CN105796638A - Applications of mixed oridonin and cryptotanshinone in preparing medicine for treating leukemia - Google Patents
Applications of mixed oridonin and cryptotanshinone in preparing medicine for treating leukemia Download PDFInfo
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- CN105796638A CN105796638A CN201610336683.7A CN201610336683A CN105796638A CN 105796638 A CN105796638 A CN 105796638A CN 201610336683 A CN201610336683 A CN 201610336683A CN 105796638 A CN105796638 A CN 105796638A
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- Prior art keywords
- cryptotanshinone
- medicine
- rubescensine
- leukemia
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Classifications
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- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
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- 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
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
- A61K36/537—Salvia (sage)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- 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
Abstract
The invention discloses applications of mixed oridonin and cryptotanshinone in preparing a medicine for treating leukemia. The research finds that after the traditional Chinese medicinal active ingredients with different anti-cancer mechanisms, namely, oridonin and cryptotanshinone are mixed at a suitable ratio, a significant synergistic interaction effect can be generated by the mixture. Through the mixing method, a medicinal composition with low concentration can kill many leukemia cells, meanwhile, the total medicine concentration available when the inhibition ratio of the medicine for the leukemia cell proliferation achieves 50% can be effectively reduced, and moreover, in the mixing method, the use amounts of the traditional Chinese medicinal active ingredients are not within the range capable of causing harm to the body. Therefore, the oridonin and cryptotanshinone mixing scheme has great significance and wide application prospects in the aspect of preparing the medicine for treating leukemia and the aspect of prevention and treatment as well as study on leukemia.
Description
Technical field
The invention belongs to biomedicine technical field.Cryptotanshinone application in preparing medicament for treatment of leukemia is combined more particularly, to rubescensine A.
Background technology
Leukemia is commonly called as " leukemia ", is the class Hematological malignancies disease that derives from hematopoietic stem cell.Currently, leukemic treatment is focused primarily upon below scheme: chemotherapy, radiotherapy, bone marrow transplantation and immunotherapy etc..Wherein, chemotherapy because its targeting is relatively strong, medical expense relative moderate and become the mainstream scheme in leukemia treating.
In conventional chemotherapy regimen, the thinking of drug combination obtains sufficient embodiment.Many based on Western medicine associating Western medicine, Western medicine Combined with Chinese Herbal in clinical conventional drug combination mode at present, and Western medicine used is mostly the specificity of cell cycle or non-specific blocking medicine, utilizes the abnormality proliferation characteristic of leukaemia that this disease is treated.
But, above-mentioned therapy there is also very big problem in the application: first, although prevent the abnormality proliferation of leukaemia based on the chemotherapy regimen of cell cycle arrest medicine, but also counteracts that the division of normal body cell；Second, Western medicine metabolic process is complicated, and the vitals damages such as the heart of patient, liver, kidney is serious；3rd, target chemotherapy medicine is expensive, and common other more difficult bears for a long time.
Summary of the invention
nullThe technical problem to be solved in the present invention is the defect and the deficiency that overcome existing treatment leukemia medicament，Mainly the targeting of chemotherapy regimen is poor (does not namely differentiate between normal cell and cancerous tumor cell，The propagation of mandatory retardance body all cells)、Side effect is strong、The drawback such as with high costs，There is provided a kind of by the Chinese herbal medicine effective ingredients rubescensine A (Oridonin of two kinds of different anticancer mechanisms，It is called for short Ori) and cryptotanshinone (Cryptotanshinone，It is called for short CPT) carry out the drug combination method of compatibility，Both significant cooperative synergism effect can have been utilized between two kinds of compounds to reach the high efficiency purpose killing leukaemia of low dosage，Simultaneously because Chinese herbal medicine low toxicity and abundance、Material is easy to get，Therapeutic process Chinese medicine can be greatly reduced and to the toxic and side effects of body and significantly reduce treatment cost.
It is an object of the invention to provide the application in preparing medicament for treatment of leukemia of the scheme of combination drug therapy of rubescensine A and cryptotanshinone compatibility.
Another object of the present invention is to provide a kind of medicament for treatment of leukemia.
Above-mentioned purpose of the present invention is achieved through the following technical solutions:
The application in the medicine of preparation leukemia prevention, treatment, auxiliary treatment and/or pre-rear defence recurrence of the Rabdosia rubescens associating Radix Salviae Miltiorrhizae.
The application in the medicine of preparation leukemia prevention, treatment, auxiliary treatment and/or pre-rear defence recurrence of the rubescensine A associating cryptotanshinone.
