CN103417561B - Paeoniflorin compound is preparing the purposes in antitumor drug - Google Patents
Paeoniflorin compound is preparing the purposes in antitumor drug Download PDFInfo
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Abstract
The invention discloses paeoniflorin compound or its pharmaceutically acceptable salt, solvate, polymorphs body, enantiomer or racemic mixture and prepare the purposes prevented and/or treated in the medicine of tumor.Preferably, described paeoniflorin compound is selected from lactone glucoside of Radix Paeoniae and/or peoniflorin.Described tumor is entity tumor.Experiment in vivo and vitro proves, described paeoniflorin compound has definite anti-tumor activity, is expected to develop anti-cancer agent, for clinical treatment tumour provides new selection.
Description
Technical field
The invention belongs to field of antineoplastic medicaments, relate to paeoniflorin compound and preparing the purposes in antitumor drug, be specifically related to lactone glucoside of Radix Paeoniae and peoniflorin is preparing the purposes in antitumor drug.
Background technology
Tumor be body under various carcinogenic factor effect, cell loses the normal regulation to its growth on gene level, causes its clonal abnormality hypertrophy and the neoplasm that formed, shows as lump.Tumor cell is different from normal cell in formalness, metabolism and function aspects, presents continuous multiplication more.According to valid data statistics, tumor threatens first of three of whole world human life's health large factors at present, so the research and development of antitumor drug become focus in recent years.
According to traditional classification and the progress of antitumor drug, conventional antitumor drug can be divided into following several large class: one, cell toxicity medicament, comprise the medicine (as cyclophosphamide, irinotecan) destroying DNA structure and function, the medicine (as 5-fluorouracil, cytosine arabinoside, methotrexate) etc. affecting Nucleic acid; Two, affect the medicine of hormonal balance, comprise anti-estrogens medicine (as toremifene), antiandrogens (as bicalutamide) and arimedex (as letrozole) etc.; Three, other and ancillary drug, comprises 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, leukocyte rising.But, above medicine more or less also exists side effect, middle severe digestive system reaction (as pernicious vomiting, stomatitis) of patient, bone marrow depression (as leukopenia, thrombocytopenia) and organ toxicity's (as neurotoxicity, Liver and kidney toxicity) can be caused as cell toxicity medicament, hormonal balance interference medicament then can cause light moderate gastrointestinal reaction, the reproductive system damage even spirit depressing symptom of patient, and most regulator and derivant etc. also can cause patient's dermoreaction in various degree and hepatic and renal function injure.Such as irinotecan (IrinotecanHydrochloride) is usually used in the treatment of adult's Metastatic Colorectal Cancer, effectiveness comparison is remarkable, but after medication, there is gastrointestinal side effect in the patient of 20%---severe diarrhea, all there is neutrophilic granulocytopenia in the patient of 78.7%, there are of short duration serious cholinergic syndrome (.Science such as Bret Wallace, 330,2010. in the patient of 9%; 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 the bone marrow depression of patient, comprise Neutrophilic granulocytopenia, thrombocytopenia, anemia or pancytopenia, the full person of Liver and kidney function avoid use (Zheng Hang etc. treatment and prevention of tumour is studied, 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 preventing the receptors bind of itself and endothelial cell surface in conjunction with VEGF, decreasing microvascular generation and inhibit metastatic lesion to be in progress.But its side effect clearly, comprise gastric-intestinal perforation, wound dehiscence syndrome, hemorrhage, (the .Clinical Colorectal Cancer such as Eric O.Gamboa such as hypertensive crisis, nephrotic syndrome and congestive heart failure, 9 (1), 2010; 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 then 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 aspect such as differentiation and Tumor suppression angiogenesis.According to effect and the action character of Chinese medicine, anti-tumor Chinese medicine can be divided into 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, as the paclitaxel (taxol) in Ramulus et folium taxi cuspidatae (Taxus brevifolia) be often commonly used by people for antitumor research, and achieve good curative effect (the sunshine Tang Dynasty etc. Chinese Clinical rehabilitation, 27,2006.; Jiang Zhiwu etc. Heilungkiang scientific and technological information, 7,2010; The .Cancer Research such as Pluznik, DH, 54 (15), 1994).Therefore, the further investigation about anti-tumor Chinese medicine effective ingredient has important theoretical significance and Clinical significance of MG.
