, lactone glucoside of Radix Paeoniae can significantly suppress growth and the transfer of CT26 intestinal cancer, LLC pulmonary carcinoma, MDA231 breast carcinoma and Hela cervical cancer.Especially, lactone glucoside of Radix Paeoniae can reach 54.41% to the suppression ratio of CT26 intestinal cancer, to the suppression ratio of Hela cervical cancer, can reach 52.3%.
In the body of nude mice model, experimental result shows, peoniflorin can significantly suppress growth and the transfer of CNE-2Z nasopharyngeal carcinoma, PANC1 cancer of pancreas and Hela cervical cancer cell.
4, the effect that prophylaxis of tumours occurs
Adopt lactone glucoside of Radix Paeoniae to process the experimental result demonstration that gene mutation agent azoxymethane (AOM) inducing mouse enteritis transforms to former intestinal cancer, lactone glucoside of Radix Paeoniae is being brought into play significant effect in treatment intestinal cancer precancerous lesion, prevention and the conversion process of blocking-up from the hyperenteritis to intestinal cancer.
The accompanying drawing explanation
Fig. 1: the impact (Transwell detection) of lactone glucoside of Radix Paeoniae on the tumor cell migration ability.
Fig. 2: the impact (Scratch Analysis detection) of lactone glucoside of Radix Paeoniae on the tumor cell migration ability.
Fig. 3: the impact (Transwell detection) of peoniflorin on the tumor cell migration ability.
Fig. 4: experimental result in lactone glucoside of Radix Paeoniae antineoplastic body; Wherein,
4A:CT26 intestinal cancer nude mice tumor growth curve;
4B:LLC pulmonary carcinoma nude mice tumor growth curve;
4C:MDA231 Breast Carcinoma in nude mice tumor growth curve;
4D:Hela cervical cancer nude mice tumor growth curve.
Fig. 5: the blocking effect experimental result that lactone glucoside of Radix Paeoniae transforms to intestinal cancer enteritis: wherein,
5A: the colon photo of three groups of mices;
5B: the HE of the colon coloration result of three groups of mices.
Fig. 6: lactone glucoside of Radix Paeoniae and Radix Paeoniae Alba total glucosides compare (Transwell detection) to the impact of tumor cell migration.
Fig. 7: peoniflorin and Radix Paeoniae Alba total glucosides compare (Transwell detection) to the impact of tumor cell migration.
The specific embodiment
Referring to specific embodiment, the present invention is described.It will be appreciated by those skilled in the art that these embodiment are only for the present invention is described, the scope that it does not limit the present invention in any way.
In following embodiment, lactone glucoside of Radix Paeoniae used and peoniflorin are purchased from the auspicious chemical industry company limited of Shanghai ancient cooking vessel (purity is more than 98%), and peony root total glycosides capsules (Pa Fulin) is purchased from Ningbo LiHua Pharmaceutical Co., Ltd.
The impact of embodiment 1 peoniflorin compounds on tumor cell proliferation
1, the impact of lactone glucoside of Radix Paeoniae on tumor cell proliferation
Experimental program: (3-(4 to adopt tetrazolium bromide, 5-dimethylthiazole-2)-2,5-diphenyl tetrazole bromine salt, MTT) experiment, lactone glucoside of Radix Paeoniae is processed respectively human rhabdomyosarcoma cells A204, nasopharyngeal carcinoma cell CNE-2Z, colon-cancer cell CT26, colon-cancer cell HT29, neuroblastoma cell SY5Y, laryngeal cancer cell Hep2, pancreatic cancer cell PANC1, cervical cancer cell Hela, breast cancer cell MDA231, breast cancer cell T47D, breast cancer cell MCF7, Skin Squamous Cell Carcinoma cell A431, renal carcinoma Wilms cell G401, prostate gland cancer cell DU145 approximately 24 hours; MTT dyeing afterwards 4 hours, dimethyl sulfoxide (DMSO) dissolves, and surveys the absorption photometric value under microplate reader 570nm.
