CN106943394A - Application of the bruceine D in the medicine for preparing treatment osteosarcoma - Google Patents
Application of the bruceine D in the medicine for preparing treatment osteosarcoma Download PDFInfo
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- CN106943394A CN106943394A CN201710219645.8A CN201710219645A CN106943394A CN 106943394 A CN106943394 A CN 106943394A CN 201710219645 A CN201710219645 A CN 201710219645A CN 106943394 A CN106943394 A CN 106943394A
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to the new application of bruceine D, and in particular to application of the bruceine D as sole active agent in the product for treating osteosarcoma is prepared, and the product is the one or more in medicine, reagent, food or health products.The present invention screens by carrying out experimental study to multiple compounds and confirms the new activity and new application of bruceine D.Experimental result is shown：Bruceine D suppresses human osteosarcoma cell proliferation, bruceine D causes osteosarcoma cell Cycle Arrest, and bruceine D promotes apoptosis in osteosarcoma cells, and bruceine D can effectively suppress the growth of osteosarcoma, therefore bruceine D can be as the medicine for treating osteosarcoma, for clinical treatment.
Description
Technical field
The present invention relates to biomedicine technical field, and in particular to bruceine D is in the medicine for preparing treatment osteosarcoma
Application
Background technology
Osteosarcoma is a kind of common malignant bone tumor, is characterized in that Malignant cell directly forms osteoid tissue, therefore also
Referred to as osteogenic sarcoma.The disease is apt to occur in teenager, is initiated by mesenchymal tissue, pernicious swollen with the characteristics of fusiformis tumour cell
Knurl, principal pathogenetic position is located at distal femur, the metaphysis of proximal tibia, and main clinical manifestation is local pain and swelling, is suffered from
Person is frequently accompanied by night pain, occasionally there is generation pathologic fracture, and x-ray shows as lesion bone metaphysis skeletonization and damaged simultaneously with osteolytic
Deposit.The most frequently used medicine is Doxorubicin, high-dose methotrexate, cis-platinum and ifosfamide, state in current osteosarcoma chemotherapy
The chemotherapy regimen of interior application is more to be adjusted application according to many clinical treatment of osteosarcoma center complex suggested designs.For occurring kindred
The patient of knurl Lung metastases, prognosis is not then universal good, and the overall survival of current this kind of patient is about 0%-50%.This dermoskeleton
The clinical treatment of sarcoma is also faced with many challenges, toxic and side effect, drug resistance of tumor cell, the recurrence of tumour and the lung of such as chemotherapeutics
Portion's transfer etc., is fully recovered even if by systematic treating also few Patients with Osteosarcoma.Therefore, new chemotherapeutics or new is developed
Medicine and traditional chemotherapy combined application, be that can avoid or reduce the generation of above-mentioned side effect in theory.
Bruceine D (Bruceine D) is a kind of quassinoids class chemical combination being separated to from Chinese medicinal plant Java brucea
Thing.Master thesis disclosed in University Of Agriculture and Forestry In Fujian 2010《Suppression of the bruceine D to cucumber green mottle mosaic virus disease
Effect》, half leaf method, leaf dish method is respectively adopted and have detected the influence that bruceine D infects and bred to CGMMV, as a result shows, its
Under 10 μ g/m L concentration for the treatment of, bruceine D is respectively 78.99% and 81.05%, crow to the inhibiting rate for infecting and breeding
The extract bruceine D of courage has anti-CGMMV activity.Master's degree opinion disclosed in Zhejiang University of Traditional Chinese Medicine in December, 2016
Text《Bruceine D is to the suppression of colon cancer strain HT29 cells propagation and induces the mechanism of its apoptosis》, bruceine D is inquired into knot
The suppression of colon-cancer cell strain HT29 propagation and mechanism, as a result show that 80 μm of ol/L bruceine Ds act on colon cancer HT29 cells
The survival rate of cell is 20.01% after 72h；80 μm of ol/L bruceine Ds act on withering for cell after colon cancer HT29 cells 72h
It is 79.37% to die rate, takes knurl body to weigh after putting to death nude mice, with the increase of bruceine D concentration for the treatment of, the bigger tumour of dosage
Weight is smaller, and bruceine D can suppress the propagation of colon cancer cell and induce it to adjust.But in the prior art, on crow courage
Applications of the son element D in the medicine for preparing treatment osteosarcoma, yet there are no report.