But, because the chemical composition in most of Chinese medicine is complicated, separating-purifying difficulty, quality control is limited and drug effect and the mechanism of action are still unintelligible, magnanimity screens antineoplastic effective composition very not easily, so many deficiencies and limitation about the research ubiquity of anti-tumor Chinese medicine effective ingredient.The paclitaxel such as extracted from Ramulus et folium taxi cuspidatae is the specificity stabilizing agent of microtubule, the assembling of microtubule can be promoted and keep microtubule stabilization, the accumulation of these microtubules disturbs the various functions of cell, cell division is particularly made to stop at mitotic phase, thus blocked the proper splitting of cell, play anticancer effect.But the side effect of paclitaxel to patient is larger, common adverse reactions has anaphylaxis (incidence rate is up to 39%), (serious neutrophilic granulocyte incidence rate is 47% in bone marrow depression, it is 5% that serious platelet reduces incidence rate), neurotoxicity (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; The .Cancer Research such as Derry, WB, 58 (6), 1998.).
Therefore, study of pharmacy personnel are still being devoted to develop new anti-tumor Chinese medicine effective ingredient.
The Radix Paeoniae Alba is the root of ranunculaceae plant Radix Paeoniae (Paeonia albiflora Pall), known pharmacological action comprises analgesia, calmness, convulsion, antiinflammatory, resisting pathogenic microbes and hepatoprotective, also there is effect to immune system, smooth muscle, can be applicable to epilepsy, analgesia, treating narcotic addiction, only dizzy clinically, treatment rheumatoid arthritis, bacillary dysentery and enteritis, viral hepatitis and Senile disease, also have the effect of the flocculation of sulfuric-resisting barium and dissolving mucus.One of active component of the Radix Paeoniae Alba is paeoniflorin compound, with lactone glucoside of Radix Paeoniae (English Albiflorin by name; English another name Paeonilactone C; Be called for short AL) and peoniflorin (English be called Paeoniflorin) be representative.The object of the present invention is to provide the new therapeutic uses of paeoniflorin compound, the prevention and therapy for clinical tumor provides new selection.
Summary of the invention
The object of the present invention is to provide class new type antineoplastic medicine a---paeoniflorin compound, this compounds derives from Chinese medicine, can be used for preventing and/or treating of kinds of tumors clinically.
In order to realize foregoing invention object, present invention employs following technical scheme:
Paeoniflorin compound or its pharmaceutically acceptable salt, solvate, polymorphs body, enantiomer or racemic mixture are preparing the purposes prevented and/or treated in the medicine of tumor.
Preferably, described paeoniflorin compound 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 be selected from 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 one or more.
In purposes of the present invention, a kind of preferred scheme is: described paeoniflorin compound is lactone glucoside of Radix Paeoniae, described tumor be selected from intestinal cancer, cancer of pancreas, laryngeal carcinoma, cervical cancer, breast carcinoma and carcinoma of prostate one or more.
In purposes of the present invention, another kind of preferred scheme is: described paeoniflorin compound is peoniflorin, described tumor be selected from laryngeal carcinoma, cervical cancer, nasopharyngeal carcinoma and cancer of pancreas one or more.
In purposes of the present invention, described intestinal cancer be selected from colon and rectum carcinoma, colorectal cancer one or more.
In purposes of the present invention, described prophylaxis of tumours refers to 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 gastrointestinal administration preparation.Preferred, be describedly selected from powder, tablet, granule, capsule, drop pill, Emulsion or suspensoid through gastrointestinal administration preparation; Describedly non-ly be selected from injection, spray, suppository, filling agent, patch or ointment through gastrointestinal administration preparation.
In purposes of the present invention, lactone glucoside of Radix Paeoniae and peoniflorin can respectively as the described sole active agent preventing and/or treating tumour medicine, also can jointly as described in prevent and/or treat the active component of tumour medicine; Tumour medicine is prevented and/or treated described in can also preparing together with other material respectively or jointly.