Experimental result: find that lactone glucoside of Radix Paeoniae all has significant inhibitory action to the propagation of pancreatic cancer cell PANC1, colon-cancer cell CT26, colon-cancer cell HT29, laryngeal cancer cell Hep2, cervical cancer cell Hela, breast cancer cell MDA231, prostate gland cancer cell DU145, nasopharyngeal carcinoma cell CNE2Z, human rhabdomyosarcoma cells A204, breast cancer cell T47D and breast cancer cell MCF7 cell.Wherein, lactone glucoside of Radix Paeoniae is the most responsive to the effect of colon-cancer cell HT29, pancreatic cancer cell PANC1, laryngeal cancer cell Hep2, cervical cancer cell Hela, breast cancer cell MDA231 and prostate gland cancer cell DU145, and concrete outcome is in Table 1.
Impact (the IC of table 1 lactone glucoside of Radix Paeoniae on tumor cell proliferation
50)
2, the impact of peoniflorin on tumor cell proliferation
Experimental program: (3-(4 to adopt tetrazolium bromide, 5-dimethylthiazole-2)-2,5-diphenyl tetrazole bromine salt, MTT) experiment, peoniflorin is processed respectively human rhabdomyosarcoma cells A204, nasopharyngeal carcinoma cell CNE-2Z, colon-cancer cell CT26, colon-cancer cell HT29, laryngeal cancer cell Hep2, pancreatic cancer cell PANC1, breast cancer cell MDA231, cervical cancer cell Hela, renal carcinoma Wilms cell G401 cell and prostate gland cancer cell DU145 approximately 24 hours, MTT dyeing afterwards 4 hours, dimethyl sulfoxide (DMSO) dissolves, and surveys the absorption photometric value under microplate reader 570nm.
Experimental result: find that peoniflorin all has significant inhibitory action to the propagation of laryngeal cancer cell Hep2, cervical cancer cell Hela, nasopharyngeal carcinoma cell CNE-2Z, pancreatic cancer cell PANC1 and human rhabdomyosarcoma cells A204 cell, wherein peoniflorin is the most responsive to the effect of laryngeal cancer cell Hep2, cervical cancer cell Hela, nasopharyngeal carcinoma cell CNE-2Z and pancreatic cancer cell PANC1 cell, and concrete outcome is in Table 2.
Impact (the IC of table 2 peoniflorin on tumor cell proliferation
50)
The impact of embodiment 2 peoniflorin compounds on tumor cell migration
1, the impact (Transwell detect and Scratch Analysis detect) of lactone glucoside of Radix Paeoniae on tumor cell migration
Experimental program:
1) adopt cell migration to detect (Transwell) experiment, A549, LLC, Hela, SY5Y, CT26, T47D, MCF7, MDA231, A204, G401, CNE-2Z, DU145, Hep2, PANC1 and SW13 tumor cell dosing lactone glucoside of Radix Paeoniae (were selected to safe dose 20 μ g/ml) after 24 hours, fix 20 minutes without water-ice methanol, violet staining 15 minutes, 100 times of light microscopics are taken pictures, and detect the number of cell migration.
2) adopt cell migration test experience (Scratch Analysis), Hela, LLC, A549, SY5Y, CT26, MCF7, MDA231 and T47D cell are added to lactone glucoside of Radix Paeoniae 6 hours and 24 hours (selecting safe dose 20 μ g/ml), 40 times of light microscopics are taken pictures, and detect the iuntercellular distance.
Experimental result: 1) the Transwell experimental result shows, lactone glucoside of Radix Paeoniae (AL) can significantly suppress lung cell A549, lung carcinoma cell LLC, cervical cancer cell Hela, neuroblastoma cell SY5Y, colon-cancer cell CT26, breast carcinoma T47D, breast carcinoma MCF7, breast carcinoma MDA231, human rhabdomyosarcoma cells A204, renal carcinoma Wilms cell G401, nasopharyngeal carcinoma cell CNE-2Z, prostate gland cancer cell DU145, laryngeal cancer cell Hep2, the migration of pancreatic cancer cell PANC1 and adrenal cortex oncocyte SW13 cell, showing as cell number in the administration group significantly reduces with respect to matched group, wherein, lactone glucoside of Radix Paeoniae is to cervical cancer cell Hela, colon-cancer cell CT26, breast cancer cell MDA231, the inhibitory action of nasopharyngeal carcinoma cell CNE2Z and pancreatic cancer cell PANC1 tumor cell migration is especially remarkable.Specifically see Fig. 1.
2) Scratch Analysis experimental result shows, for matched group, the relative Normal group of cut width of lactone glucoside of Radix Paeoniae administration group all obviously increases, and proves that lactone glucoside of Radix Paeoniae can suppress the migration of surveyed tumor cell.Specifically see Fig. 2.