The content of the invention
The purpose of the present invention is that there is provided the new application of bruceine D for deficiency of the prior art.
To achieve the above object, the present invention is adopted the technical scheme that：
Application of the bruceine D as sole active agent in the product for treating osteosarcoma is prepared, the product is medicine
One or more in thing, reagent, food or health products.
Application of the bruceine D as sole active agent in the medicine for suppressing human osteosarcoma cell proliferation is prepared.
Application of the bruceine D as sole active agent in the medicine for promoting apoptosis in osteosarcoma cells is prepared.
Further, the osteosarcoma cell is human osteosarcoma cell 143B or human osteosarcoma cell HOS.
Further, the bruceine D can be used alone or be used in the form of pharmaceutical composition, the medicine group
Compound includes the bruceine D of therapeutically effective amount, its pharmaceutically acceptable salt or its prodrug, and carrier pharmaceutically.
Further, the one or more in the carrier pharmaceutically, including excipient, such as starch or water；Lubricant, such as
One or more in glycerine or magnesium stearate etc.；Disintegrant, such as microcrystalline cellulose；In filler, such as starch or lactose
One or more；Bonding agent, such as pregelatinized starch, dextrin, cellulose derivative, alginates, gelatin or polyvinylpyrrolidine
One or more in ketone etc.；One or more in osmotic pressure regulator, such as glucose, sucrose, sorbierite or mannitol；
Diluent, such as water；One or more in disintegrant, such as agar, calcium carbonate or sodium acid carbonate；Sorbefacient, such as season
Ammonium compounds etc.；Surfactant, such as hexadecanol；One or more in absorption carrier, such as kaolin or soap clay；
One or more in lubricant, such as talcum powder, calcium stearate, magnesium stearate or polyethylene glycol；Furthermore it is also possible in medicine
The one or more added in composition in other assistant agents, such as flavouring agent or sweetener.
The invention has the advantages that：
The present invention screens by carrying out experimental study to multiple compounds and confirms the new activity and new use of bruceine D
On the way.Test result indicate that：Bruceine D suppress human osteosarcoma cell proliferation, bruceine D cause osteosarcoma cell Cycle Arrest,
Bruceine D promotes apoptosis in osteosarcoma cells, and bruceine D can effectively suppress the growth of osteosarcoma, therefore bruceine D can be made
To treat the medicine of osteosarcoma, for clinical treatment.
Brief description of the drawings
Accompanying drawing 1 is the experimental result that bruceine D suppresses human osteosarcoma cell proliferation.
Accompanying drawing 2 causes the experimental result of osteosarcoma cell Cycle Arrest for bruceine D.
Accompanying drawing 3 is the experimental result that bruceine D promotes apoptosis in osteosarcoma cells.
Accompanying drawing 4 is the experiment knot that Western blot experiment detects cell death related protein cleaved-PARP expressions
Really.
Accompanying drawing 5 is the experimental result that bruceine D suppresses the growth of osteosarcoma model in situ.
Embodiment
The invention will be further elucidated with reference to specific embodiments.It should be understood that these embodiments are merely to illustrate this hair
Bright rather than limitation the scope of the present invention.In addition, it is to be understood that after the content of the invention recorded has been read, art technology
Personnel can make various changes or modifications to the present invention, and these equivalent form of values equally fall within the application appended claims and limited
Fixed scope.
Term used herein " acceptable ", refers to the health of a prescription component or active component to general treatment target
There is no undue adverse effect.