Experiment in vivo and vitro shows, paeoniflorin compound 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; Paeoniflorin compound can also treat precancerous lesion, effectively blocks the conversion of hyperenteritis to intestinal cancer, to treatment intestinal cancer precancerous lesion, the incidence rate reducing 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
MTT testing result shows, and the propagation of lactone glucoside of Radix Paeoniae to 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 has remarkable inhibitory action.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.
Mtt assay testing result shows, and the propagation of peoniflorin to kinds of tumor cells such as nasopharyngeal carcinoma cell CNE-2Z, laryngeal cancer cell Hep2, pancreatic cancer cell PANC1 and cervical cancer cell Hela and human rhabdomyosarcoma cells A204 has remarkable inhibitory action.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
Tumor cell migration test experience result shows, and the migration of lactone glucoside of Radix Paeoniae to 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. has remarkable inhibitory action.Wherein, the lactone glucoside of Radix Paeoniae inhibitory action of moving cervical cancer cell Hela, colon-cancer cell CT26, breast cancer cell MDA231, nasopharyngeal carcinoma cell CNE2Z and pancreatic cancer cell PANC1 is especially remarkable.
Tumor cell migration test experience result shows, and the migration of peoniflorin 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 adrenal cortex oncocyte SW13 etc. has remarkable inhibitory action.Wherein, the inhibitory action of peoniflorin to colon-cancer cell CT26, nasopharyngeal carcinoma cell CNE2Z, laryngeal cancer cell Hep2 and adrenal cortex oncocyte SW13 is especially remarkable.
3, Anticancer effect in vivo
The experiment in vivo result display of nude mice model, lactone glucoside of Radix Paeoniae significantly can 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, can reach 52.3% to the suppression ratio of Hela cervical cancer.
The experiment in vivo result display of nude mice model, peoniflorin significantly can suppress growth and the transfer of CNE-2Z nasopharyngeal carcinoma, PANC1 cancer of pancreas and Hela cervical cancer cell.
4, the effect of prophylaxis of tumours generation
Adopt the experimental result display that lactone glucoside of Radix Paeoniae process gene mutation agent azoxymethane (AOM) inducing mouse enteritis transforms to former intestinal cancer, lactone glucoside of Radix Paeoniae plays significant effect in treatment intestinal cancer precancerous lesion, prevention and the conversion process of blocking-up from hyperenteritis to intestinal cancer.
Accompanying drawing explanation
Fig. 1: lactone glucoside of Radix Paeoniae is on the impact (Transwell detection) of tumor cell migration ability.
Fig. 2: lactone glucoside of Radix Paeoniae is on the impact (Scratch Analysis detects) of tumor cell migration ability.
Fig. 3: peoniflorin is on the impact (Transwell detection) of tumor cell migration ability.
Fig. 4: lactone glucoside of Radix Paeoniae antineoplastic experiment in vivo result; Wherein,
4A:CT26 intestinal cancer nude mouse 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 mouse tumor growth curve.
Fig. 5: the blocking effect experimental result that lactone glucoside of Radix Paeoniae transforms to intestinal cancer enteritis: wherein,
The colon photo of 5A: three groups of mices;
The colon HE coloration result of 5B: three groups of mices.
Fig. 6: lactone glucoside of Radix Paeoniae and the impact of Radix Paeoniae Alba total glucosides on tumor cell migration are compared (Transwell detection).
Fig. 7: peoniflorin and the impact of Radix Paeoniae Alba total glucosides on tumor cell migration are compared (Transwell detection).
Detailed description of the invention
Referring to specific embodiment, the present invention is described.It will be appreciated by those skilled in the art that these embodiments are only for illustration of the present invention, its scope do not limited the present invention in any way.
Lactone glucoside of Radix Paeoniae used in following embodiment and peoniflorin are purchased from Shanghai Ding Rui Chemical Co., Ltd. (purity is more than 98%), and peony root total glycosides capsules (Pa Fulin) is purchased from Ningbo LiHua Pharmaceutical Co., Ltd.