In sum, experimental result prompting lactone glucoside of Radix Paeoniae to the migration of tumor cell have widely, significant inhibitory action.
2, the impact (Transwell detection) of peoniflorin on tumor cell migration
Experimental program: adopt cell migration to detect (Transwell) experiment, A204, CNE-2Z, CT26, DU145, Hep2, PANC1 and SW13 tumor cell are added respectively to the peoniflorin effect 24 hours (selecting safe dose 10 μ M), fix 20 minutes without water-ice methanol, violet staining 15 minutes, 100 times of light microscopics are taken pictures and are detected the number of migrating cell.
Experimental result: peoniflorin can significantly suppress human rhabdomyosarcoma cells A204, nasopharyngeal carcinoma cell CNE-2Z, colon-cancer cell CT26, prostate gland cancer cell DU145, laryngeal cancer cell Hep2, pancreatic cancer cell PANC1 and adrenal cortex oncocyte SW13 tumor cell migration, shows as cell number in the administration group and significantly reduces with respect to matched group.Wherein, peoniflorin is especially remarkable to the inhibitory action of colon-cancer cell CT26, nasopharyngeal carcinoma cell CNE2Z, laryngeal cancer cell Hep2 and adrenal cortex oncocyte SW13.Specifically see Fig. 3.
Embodiment 3 peoniflorin compounds anti-tumor in vivo effects
1, lactone glucoside of Radix Paeoniae anti-tumor in vivo effect
Experimental program: adopt tumor piece inoculation technique, at nude mice right side axillary fossa subcutaneous vaccination solid tumor piece, CT26, LLC, MDA231 and Hela are tetra-kinds altogether.Every kind of solid tumor transplantation model nude mice is divided into 3 groups at random: matched group (finger kind tumor piece and not administration), lactone glucoside of Radix Paeoniae administration group in advance (administration on the same day of finger kind tumor piece) (refer to into the tumor volume and reach 70-100mm with lactone glucoside of Radix Paeoniae administration group
3Administration when above), every group of 5-6 nude mice.
Lactone glucoside of Radix Paeoniae administration group in advance is at inoculation tumor piece intraperitoneal injection on the same day, and dosage is 200mg/kg, administration frequency be 2 days once, administration is 3 weeks altogether, after administration finishes, second day is put to death mice.Lactone glucoside of Radix Paeoniae administration group, treat that the tumor volume reaches 70-100mm
3When above, the lumbar injection lactone glucoside of Radix Paeoniae, dosage is 300mg/kg, administration frequency be 2 days once, altogether administration is 2 weeks, after administration finishes, second day is put to death mice.Detect gross tumor volume and weight, calculate tumour inhibiting rate.
Experimental result: in intestinal cancer, pulmonary carcinoma, breast carcinoma, four kinds of different animal models for tumour of cervical cancer, lactone glucoside of Radix Paeoniae administration group in advance, lactone glucoside of Radix Paeoniae administration group be obviously growth and the transfer of inhibition tumor cell all, especially very remarkable to the effect of CT26 intestinal cancer and Hela cervical cancer model.Concrete antitumor the results are shown in Table 3A, table 3B, table 3C and table 3D.
1. CT26 intestinal cancer model experiment results (seeing Fig. 4 A):
Being grown in about 12 days of A.CT26 tumor reach requirement of experiment, and volume reaches 100mm
3
B. with matched group, compare, in lactone glucoside of Radix Paeoniae administration group in advance, administration group, gross tumor volume and weight all obviously reduce, and show that lactone glucoside of Radix Paeoniae has significant preventive and therapeutic action to intestinal cancer.
2. LLC lung cancer model experimental result (accompanying drawing 4B):
The speed of growth of A.LLC tumor and CT26 tumor is suitable, and the volume size reaches 100mm
3Be about 12 days;
B. with matched group, compare, in lactone glucoside of Radix Paeoniae administration group in advance, administration group, gross tumor volume and weight all obviously reduce, and show that lactone glucoside of Radix Paeoniae has certain prevention and treatment pulmonary carcinoma effect.