Term used herein " treatment ", including relax, suppress or improve the symptom or situation of disease；Suppress complication
Produce；Improve or prevent potential metabolic syndrome；Suppress the development of the generation of disease or symptom, such as control disease or situation；Subtract
Light disease or symptom；Disease or symptom is set to decline；Mitigate the complication as caused by disease or symptom, or prevention or treatment by disease
Or sign caused by symptom.As used herein, a certain compound or pharmaceutical composition, after administration, can make a certain disease, symptom
Or situation is improved, espespecially its severity is improved, delayed onset, slows down disease progression, or reduce the state of an illness duration.
No matter fix administration or interim administration, be administered continuously or interrupted continuous administration, can be attributed to or the situation relevant with administration.
Term used herein " pharmaceutically acceptable " herein refers to a kind of material, such as carrier or dilution, will not make chemical combination
The bioactivity or property of thing disappear, and relative nontoxic, e.g., give individual something, will not cause undesired biotic influence
Or in harmful manner with any component that it contains interact.The example of pharmaceutically acceptable carrier includes one or more
Water, salt solution, phosphate buffered saline, glucose, glycerine or ethanol etc. and combinations thereof in one or more.In many situations
Under, isotonic agent is preferably included in the composition, for example, sugar, such as mannitol, sorbierite, the polyalcohol of sorbierite or chlorination
One or more in sodium etc..Pharmaceutically acceptable carrier can also include a small amount of auxiliary substance, such as wetting agent or breast
One or more in agent, preservative or buffer solution etc..
At specifically used aspect, bruceine D of the present invention can be used alone, can also be with other many chemical substances
It is applied in combination.No matter whether these chemical substances have bioactivity or the function with treatment disease, including miscellaneous function is such as
Cooperate with amplification, antagonism or alleviate side effect of bruceine D etc., these chemical substances are including pharmaceutically acceptable
One or more in carrier, food, natural products, chemical synthetic drug or human administration etc.；Preferably include pharmaceutically may be used
One or more in carrier or food of receiving etc.；Further preferred pharmaceutically acceptable carrier.
The Chinese medicine standard items of embodiment 1-bruceine D suppresses the experimental study of Growth of Osteosarcoma
(1)
1. material and method
1.1 material cell line of human osteosarcoma 143B and HOS is purchased from American Type Culture Collecti (ATCC).Bruceine D
(Bruceine D, BD) (analytical standard product；Purity HPLC>98%, article No. B21415-20mg) it is purchased from Shanghai source leaf biotechnology
Co., Ltd, is dissolved in dimethyl sulfoxide (DMSO), is configured to 20mMol/L working stocks, be placed in it is standby in -20 DEG C of refrigerator,
With DMEM serum free culture system liquid required concentration is adjusted to using preceding.
Experiment reagent and instrument：DMEM high glucose mediums, hyclone (Thermo companies of the U.S.)；P-PARP antibody, LC-
3B antibody, GAPDH antibody, horseradish peroxidase-labeled secondary antibody (this letter bio tech ltd)；Dimethyl sulfoxide (DMSO) (the U.S.
Sigma companies)；0.02%EDTA+0.25% trypsase (German Miltenyi Biotec companies)；Constant incubator (Shanghai
Rong Yan instrument companies)；Flow cytometer (Becton Dickinson companies of the U.S.)；Multi-function microplate reader (U.S. Molecular
Devices companies).
1.2 experimental methods
1.2.1 osteosarcoma cell line HOS, 143B are cultivated in cell culture (contains volume integral in DMEM complete culture solutions
Number be 10% hyclone, 0.1g/L streptomysins, 100U/mL penicillin), in 37 DEG C, volume fraction be 5%CO2It is incubated
Cultivated in case.When cell fusion degree reaches 85% or so, carried out with 0.02%EDTA+0.25% trypsase mixture slaking liquid
Digestion, then collects cell 1000r/min centrifugation 3min, Secondary Culture.