Embodiment 1 paeoniflorin compound is on the impact of tumor cell proliferation
1, lactone glucoside of Radix Paeoniae is on the impact of tumor cell proliferation
Experimental program: adopt tetrazolium bromide (3-(4,5-dimethylthiazole-2)-2,5-diphenyltetrazolium bromide bromine salt, MTT) test, lactone glucoside of Radix Paeoniae processes 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 about 24 hours respectively; MTT dyes 4 hours afterwards, and dimethyl sulfoxide (DMSO) dissolves, and surveys absorption photometric value under microplate reader 570nm.
Experimental result: find that the propagation of lactone glucoside of Radix Paeoniae to 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 all has significant inhibitory action.Wherein, the effect of lactone glucoside of Radix Paeoniae to 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 is the most responsive, and concrete outcome is in table 1.
Table 1 lactone glucoside of Radix Paeoniae is on the impact (IC of tumor cell proliferation
50)
2, peoniflorin is on the impact of tumor cell proliferation
Experimental program: adopt tetrazolium bromide (3-(4,5-dimethylthiazole-2)-2,5-diphenyltetrazolium bromide bromine salt, MTT) test, peoniflorin processes 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 about 24 hours respectively, MTT dyes 4 hours afterwards, dimethyl sulfoxide (DMSO) dissolves, and surveys absorption photometric value under microplate reader 570nm.
Experimental result: find that the propagation of peoniflorin to laryngeal cancer cell Hep2, cervical cancer cell Hela, nasopharyngeal carcinoma cell CNE-2Z, pancreatic cancer cell PANC1 and human rhabdomyosarcoma cells A204 cell all has significant inhibitory action, wherein the effect of peoniflorin to laryngeal cancer cell Hep2, cervical cancer cell Hela, nasopharyngeal carcinoma cell CNE-2Z and pancreatic cancer cell PANC1 cell is the most responsive, and concrete outcome is in table 2.
Table 2 peoniflorin is on the impact (IC of tumor cell proliferation
50)
Embodiment 2 paeoniflorin compound is on the impact of tumor cell migration
1, lactone glucoside of Radix Paeoniae is on the impact (Transwell detects and Scratch Analysis detects) of tumor cell migration
Experimental program:
1) cell migration is adopted to detect (Transwell) experiment, (safe dose 20 μ g/ml was selected) after 24 hours to 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, 20 minutes are fixed without water-ice methanol, violet staining 15 minutes, 100 times of light microscopics are taken pictures, and detect the number of cell migration.
2) cell migration test experience (Scratch Analysis) is adopted, lactone glucoside of Radix Paeoniae 6 hours and 24 hours (selecting safe dose 20 μ g/ml) are added to Hela, LLC, A549, SY5Y, CT26, MCF7, MDA231 and T47D cell, 40 times of light microscopics are taken pictures, and detect iuntercellular distance.
Experimental result: 1) Transwell experimental result display, lactone glucoside of Radix Paeoniae (AL) significantly can 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, show as cell number in administration group significantly to reduce relative 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 display, for matched group, the relative Normal group of scratch 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, the experimental result prompting migration of lactone glucoside of Radix Paeoniae to tumor cell have widely, significant inhibitory action.
2, peoniflorin is on the impact (Transwell detection) of tumor cell migration
Experimental program: adopt cell migration to detect (Transwell) experiment, peoniflorin effect is added respectively 24 hours (selecting safe dose 10 μMs) to A204, CNE-2Z, CT26, DU145, Hep2, PANC1 and SW13 tumor cell, 20 minutes are fixed 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 significantly can 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 administration group and significantly reduces relative to matched group.Wherein, the inhibitory action of peoniflorin to colon-cancer cell CT26, nasopharyngeal carcinoma cell CNE2Z, laryngeal cancer cell Hep2 and adrenal cortex oncocyte SW13 is especially remarkable.Specifically see Fig. 3.