3. MDA231 breast cancer model experimental result (accompanying drawing 4C):
A.MDA231 cell behaviour source, for LLC and CT26 tumor, at nude mice by subcutaneous, become the tumor time slower, tumor growth rate is also relatively slow, and the volume size reaches 70mm
3Be about about 18 days;
B. with matched group, compare, in lactone glucoside of Radix Paeoniae administration group in advance, administration group, gross tumor volume and weight all obviously reduce, and show that lactone glucoside of Radix Paeoniae has certain prevention and treatment breast carcinoma effect.
4. Hela cervical cancer model experiment results (accompanying drawing 4D):
A.Hela cell behaviour source, for LLC and CT26 tumor, at nude mice by subcutaneous, become the tumor time slower, tumor growth rate is also relatively slow, and the volume size reaches 70mm
3Be about about 20 days;
B. with matched group, compare, in lactone glucoside of Radix Paeoniae administration group in advance, administration group, gross tumor volume and weight all obviously reduce, and show that lactone glucoside of Radix Paeoniae has significant preventive and therapeutic action to cervical cancer.
Table 3A lactone glucoside of Radix Paeoniae anti-tumor in vivo effect experimental result (CT26 intestinal cancer model)
| ? | Matched group | Lactone glucoside of Radix Paeoniae administration group in advance | Lactone glucoside of Radix Paeoniae administration group |
| Dosage (mg/kg) | ? | 200 | 300 |
| Nude mice body weight (g) | 20.48±0.43 | 20.71±0.50 | 20.61±0.39 |
| Tumor heavy (g) | 2.30±0.17 | 1.05±0.26 * | 1.73±0.24 * |
| Tumour inhibiting rate (%) | ? | 54.41 | 25.11 |
*: with matched group ratio, P ﹤ 0.01.
Table 3B lactone glucoside of Radix Paeoniae anti-tumor in vivo effect experimental result (LLC lung cancer model)
| ? | Matched group | Lactone glucoside of Radix Paeoniae administration group in advance | Lactone glucoside of Radix Paeoniae administration group |
| Dosage (mg/kg) | ? | 200 | 300 |
| Nude mice body weight (g) | 21.04±0.59 | 21.21±0.35 | 20.94±0.52 |
| Tumor heavy (g) | 3.05±0.41 | 2.19±0.24 * | 2.53±0.21 ** |
| Tumour inhibiting rate (%) | ? | 28.22 | 16.86 |
*: with matched group ratio, P ﹤ 0.01;
*: with matched group ratio, P ﹤ 0.05.
Table 3C lactone glucoside of Radix Paeoniae anti-tumor in vivo effect experimental result (MDA231 breast cancer model)
| ? | Matched group | Lactone glucoside of Radix Paeoniae administration group in advance | Lactone glucoside of Radix Paeoniae administration group |
| Dosage (mg/kg) | ? | 200 | 300 |
| Nude mice body weight (g) | 20.14±0.47 | 19.98±0.66 | 20.31±0.45 |
| Tumor heavy (g) | 1.65±0.14 | 1.18±0.16 * | 1.27±0.19 * |
| Tumour inhibiting rate (%) | ? | 32.80 | 27.66 |
*: with matched group ratio, P ﹤ 0.01.
Table 3D lactone glucoside of Radix Paeoniae anti-tumor in vivo effect experimental result (Hela cervical cancer model)
| ? | Matched group | Lactone glucoside of Radix Paeoniae administration group in advance | Lactone glucoside of Radix Paeoniae administration group |
| Dosage (mg/kg) | ? | 200 | 300 |
| Nude mice body weight (g) | 21.13±0.24 | 20.99±0.42 | 21.07±0.46 |
| Tumor heavy (g) | 1.78±0.13 | 0.81±0.075 * | 1.15±0.064 * |
| Tumour inhibiting rate (%) | ? | 52.30 | 32.23 |
*: with matched group ratio, P ﹤ 0.01.
2, peoniflorin anti-tumor in vivo effect
Experimental program: select advantage tumor kind---cancer of pancreas PANC1 cell and the s of peoniflorin extracorporeal anti-tumor, set up nude mice by subcutaneous lotus tumor model.Treat that gross tumor volume reaches 70mm
3Pneumoretroperitoneum injection peoniflorin, dosage is 300mg/kg, administration frequency be 2 days once, administration is 2 weeks altogether, take model group as contrast.After administration finishes, second day is put to death mice.Detect gross tumor volume and weight, calculate tumour inhibiting rate.