1.2.2cck-8 detection cell proliferative conditions collect HOS, 143B cell of exponential phase, and PBS is counted,
It is in charge of, is added by 3000/hole cell number in 96 orifice plates, culture 24h makes cell attachment, and the amount concentration of different material is added afterwards
Bruceine D (0,0.25,0.5,1,2,4 μm of ol/L) carries out culture 24h, is then detected.Add and cultivated with DMEM per hole
The μ L of cck-8 reagents 100 that base dilutes 10 times are incubated 45 minutes in 37 DEG C.Extinction of each hole at 450nm is detected using ELIASA
Angle value.
1.2.3 the bruceine D (0,1,2,4 μm of ol/L) of the amount concentration of plate clone experiment different material to HOS,
143B cells are handled, and suck supernatant liquid, and 15min is fixed with 4% paraformaldehyde, and PBS is rinsed 3 times, uses 0.1% crystal violet
10min is dyed, PBS is rinsed 2 times, is taken pictures after air-drying.
1.2.4 143B, HOS cell are added to the amount concentration crow containing different material by the flow cytomery cell cycle
Cultivated in courage element D (0,1,2,4 μm of mol/L) nutrient solution, cell, 1000r/min centrifugations 1min, PBS are collected after 24h
Cleaning.Fixed with 70% ethanol, add cycle kit PI dye liquor, room temperature lucifuge is incubated 15min, examined with flow cytometer
Survey.Image is analyzed using ModFit softwares.Repeat experiment 3 times.
1.4.5 143B, HOS cell are added to the amount concentration crow containing different material by flow cytomery Apoptosis
Cultivated in courage element D (0,1,2,4 μm of mol/L) nutrient solution, cell, 1000r/min centrifugations 1min, PBS are collected after 24h
Cleaning.Then its apoptosis situation is detected using Annexin-V-FITC/PI cell apoptosis detection kits, cell is added to
Resuspended in 100 μ L 1 × Binding buffer solutions, 5 μ LAnnexin V-FITC of addition and 2.5 μ L PI dyestuffs carry out lucifuge vibration
Mix, react at room temperature 15min, then add 300 μ L1 × Binding buffer solutions, mix, flow cytometer is detected.
Repeat experiment 3 times.
1.2.6 immunoblot experiment detection cell death related protein extract respectively with containing 0,1,2,4 μm of mol/L differences it is dense
Spend bruceine D nutrient solution culture 24h 143B cells and the total protein in HOS cell born of the same parents, detection apoptotic proteins cleaved-
PARP expression, is quantified, and then carries out electrophoresis using 10% separation gel.The 100V transferring films 1h under ice bath.It is de- using 5%
Fat milk room temperature closes 1h, adds the 4 DEG C of incubations of corresponding primary antibody (cleaved-PARP antibody and internal reference Protein G APDH antibody)
Overnight, washing 3 times, each 10min are carried out using TBST.Add secondary antibody afterwards, 37 DEG C of incubation 1h wash 3 times, often using TBST
Then secondary 15min, the compressing tablet in darkroom is developed, is fixed.
The amount concentration bruceine D of 1.3 MAIN OUTCOME MEASURES different materials can induce the propagation of osteosarcoma cell line, lure
Lead its cell-cycle arrest and apoptosis.