Embodiment 3 paeoniflorin compound Anticancer effect in vivo
1, lactone glucoside of Radix Paeoniae Anticancer effect in vivo
Experimental program: adopt tumor block inoculation technique, axillary fossa subcutaneous vaccination solid tumor block on the right side of nude mice, altogether CT26, LLC, MDA231 and Hela tetra-kinds.Often kind of solid tumor transplantation model nude mice is divided into 3 groups at random: matched group (finger kind tumor block and not administration), lactone glucoside of Radix Paeoniae administration group in advance (administration on the same day of finger kind tumor block) (refer to into tumor volume with lactone glucoside of Radix Paeoniae administration group and reach 70-100mm
3administration time above), often organize 5-6 nude mice.
Lactone glucoside of Radix Paeoniae administration group is in advance at inoculation tumor block intraperitoneal injection on the same day, and dosage is 200mg/kg, administration frequency be 2 days once, administration 3 weeks altogether, administration terminates latter second day execution mice.Lactone glucoside of Radix Paeoniae administration group, treats that tumor volume reaches 70-100mm
3time above, lumbar injection lactone glucoside of Radix Paeoniae, dosage is 300mg/kg, administration frequency be 2 days once, altogether administration 2 weeks, administration terminates latter second day execution mice.Detect gross tumor volume and weight, calculate tumour inhibiting rate.
Experimental result: in the animal model for tumour that intestinal cancer, pulmonary carcinoma, breast carcinoma, cervical cancer four kinds are different, the growth of the obvious inhibition tumor cell of the equal energy of lactone glucoside of Radix Paeoniae administration group in advance, lactone glucoside of Radix Paeoniae administration group and transfer, 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 (see Fig. 4 A):
Namely the growth of A.CT26 tumor reached requirement of experiment at about 12 days, and namely volume reaches 100mm
3;
B. compare with matched group, 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 volume size reaches 100mm
3be about 12 days;
B. compare with matched group, 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 therapy pulmonary carcinoma effect.
3. MDA231 breast cancer model experimental result (accompanying drawing 4C):
A.MDA231 cell behaviour source, for LLC and CT26 tumor, become the tumor time comparatively slow at nude mice by subcutaneous, tumor growth rate is also relatively slow, and volume size reaches 70mm
3be about about 18 days;
B. compare with matched group, 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 therapy breast carcinoma effect.
4. Hela cervical cancer model experiment results (accompanying drawing 4D):
A.Hela cell behaviour source, for LLC and CT26 tumor, become the tumor time comparatively slow at nude mice by subcutaneous, tumor growth rate is also relatively slow, and volume size reaches 70mm
3be about about 20 days;
B. compare with matched group, 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 Anticancer effect in vivo 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 Anticancer effect in vivo 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 Anticancer effect in vivo 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 Anticancer effect in vivo 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 Anticancer effect in vivo
Experimental program: advantage tumor kind---cancer of pancreas PANC1 cell and the s of selecting peoniflorin extracorporeal anti-tumor, sets 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, altogether administration 2 weeks is contrast with model group.Administration terminates to put to death mice in latter second day.Detect gross tumor volume and weight, calculate tumour inhibiting rate.
Experimental result: in cancer of pancreas and cervical cancer two kinds of animal models for tumour, the growth of the obvious inhibition tumor cell of the equal energy of peoniflorin administration group and transfer, show 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 Anticancer effect in vivo experimental result (PANC1 pancreatic cancer models)
*: with matched group ratio, P ﹤ 0.01.
Table 4B peoniflorin Anticancer effect in vivo experimental result (Hela cervical cancer model)
*: with matched group ratio, P ﹤ 0.05.
Embodiment 4 lactone glucoside of Radix Paeoniae is to the therapeutical effect of 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, often organize 5.Model group and intervention group mouse peritoneal injection gene mutation agent azoxymethane (AOM, 20mg/Kg).The 2nd day intraperitoneal injection (100mg/Kg) that lactone glucoside of Radix Paeoniae intervention group is injected at AOM, two days once, totally 3 times.Model group is without any drug treating.AOM administration replaced normal drinking water with 3% sodium dextran sulfate (DSS) after one week, and mice drinks 7 days continuously; Gain normal drinking water afterwards, mice drinks 14 days continuously.From AOM injection, drink DSS water and repeat 3 times altogether to drinking the normal water cycle of 14 days, lactone glucoside of Radix Paeoniae intervention group is all normal administration in 3 cycles.Normal group mice diet and drinking-water, do not add any process.During the 3rd end cycle, put to death mice, cut intestinal tissue, prepare pathological section, carry out HE dyeing.