Experimental result: in cancer of pancreas and two kinds of animal models for tumour of cervical cancer, peoniflorin administration group is obviously growth and the transfer of inhibition tumor cell all, shows that peoniflorin all has remarkable inhibitory action to cancer of pancreas and cervical cancer cell.Concrete outcome is in Table 4A and table 4B.
Table 4A peoniflorin anti-tumor in vivo effect experimental result (PANC1 cancer of pancreas model)
*: with matched group ratio, P ﹤ 0.01.
Table 4B peoniflorin anti-tumor in vivo effect experimental result (Hela cervical cancer model)
*: with matched group ratio, P ﹤ 0.05.
The therapeutical effect of embodiment 4 lactone glucoside of Radix Paeoniae to the intestinal cancer precancerous lesion
Experimental program: BALB/C mice is divided into 3 groups: normal group, model group and lactone glucoside of Radix Paeoniae intervention group, 5 every group.Model group and intervention group mouse peritoneal injection gene mutation agent azoxymethane (AOM, 20mg/Kg).The lactone glucoside of Radix Paeoniae intervention group is at the 2nd day intraperitoneal injection (100mg/Kg) of AOM injection, and two days once, totally 3 times.Model group is without any drug treating.The AOM administration replaced normal drinking water with 3% sodium dextran sulfate (DSS) after one week, and mice is drunk 7 days continuously; Gain afterwards normal drinking water, mice is drunk 14 days continuously.From AOM injection, drink DSS water and repeat altogether 3 times to drinking the normal water cycle of 14 days, the lactone glucoside of Radix Paeoniae intervention group is all normal administrations in 3 cycles.The normal feeding of normal group mice and drinking-water, do not add any processing.During the 3rd end cycle, put to death mice, cut intestinal tissue, prepare pathological section, carry out HE dyeing.
Experimental result: outward appearance shows, the colon even thickness of normal mouse, and mucosa does not have hyperemia.With respect to normal mouse, model group mice colonic mucosa is obviously congested, intestinal thickness inequality, and generated several tumors; And lactone glucoside of Radix Paeoniae intervention group mice colon thickness is comparatively even, without obvious petechia, also have no tumor and generate, specifically see accompanying drawing 5A.
Pathological section HE coloration result shows, normal mouse intestinal tissue gland structure is complete and be evenly distributed, without obvious inflammatory cell infiltration, without mucosa bleed bottom and ulcer phenomenon.Mucosa ulcer appears in model group mice intestinal tissue, a plurality of body of gland disappearance companion inflammatory cell infiltrations, and cancer cell infiltration, to intestinal mucosa layer and Submucosa, presents the typical characteristic of original position intestinal cancer.Though, and the kitchen range inflammatory cell infiltration appears in lactone glucoside of Radix Paeoniae intervention group mice intestinal tissue, indivedual body of gland disappearances, without obvious cancer cell infiltration phenomenon, show the typical characteristic of enteritis, specifically sees accompanying drawing 5B.
The result demonstration, lactone glucoside of Radix Paeoniae is being brought into play effectively blocking effect in the conversion process from the hyperenteritis to intestinal cancer mice, the treatment precancerous lesion is had to important function.
The effect that embodiment 5 peoniflorin constituents and Radix Paeoniae Alba total glucosides suppress tumor compares
1, lactone glucoside of Radix Paeoniae and Radix Paeoniae Alba total glucosides compare (MTT) to the impact of tumor cell proliferation
Experimental program: (3-(4 to adopt tetrazolium bromide, 5-dimethylthiazole-2)-2,5-diphenyl tetrazole bromine salt, MTT) experiment, lactone glucoside of Radix Paeoniae and Radix Paeoniae Alba total glucosides are processed respectively A204, CNE-2Z, CT26, Hep2 and PANC1 tumor cell 24 hours, MTT dyeing afterwards 4 hours, dimethyl sulfoxide (DMSO) dissolves, and surveys the absorption photometric value under microplate reader 570nm.