The specifically pharmaceutical composition of the high-efficiency low-toxicity of rubescensine A associating cryptotanshinone compatibility by a certain percentage application in the medicine of preparation leukemia prevention, treatment, auxiliary treatment and/or pre-rear defence recurrence.
Described rubescensine A or cryptotanshinone include its pharmaceutically useful salt and ester, selectivity replaces analog or the combination of one or more aforesaid compounds；Also include the derivant of the two or the solvate of the two and derivant thereof pharmaceutically acceptable salt or salt.
The advantage that above-mentioned medicine has high-efficiency low-toxicity.
Preferably, described leukemia is chronic myelogenous leukemia or acute myeloid leukaemia.
It is highly preferred that described leukemia is chronic myelogenous leukemia cell cycling inhibiting cell or acute myeloid leukemia cells in children strain HL60 cell.
The active component playing attenuation synergistic in above-mentioned associating compatibility program is rubescensine A and cryptotanshinone.
Preferably, in above-mentioned application scheme, the molar concentration rate of rubescensine A and cryptotanshinone is 0.1～15:0.1～20.
Preferably, when preparation is for the medicine of chronic myelogenous leukemia, the molar concentration rate of rubescensine A and cryptotanshinone is 5～10:3～7.5；When preparation is for the medicine of acute myeloid leukaemia, the molar concentration rate of rubescensine A and cryptotanshinone is 1～2.5:2.5～5.
It is highly preferred that when preparation is for the medicine of chronic myelogenous leukemia, the molar concentration rate of rubescensine A and cryptotanshinone is 5:7.5 or 10:3；When preparation is for the medicine of acute myeloid leukaemia, the molar concentration rate of rubescensine A and cryptotanshinone is 1:5 or 2.5:2.5.
Furthermore it is preferred that the concentration of rubescensine A and cryptotanshinone coupling is respectively as follows: the concentration of rubescensine A compatibility less than 15 μMs, the concentration of cryptotanshinone compatibility is less than 20 μMs.
It is highly preferred that the concentration of rubescensine A compatibility is less than 10 μMs, the concentration of cryptotanshinone compatibility is less than 20 μMs.
Most preferably: when preparation is for the medicine of chronic myelogenous leukemia, best compatibility program is the cryptotanshinone of the rubescensine A compatibility 7.5 μMs of 5 μMs, or the cryptotanshinone of the rubescensine A compatibility of 10 μMs 3 μMs；When preparation is for the medicine of acute myeloid leukaemia, best compatibility program is the cryptotanshinone of the rubescensine A compatibility 5 μMs of 1 μM, or the cryptotanshinone of the rubescensine A compatibility of 2.5 μMs 2.5 μMs.
Result of study shows, when 5 μMs of compatibility cryptotanshinones of rubescensine A 7.5 μMs or 10 μMs of compatibility cryptotanshinones of rubescensine A 3 μMs, pharmaceutical composition to the proliferation inhibition rate of chronic myelogenous leukemia cell namely up to 50%；When 1 μM of compatibility cryptotanshinone of rubescensine A 5 μMs or 2.5 μMs of compatibility cryptotanshinones of rubescensine A 2.5 μMs, pharmaceutical composition to the proliferation inhibition rate of acute myeloid leukemia cells in children namely up to 50%；And the consumption that makes of these two kinds of compatibility modes is not admitted to the scope that can body be damaged.
One treats leukemic pharmaceutical composition, comprises Rabdosia rubescens and the Radix Salviae Miltiorrhizae of effective dose, or comprises rubescensine A and the cryptotanshinone of effective dose.Described medicine can also is that comprise rubescensine A or cryptotanshinone derivant and pharmaceutically acceptable salt thereof and ester, the compositions of analog that selectivity replaces or one or more aforesaid compounds.
Further, aforementioned pharmaceutical compositions can also include acceptable pharmaceutical carrier and make various pharmaceutically acceptable preparation, including pin or freeze-dried powder, pill, decoction, tablet, granule, hard capsule, soft capsule, controlled release, slow releasing preparation, injection or oral formulations.
Described pharmaceutical carrier includes (but being not limited to): the combination of one or more in saline, buffer, glucose, water, glycerol, ethanol, low-molecular-weight dextran, PEG400, polyethylene glycol 6000, mannitol, lactose, glucose, sucrose, sodium chloride and sorbitol.