2. result
2.1 bruceine Ds suppress human osteosarcoma cell proliferation
Contain nutrient solution culture the osteosarcoma cell 24h and 48h of 0,0.25,0.5,1,2,4 μm of mol/L bruceine D, train
Support 24h when 143B each groups living cells be respectively non-dosing group (89.52 ± 3.47) % (P ＜ 0.05), (79.06 ±
1.36) % (P ＜ 0.05), (60.76 ± 1.49) % (P ＜ 0.01), (49.08 ± 0.94) % (P ＜ 0.01) and (40.35 ±
1.30) % (P ＜ 0.01), the living cells of HOS each groups be respectively (90.53 ± 0.53) % (P ＜ 0.01) of non-dosing group,
(80.61 ± 1.76) % (P ＜ 0.01), (72.90 ± 2.51) % (P ＜ 0.01), (57.13 ± 2.17) % (P ＜ 0.01) and
(49.12 ± 1.61) % (P ＜ 0.01), culture 48h when 143B each groups living cells be respectively non-dosing group (71.20 ±
1.07) % (P ＜ 0.01), (62.31 ± 2.51) % (P ＜ 0.01), (42.78 ± 2.64) % (P ＜ 0.01), (18.72 ±
1.63) % (P ＜ 0.01) and (11.41 ± 2.22) % (P ＜ 0.01), the living cells of HOS each groups is respectively non-dosing group
(68.90 ± 1.48) % (P ＜ 0.01), (56.09 ± 1.38) % (P ＜ 0.01), (48.28 ± 2.15) % (P ＜ 0.01),
(23.55 ± 2.48) % (P ＜ 0.01) and (8.12 ± 0.60) % (P ＜ 0.01), the amount of different material in identical action time
The cell that the cell of concentration bruceine D processing is handled with unused bruceine D difference on inhibiting rate is respectively provided with statistics meaning
Justice, and as the rise of bruceine D substance withdrawl syndrome, the proliferation rate of cell decline, crow courage is used under identical activity
The difference on inhibiting rate has statistical significance to sub- element D processing 24h cell with processing 48h cell, and with action time
Extension, the proliferation rate of cell declines (Fig. 1 a).With the increase of drug concentration, the Clone formation number of cell gradually decreases (figure
1b)。
2.2 bruceine Ds cause osteosarcoma cell Cycle Arrest
With the nutrient solution culture cell 24h containing 0,2,4,8 μm of mol/L bruceine D, its each cycle of flow cytomery
Phase accounting.The G0/G1 phase cell accountings of 143B cells are respectively under different activities：37.20%th, (44.81 ± 5.27) %
(P ＜ 0.05), (50.23 ± 2.56) % (P ＜ 0.01) and (55.26 ± 2.79) % (P ＜ 0.01), G2/M phase cells accounting point
Not Wei 12.26%, (9.10 ± 1.79) % (P ＜ 0.05), (2.32 ± 1.12) % (P ＜ 0.05) and (1.31 ± 0.53) % (P
＜ 0.05).The G0/G1 phase cell accountings of HOS cells are respectively 37.65%, (54.51 ± 8.31) % (P under different activities
＜ 0.05), (61.49 ± 3.88) % (P ＜ 0.01) and (66.63 ± 1.37) % (P ＜ 0.01), G2/M phase cells accounting difference
For 13.55%, (8.49 ± 3.08) % (P ＜ 0.05), (7.35 ± 2.42) % (P ＜ 0.05) and (4.60 ± 2.24) % (P ＜
0.05).It can be seen that, with the rise of activity, the cell proportion of G0/G1 phases gradually rises, and the cell proportion of G2/M phases is gradually
Decline, the difference statistically significant (P ＜ 0.05) (Fig. 2 a, Fig. 2 b) compared with control group (0 μm of mol/L).
2.3 bruceine Ds promote apoptosis in osteosarcoma cells
With the nutrient solution culture cell 24h containing 0,1,2,4 μm of mol/L bruceine D, its apoptosis of flow cytomery
Rate.The apoptosis rate of 143B cell each groups is respectively 17.05%, (30.37 ± 3.96) % (P ＜ 0.05), (39.07 ± 1.40) %
(P ＜ 0.01), (63.37 ± 9.27) % (P ＜ 0.01), the apoptosis rates of HOS cell each groups is respectively 11.20%, (18.47 ±
6.70) % (P ＜ 0.05), (29.13 ± 5.18) % (P ＜ 0.05), (43.30 ± 7.40) % (P ＜ 0.01), with Java brucea
The rise of plain D mass concentrations, the apoptosis rate increase (Fig. 3 a, Fig. 3 b) of cell.The amount concentration bruceine D processing of different material
Cell difference on apoptosis rate compared with control group (0 μm of mol/L), which is respectively provided with to compare between statistical significance, various concentrations, also difference
Different statistical significance (P ＜ 0.05).