Experimental result: find that lactone glucoside of Radix Paeoniae and Radix Paeoniae Alba total glucosides are all inhibited to the propagation of human rhabdomyosarcoma cells A204, nasopharyngeal carcinoma cell CNE-2Z, colon-cancer cell CT26, laryngeal cancer cell Hep2 and pancreatic cancer cell PANC1, but lactone glucoside of Radix Paeoniae is to the IC of these tumors
50(half suppression ratio) value, all lower than Radix Paeoniae Alba total glucosides, illustrates that lactone glucoside of Radix Paeoniae is better than Radix Paeoniae Alba total glucosides to the inhibitory action of human rhabdomyosarcoma cells A204, nasopharyngeal carcinoma cell CNE-2Z, colon cancer cell CT26, laryngeal cancer cell Hep2 and pancreatic cancer cell PANC1 tumor cell proliferation.Concrete outcome is in Table 5.
Table 5 lactone glucoside of Radix Paeoniae and the Radix Paeoniae Alba total glucosides impact (IC on tumor cell proliferation
50)
2, lactone glucoside of Radix Paeoniae and Radix Paeoniae Alba total glucosides compare (Transwell) to the impact of tumor cell migration
Experimental program: adopt cell migration to detect (Transwell) experiment, A204, CNE-2Z, CT26, DU145, Hep2, PANC1 and SW13 tumor cell are added respectively to lactone glucoside of Radix Paeoniae and Radix Paeoniae Alba total glucosides effect 24 hours (selecting safe dose 10 μ M), fix 20 minutes without water-ice methanol, violet staining 15 minutes, 100 times of light microscopics are taken pictures and are detected the number of migrating cell.
Experimental result: lactone glucoside of Radix Paeoniae and Radix Paeoniae Alba total glucosides can significantly suppress, to human rhabdomyosarcoma cells A204, nasopharyngeal carcinoma cell CNE-2Z, colon-cancer cell CT26, prostate gland cancer cell DU145, laryngeal cancer cell Hep2, pancreatic cancer cell PANC1 and adrenocortical tumor SW13 tumor cell migration, to show as cell number in the administration group and significantly reduce with respect to matched group; But lactone glucoside of Radix Paeoniae is to the whole strong Radix Paeoniae Alba total glucosidess of crossing of the inhibitory action of human rhabdomyosarcoma cells A204, nasopharyngeal carcinoma cell CNE-2Z, colon-cancer cell CT26, prostate gland cancer cell DU145, laryngeal cancer cell Hep2, pancreatic cancer cell PANC1 and adrenocortical tumor SW13 tumor cell migration.Specifically see Fig. 6.
3, peoniflorin and Radix Paeoniae Alba total glucosides compare (MTT) to the impact of tumor cell proliferation
Experimental program: (3-(4 to adopt tetrazolium bromide, 5-dimethylthiazole-2)-2,5-diphenyl tetrazole bromine salt, MTT) experiment, peoniflorin and Radix Paeoniae Alba total glucosides are processed respectively CNE-2Z, Hela and HT29 tumor cell 24 hours, MTT dyeing 4 hours, dimethyl sulfoxide (DMSO) dissolves, and surveys the absorption photometric value under microplate reader 570nm.
Experimental result: find that peoniflorin and Radix Paeoniae Alba total glucosides are all inhibited to the propagation of nasopharyngeal carcinoma cell CNE-2Z, cervical cancer cell Hela and colon-cancer cell HT29, but peoniflorin is to the IC of nasopharyngeal carcinoma cell CNE2Z, cervical cancer cell Hela and colon-cancer cell HT29
50(half suppression ratio), all lower than Radix Paeoniae Alba total glucosides, illustrates that peoniflorin is better than Radix Paeoniae Alba total glucosides to the inhibitory action of these several tumor cell proliferations.Concrete outcome is in Table 6.
Table 6 peoniflorin and the Radix Paeoniae Alba total glucosides impact (IC on tumor cell proliferation
50)
4, peoniflorin and Radix Paeoniae Alba total glucosides compare (Transwell) to the impact of tumor cell migration
Experimental program: adopt cell migration to detect (Transwell) experiment, HT29, DU145 and Hela tumor cell are added respectively to peoniflorin and Radix Paeoniae Alba total glucosides effect 24 hours (selecting safe dose 10 μ M), fix 20 minutes without water-ice methanol, violet staining 15 minutes, 100 times of light microscopics are taken pictures, and detect the number of migrating cell.