The preparation method of the medicine of the rubescensine A of the present invention and cryptotanshinone composition does not do strict restriction, as being made into injection form, for instance be prepared by conventional method with normal saline or the aqueous solution containing glucose and other adjuvant.The pharmaceutical composition of such as tablet and capsule etc, can be prepared by conventional method.Pharmaceutical composition such as injection, solution, tablet and capsule should aseptically manufacture.
Further, above-mentioned pharmaceutical composition can also include more than one pharmaceutically acceptable excipient.
Additionally, above-mentioned pharmaceutical composition may also include other chemotherapeutics, anti-inflammatory drug, hormone medicine, little molecular targeted agents, antibody drug, compound Chinese medicinal preparation and Chinese medicine extract and/or Chinese medicine monomer and derivant thereof, thus preparing into difference medicine targetedly.
Particularly preferably, other chemotherapeutics described or antitumor and anticancer agent can be one or more of below (but not limited to): etoposide, 5-fluorouracil, cyclophosphamide, amycin, daunorubicin, epirubicin, cytosine arabinoside, isatin, cisplatin, carboplatin, etoposide, topotecan, irinotecan etc..
Described anti-inflammatory drug or immunostimulant can be one or more of below (but not limited to): aspirin, interferon, c-AMP, globulin etc..
Described hormone medicine can be one or more of below (but not limited to): glucocorticoid, estrogen, progestogen etc..
Described little molecular targeted agents can be one or more of below (but not limited to): imatinib (Imatinib), Dasatinib (Dasatinib), nilotinib (Nilotinib), Bosutinib (Bosutinib), Sutent (Sutent, Sunitinib), Sorafenib (Nexavar, Sorafenib), Lapatinib (Lapatinib), Iressa (Gefitinib) etc..
Described antibody class medicine can be one or more of below (but not limited to): Mabthera (Rituximab, Rituxan), He Saiting (Trastuzumab, Herceptin), Erbitux (Cetuximab, Erbitux), bevacizumab (Bevacizumab, Avastin), Victibix (Panitumumab), Buddhist nun's trastuzumab (Nimotuzumab) etc..
Described anti-tumor Chinese medicine compound preparation and Chinese medicine extract can be with one or more under (but not limited to): Ganoderma extract, Coriolus Versicolor P.E., Poria extract, Semen Coicis extract, Fengling mixture, Venenum Bufonis spirit etc..
Described Chinese medicine monomer and derivant thereof can be one or more of below (but not limited to): paclitaxel, camptothecine, homoharringtonine, arteannuin, soybean isoflavone, ginsenoside, vincristine, colchicine, naringenin, rheum emodin and derivant, matrine and derivant, triptolide and derivant thereof etc..
Additionally; aforementioned pharmaceutical compositions preparing the antileukemie medicine of attenuation synergistic, prevent leukemic medicine, improve the medicine of immunity of organisms, health care medicine or health food in application; and the described medicine thus prepared, also within protection scope of the present invention.
Wherein it is preferred to, described leukemia is chronic myelogenous leukemia or acute myeloid leukaemia.
It is highly preferred that described leukemia is chronic myelogenous leukemia cell cycling inhibiting cell or acute myeloid leukemia cells in children strain HL60 cell.
The present invention proposes the drug combination mode that the Chinese herbal medicine effective ingredients rubescensine A and cryptotanshinone with different anticancer mechanism carry out compatibility, and give the suppression situation of cell proliferation under concrete compatibility dosage and corresponding dosage, this compatibility mode can be greatly improved the medicine proliferation inhibiting effect to leukaemia, and the medicine total concentration making medicine corresponding when the proliferation inhibition rate of leukaemia is reached 50% is remarkably decreased.
The present invention further defines this pharmaceutical composition (rubescensine A and cryptotanshinone compatibility) and has obvious cooperative synergism effect when doses compatibility, this makes them can with relatively low dose application in the associated treatment of leukemic clinical treatment, auxiliary treatment and the recurrence of pre-rear defence, and this compatible combination had both improve the total effects of medicine and decreased the generation of side effect.The invention discloses the pharmaceutical composition containing described compound and relevant proportioning thereof and described pharmaceutical composition in the application in anti-treating leukemia of the high-efficiency low-toxicity ground.
The method have the advantages that
The invention discloses the Chinese herbal medicine effective ingredients combined effect of different anticancer mechanism and leukemia is carried out the treatment of high-efficiency low-toxicity, mainly the effective ingredient rubescensine A in Chinese herbal medicine Rabdosia rubescens and Radix Salviae Miltiorrhizae and cryptotanshinone are carried out the drug combination of quantitative compatibility, creates the effect of significant Synergistic.