Experimental result: outward appearance shows, and the colon even thickness of normal mouse, mucosa does not have hyperemia.Relative to normal mouse, model group mouse Colon mucosa is obviously congested, and intestinal thickness is uneven, and has generated several tumors; And lactone glucoside of Radix Paeoniae intervention group mouse 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, and normal mouse intestinal tissue gland structure is complete and be evenly distributed, without obvious inflammatory cell infiltration, without mucosa bleed bottom and ulcerative phenomena.There is mucosa ulcer in model group mice intestinal tissue, multiple body of gland disappearance companion inflammatory cell infiltration, cancer cell infiltration, to intestinal mucosa layer and Submucosa, presents the typical characteristic of original position intestinal cancer.And though stove inflammatory cell infiltration appears in lactone glucoside of Radix Paeoniae intervention group mice intestinal tissue, indivedual body of gland disappearance, without obvious cancer cell infiltration phenomenon, the typical characteristic of display enteritis, is specifically shown in accompanying drawing 5B.
Result shows, and lactone glucoside of Radix Paeoniae plays effective blocking effect in the conversion process of mice from hyperenteritis to intestinal cancer, has important function to treatment precancerous lesion.
The effectiveness comparison of embodiment 5 peoniflorin constituents and Radix Paeoniae Alba total glucosides Tumor suppression
1, lactone glucoside of Radix Paeoniae and the impact of Radix Paeoniae Alba total glucosides on tumor cell proliferation are compared (MTT)
Experimental program: adopt tetrazolium bromide (3-(4,5-dimethylthiazole-2)-2,5-diphenyltetrazolium bromide bromine salt, MTT) test, lactone glucoside of Radix Paeoniae and Radix Paeoniae Alba total glucosides process A204, CNE-2Z, CT26, Hep2 and PANC1 tumor cell 24 hours respectively, MTT dyes 4 hours afterwards, and dimethyl sulfoxide (DMSO) dissolves, and surveys absorption photometric value under microplate reader 570nm.
Experimental result: find lactone glucoside of Radix Paeoniae and the propagation of Radix Paeoniae Alba total glucosides to human rhabdomyosarcoma cells A204, nasopharyngeal carcinoma cell CNE-2Z, colon-cancer cell CT26, laryngeal cancer cell Hep2 and pancreatic cancer cell PANC1 all inhibited, 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 the inhibitory action of lactone glucoside of Radix Paeoniae to 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 is better than Radix Paeoniae Alba total glucosides.Concrete outcome is in table 5.
Table 5 lactone glucoside of Radix Paeoniae and Radix Paeoniae Alba total glucosides are on the impact (IC of tumor cell proliferation
50)
2, lactone glucoside of Radix Paeoniae and the impact of Radix Paeoniae Alba total glucosides on tumor cell migration are compared (Transwell)
Experimental program: adopt cell migration to detect (Transwell) experiment, lactone glucoside of Radix Paeoniae and Radix Paeoniae Alba total glucosides effect 24 hours (selecting safe dose 10 μMs) are added respectively to A204, CNE-2Z, CT26, DU145, Hep2, PANC1 and SW13 tumor cell, 20 minutes are fixed 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: lactone glucoside of Radix Paeoniae and Radix Paeoniae Alba total glucosides 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 adrenocortical tumor SW13 tumor cell migration, shows as cell number in administration group and significantly reduces relative to matched group; But lactone glucoside of Radix Paeoniae crosses Radix Paeoniae Alba total glucosides to 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 is all strong.Specifically see Fig. 6.