Experimental result: peoniflorin and Radix Paeoniae Alba total glucosides can significantly suppress colon-cancer cell HT29, prostate gland cancer cell DU145 and cervical cancer cell Hela tumor cell migration, show as cell number in the administration group and significantly reduce with respect to matched group; But inhibitory action strong the cross Radix Paeoniae Alba total glucosides of peoniflorin to colon-cancer cell HT29, prostate gland cancer cell DU145 and cervical cancer cell Hela tumor cell migration.Specifically see Fig. 7.
Sum up, lactone glucoside of Radix Paeoniae can effectively suppress growth and the transfer of intestinal cancer, pulmonary carcinoma, cancer of pancreas, laryngeal carcinoma, cervical cancer, breast carcinoma, carcinoma of prostate, nasopharyngeal carcinoma, rhabdomyosarcoma, pulmonary carcinoma, neuroblastoma, renal carcinoma and adrenocortical tumor, can effectively suppress especially growth and the transfer of intestinal cancer, cancer of pancreas, laryngeal carcinoma, cervical cancer, breast carcinoma and carcinoma of prostate; Peoniflorin can effectively suppress growth and the transfer of laryngeal carcinoma, cervical cancer, nasopharyngeal carcinoma, cancer of pancreas and rhabdomyosarcoma, can effectively suppress especially growth and the transfer of laryngeal carcinoma, cervical cancer, nasopharyngeal carcinoma and cancer of pancreas.There is some difference for the advantage tumor kind of lactone glucoside of Radix Paeoniae and peoniflorin treatment.Lactone glucoside of Radix Paeoniae can also effectively be treated the intestinal cancer precancerous lesion, obviously blocks the conversion of severe ulcerative enteritis to intestinal cancer.Therefore, the inside and outside experimental result of body comprehensively shows, the peoniflorin compounds can suppress growth and the transfer of kinds of tumors effectively, has the antitumor action of wide spectrum; The peoniflorin compounds can also be treated the intestinal cancer precancerous lesion, and the blocking-up hyperenteritis is to the conversion of intestinal cancer.
Claims (10)
1. peoniflorin compounds or its pharmaceutically acceptable salt, solvate, polymorphs body, enantiomer or racemic mixture prevent and/or treat the purposes in the medicine of tumor in preparation.
2. purposes according to claim 1, it is characterized in that: described peoniflorin compounds is selected from the lactone glucoside of Radix Paeoniae of structural formula 1 and/or the peoniflorin of structural formula 2:
3. purposes according to claim 1 and 2, it is characterized in that: described tumor is entity tumor.
4. according to the described purposes of any one in claims 1 to 3, it is characterized in that: described tumor is selected from one or more in intestinal cancer, pulmonary carcinoma, hepatocarcinoma, neuroblastoma, cerebroma, breast carcinoma, cervical cancer, rhabdomyosarcoma, nasopharyngeal carcinoma, cancer of pancreas, laryngeal carcinoma, carcinoma of prostate, renal carcinoma, adrenocortical tumor, skin carcinoma, melanoma, ovarian cancer, bladder cancer, lymphatic cancer and gastric cancer;
Preferably, described tumor is selected from one or more in intestinal cancer, pulmonary carcinoma, neuroblastoma, breast carcinoma, cervical cancer, rhabdomyosarcoma, nasopharyngeal carcinoma, cancer of pancreas, laryngeal carcinoma, carcinoma of prostate, renal carcinoma and adrenocortical tumor.
5. purposes according to claim 1, it is characterized in that: described peoniflorin compounds is lactone glucoside of Radix Paeoniae, and described tumor is selected from one or more in intestinal cancer, cancer of pancreas, laryngeal carcinoma, cervical cancer, breast carcinoma and carcinoma of prostate.
6. according to the described purposes of claim 1 to 5 any one, it is characterized in that: described intestinal cancer is selected from one or more in colon and rectum carcinoma and colorectal cancer.
7. purposes according to claim 1, it is characterized in that: described peoniflorin compounds is peoniflorin, and described tumor is selected from one or more in laryngeal carcinoma, cervical cancer, nasopharyngeal carcinoma and cancer of pancreas.
8. according to the described purposes of any one in claims 1 to 3, it is characterized in that: described prophylaxis of tumours refers to the treatment precancerous lesion;
Preferably, described prophylaxis of tumours refers to treatment intestinal cancer precancerous lesion, and prevention serious symptom enteritis changes intestinal cancer into.