In addition, be have detected using Western blot experiment 0,1,2,4 μm of mol/L various concentrations bruceine D nutrient solutions
The lower cell death related protein cleaved-PARP of processing expression.Added with cleaved- in bruceine D group cell
The expression of PARP albumen is apparently higher than non-dosing group, and with the rise of drug concentration, the table of cleaved-PARP albumen
Up to also rising (Fig. 4) therewith
(2), the observation of osteosarcoma mouse model
Using BALB/c nude mices, treatment group and control group are randomly divided into, treatment group is noted with 143B human osteosarcoma cells suspension
Enter mouse right hind bone subperiosteum, control group injection equivalent PBS.After 7~8 days, small enclosed mass is formed, and is started gavage and is given
Medicine：20mg/kg/day bruceine D is given by treatment group；Control group gives equivalent 0.5%CMC-Na, persistently intervenes 2 weeks.
7~8 days after transplanting, using oil ga(u)ge kind of calliper knurl footpath, it is spaced two days and measures 1 time, and claim Mouse Weight.Test the 3rd week, vein
The excessive yellow Jackets of injection put to death mouse, and clip mouse lung tissue will carry out amputation to lotus knurl side hind leg and contralateral hind limb
And fixed with 5% formalin, sample is prepared, sample is soaked transparent in dimethylbenzene, pathological analysis is carried out.
Pathological analysis shows that tumor tissues sample is human osteosarcoma.Gross tumor volume result is shown：It is right into after knurl 2 weeks
Increase obvious according to group knurl body, the 21st day after transplanting, control group tumor volume reaches 1560mm3, treatment group's tumor volume increases slow
Slowly, the 30th day after transplanting, treatment tumor volume is 625mm3.The above results show：Bruceine D can effectively suppress osteosarcoma
Grow (Fig. 5).
The above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
Member, on the premise of the inventive method is not departed from, can also make some improvement and supplement, and these are improved and supplement also should be regarded as
Protection scope of the present invention.
Claims (5)
1. bruceine D as sole active agent prepare treat osteosarcoma product in application, the product be medicine,
One or more in reagent, food or health products.
2. application of the bruceine D as sole active agent in the medicine for suppressing human osteosarcoma cell proliferation is prepared.
3. application of the bruceine D as sole active agent in the medicine for promoting apoptosis in osteosarcoma cells is prepared.
4. the application according to claim 2-3, it is characterised in that the osteosarcoma cell be human osteosarcoma cell 143B or
Human osteosarcoma cell HOS.
5. the application according to claim 1-3, it is characterised in that the bruceine D can be used alone or with medicine
The form of compositions is used, and described pharmaceutical composition includes the bruceine D of therapeutically effective amount, its pharmaceutically acceptable salt
Or its prodrug, and carrier pharmaceutically.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109223771A (en) * | 2018-11-16 | 2019-01-18 | 中国医学科学院医药生物技术研究所 | Application of the bruceine A in preparation prevention and treatment osteoporosis agents |
| CN117357515A (en) * | 2023-11-27 | 2024-01-09 | 宁夏医科大学 | Application of brucea javanica kurrow kurarine D in preparing medicament for inhibiting tumor angiogenesis |
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2017
- 2017-04-06 CN CN201710219645.8A patent/CN106943394A/en active Pending
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| CN109223771A (en) * | 2018-11-16 | 2019-01-18 | 中国医学科学院医药生物技术研究所 | Application of the bruceine A in preparation prevention and treatment osteoporosis agents |
| CN109223771B (en) * | 2018-11-16 | 2021-05-04 | 中国医学科学院医药生物技术研究所 | Application of brucine A in preparing medicine for preventing and treating osteoporosis |
| CN117357515A (en) * | 2023-11-27 | 2024-01-09 | 宁夏医科大学 | Application of brucea javanica kurrow kurarine D in preparing medicament for inhibiting tumor angiogenesis |
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