3, peoniflorin and the impact of Radix Paeoniae Alba total glucosides on tumor cell proliferation are compared (MTT)
Experimental program: adopt tetrazolium bromide (3-(4,5-dimethylthiazole-2)-2,5-diphenyltetrazolium bromide bromine salt, MTT) test, peoniflorin and Radix Paeoniae Alba total glucosides process CNE-2Z, Hela and HT29 tumor cell 24 hours respectively, MTT dyes 4 hours, and dimethyl sulfoxide (DMSO) dissolves, and surveys absorption photometric value under microplate reader 570nm.
Experimental result: find peoniflorin and the propagation of Radix Paeoniae Alba total glucosides to nasopharyngeal carcinoma cell CNE-2Z, cervical cancer cell Hela and colon-cancer cell HT29 all inhibited, 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 the inhibitory action of peoniflorin to this several tumor cell proliferation is better than Radix Paeoniae Alba total glucosides.Concrete outcome is in table 6.
Table 6 peoniflorin and Radix Paeoniae Alba total glucosides are on the impact (IC of tumor cell proliferation
50)
4, peoniflorin and the impact of Radix Paeoniae Alba total glucosides on tumor cell migration are compared (Transwell)
Experimental program: adopt cell migration to detect (Transwell) experiment, peoniflorin and Radix Paeoniae Alba total glucosides effect 24 hours (selecting safe dose 10 μMs) are added respectively to HT29, DU145 and Hela tumor cell, 20 minutes are fixed 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 significantly can suppress colon-cancer cell HT29, prostate gland cancer cell DU145 and cervical cancer cell Hela tumor cell migration, shows as cell number in administration group and significantly reduces relative to matched group; But the inhibitory action of peoniflorin to colon-cancer cell HT29, prostate gland cancer cell DU145 and cervical cancer cell Hela tumor cell migration is strong crosses Radix Paeoniae Alba total glucosides.Specifically see Fig. 7.
Sum up, lactone glucoside of Radix Paeoniae effectively can 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, effectively can suppress growth and the transfer of intestinal cancer, cancer of pancreas, laryngeal carcinoma, cervical cancer, breast carcinoma and carcinoma of prostate especially; Peoniflorin effectively can suppress growth and the transfer of laryngeal carcinoma, cervical cancer, nasopharyngeal carcinoma, cancer of pancreas and rhabdomyosarcoma, effectively can suppress growth and the transfer of laryngeal carcinoma, cervical cancer, nasopharyngeal carcinoma and cancer of pancreas especially.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 treat 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, paeoniflorin compound can suppress growth and the transfer of kinds of tumors effectively, has the antitumor action of wide spectrum; Paeoniflorin compound can also treat intestinal cancer precancerous lesion, blocks the conversion of hyperenteritis to intestinal cancer.
Claims (5)
1. the lactone glucoside of Radix Paeoniae of structural formula 1 or its pharmaceutically acceptable salt, enantiomer or racemic mixture are preparing the purposes prevented and/or treated in the medicine of tumor, it is characterized in that: described tumor is intestinal cancer; Lactone glucoside of Radix Paeoniae is as the described sole active agent preventing and/or treating tumour medicine;
2. purposes according to claim 1, is characterized in that: described prophylaxis of tumours refers to treatment intestinal cancer precancerous lesion, and prevention serious symptom enteritis changes intestinal cancer into.
3. purposes according to claim 1 and 2, is characterized in that: described medicine is acceptable arbitrary dosage form clinically, comprises through gastrointestinal administration preparation and non-through gastrointestinal administration preparation.
4. purposes according to claim 3, is characterized in that: described through gastrointestinal administration preparation optionally from powder, tablet, granule, capsule, drop pill, Emulsion or suspensoid.
5. purposes according to claim 3, is characterized in that: described non-through gastrointestinal administration preparation optionally from injection, spray, suppository, filling agent, patch or ointment.
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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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| 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 |
| EP3566707A4 (en) * | 2017-01-06 | 2020-08-19 | Zuoguang Zhang | Application of albiflorin as indoleamine 2,3-dioxygenase (ido) inhibitor |
| 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 |
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