9. according to the described purposes of any one in claim 1 to 8, it is characterized in that: described medicine is acceptable arbitrary dosage form clinically, comprises through gastrointestinal administration preparation and non-through the gastrointestinal administration preparation;
Preferably, described through the gastrointestinal administration preparation optionally from powder, tablet, granule, capsule, drop pill, Emulsion or suspensoid;
Preferably, described non-through the gastrointestinal administration preparation optionally from injection, spray, suppository, filling agent, patch or ointment.
10. according to the described purposes of claim 1 to 9 any one, it is characterized in that: lactone glucoside of Radix Paeoniae and peoniflorin are respectively as the described unique active component that prevents and/or treats tumour medicine, or common as the described active component that prevents and/or treats tumour medicine, or prepare respectively or jointly the described medicine that prevents and/or treats tumor together with other material.
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| CN201310180327.7A CN103417561B (en) | 2012-05-15 | 2013-05-15 | Paeoniflorin compound is preparing the purposes in antitumor drug |
| CN201510043887.7A CN104706647B (en) | 2012-05-15 | 2013-05-15 | Purposes of the albiflorin in anti-pancreatic cancer medicament is prepared |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107397752A (en) * | 2016-10-11 | 2017-11-28 | 张作光 | Purposes of the albiflorin in the product for improving gut flora systemic-function is prepared |
| CN107496434A (en) * | 2017-01-06 | 2017-12-22 | 张作光 | Albiflorin is as indoleamine 2,3 dioxygenases（IDO）The purposes of inhibitor |
| CN108823157A (en) * | 2018-07-05 | 2018-11-16 | 浙江大学 | Crocin II and albiflorin are promoting Marrow Mesenchymal Stem Cells In Vitro proliferation and are inhibiting the application in replicative senescence |
| CN109481453A (en) * | 2019-01-07 | 2019-03-19 | 安徽医科大学 | A kind of purposes of paeoniflorins CP-25 |
| CN109481452A (en) * | 2019-01-07 | 2019-03-19 | 安徽医科大学 | A kind of purposes of Paeoniflorin -6-O '-benzene sulfonate |
| WO2020020343A1 (en) * | 2018-07-26 | 2020-01-30 | 张作光 | Use of total glucosides of paeony as potentiating agent for immunological checkpoint inhibitor for tumor treatment |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105273015B (en) * | 2015-11-18 | 2018-11-30 | 上海同田生物技术股份有限公司 | A kind of preparation method of high-purity Paeoniflorin and albiflorin |
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| CN107397752A (en) * | 2016-10-11 | 2017-11-28 | 张作光 | Purposes of the albiflorin in the product for improving gut flora systemic-function is prepared |
| WO2018068566A1 (en) * | 2016-10-11 | 2018-04-19 | 张作光 | Application of albiflorin in production of products for improving function of intestinal flora system |
| US11020415B2 (en) | 2016-10-11 | 2021-06-01 | Zuoguang Zhang | Use of albiflorin in preparation of products for improving function of intestinal flora system |
| CN107496434A (en) * | 2017-01-06 | 2017-12-22 | 张作光 | Albiflorin is as indoleamine 2,3 dioxygenases（IDO）The purposes of inhibitor |
| WO2018126673A1 (en) * | 2017-01-06 | 2018-07-12 | 张作光 | Application of albiflorin as indoleamine 2,3-dioxygenase (ido) inhibitor |
| CN108823157A (en) * | 2018-07-05 | 2018-11-16 | 浙江大学 | Crocin II and albiflorin are promoting Marrow Mesenchymal Stem Cells In Vitro proliferation and are inhibiting the application in replicative senescence |
| CN108823157B (en) * | 2018-07-05 | 2020-06-05 | 浙江大学 | Application of crocin II and albiflorin in promoting proliferation of mesenchymal stem cells cultured in vitro and inhibiting replicative senescence |
| WO2020020343A1 (en) * | 2018-07-26 | 2020-01-30 | 张作光 | Use of total glucosides of paeony as potentiating agent for immunological checkpoint inhibitor for tumor treatment |
| CN109481453A (en) * | 2019-01-07 | 2019-03-19 | 安徽医科大学 | A kind of purposes of paeoniflorins CP-25 |
| CN109481452A (en) * | 2019-01-07 | 2019-03-19 | 安徽医科大学 | A kind of purposes of Paeoniflorin -6-O '-benzene sulfonate |
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