In above-mentioned compatibility mode (rubescensine A and cryptotanshinone), rubescensine A and being used in combination of cryptotanshinone can play good synergistic function, this drug regimen can substantially reduce the medicine total concentration (can effectively lower medicine and leukemia cell proliferation inhibition rate reaches medicine total concentration corresponding when 50%) making leukaemia corresponding when reaching half proliferation inhibition rate, and the consumption that makes of these two kinds of compatibility modes is not admitted to the scope that can body be damaged.
Therefore, the rubescensine A associating cryptotanshinone combination medicine scheme of the present invention, in preparing medicament for treatment of leukemia and leukemic preventing and treating and research, all has great importance and is widely applied prospect.
Accompanying drawing explanation
Fig. 1 is the compatibility of drugs mode of 5 μMs and the 10 μMs rubescensine A coupling variable concentrations cryptotanshinones Proliferation Ability situation to chronic myelogenous leukemia cell cycling inhibiting cell.
Fig. 2 is the compatibility of drugs mode of 1 μM and the 2.5 μMs rubescensine A coupling variable concentrations cryptotanshinone Proliferation Ability situation to acute myeloid leukemia cells in children strain HL60 cell.
Detailed description of the invention
Further illustrate the present invention below in conjunction with Figure of description and specific embodiment, but the present invention is not limited in any form by embodiment.Unless stated otherwise, the present invention adopts reagent, method and apparatus are the art conventional reagent, method and apparatus.
Unless stated otherwise, following example agents useful for same and material are commercial.
Embodiment 1 rubescensine A and the research in chronic myelogenous leukemia cell strain of the cryptotanshinone drug combination
The rubescensine A selecting finite concentration gradient processes chronic myelogenous leukemia K562 cell 24 hours respectively with cryptotanshinone, the concentration simultaneously fixing cancer therapy drug rubescensine A, the cryptotanshinone that different gradient concentration is used in combination process K562 leukemic cells 24 hours, calculate cell respective Proliferation Ability intensity under drug treating pattern three kinds different by MTT colorimetry.
Concrete research method is as follows:
1, experimental cell strain
K562 chronic myelogenous leukemia cell takes from Zhongshan University's bio-engineering research center (Guangdong, Guangzhou).
2, cell is cultivated:
K562 cell complete medium (containing the RPMI-1640 culture medium that 10%FBS and 1% is dual anti-) carries out regular growth cultivation, adopts 37 DEG C of constant temperature, 5%CO during cultivation2Condition carry out.
3, mother liquid medicine preparation experiment:
Take purchased from Henan benefit mankind pharmaceutical Co. Ltd rubescensine A powder and purchased from the cryptotanshinone powder of SelleckChemicals company, weigh, and dissolve with DMSO solution, respectively to final concentration of 40mM(Ori) and 5mM(CPT).
4, cell growth inhibition assay:
(1) cell is obtained
Taking the K562 leukemic cells being cultured to exponential phase, 750rpm is centrifugal to be collected for 3 minutes, with the RPIM1640 culture medium re-suspended cell containing 10% hyclone, and the concentration of cell suspension is adjusted to 3 × 105Individual/ml, accesses above-mentioned cell suspension in 96 orifice plates with the amount in 98 μ L/ holes, is placed in 37 DEG C, 5%CO2Incubator is cultivated 24 hours；
(2) agent-feeding treatment
A. the 40mM rubescensine A mother solution DMSO solution dilution for preparing is taken to 100 times of working concentration (5 μMs and 10 μMs), therefore compound concentration respectively 0.5mM and 1mM, piping and druming mixing；
B. the 5mM cryptotanshinone mother solution DMSO solution dilution for preparing is taken to 100 times of working concentration (2.5 μMs, 5 μMs, 7.5 μMs, 10 μMs and 20 μMs), therefore compound concentration respectively 0.25mM, 0.5mM, 0.75mM, 1mM and 2mM, piping and druming mixing；
C. in (1) the every porocyte suspension in 96 orifice plates adds medicine dilute, is divided into the independent medication group of cryptotanshinone, 5 μMs of rubescensine A and cryptotanshinone drug combination group, 10 μMs of rubescensine A and cryptotanshinone drug combination group:
Cryptotanshinone independent medication group: every hole adds each concentration cryptotanshinone solution and 1 μ LDMSO solution that have diluted in 1 μ LB, 0 μM of control wells of cryptotanshinone, for only to add 2 μ LDMSO solution, is rocked culture plate with mixing, is placed in 37 DEG C, 5%CO2Incubator is cultivated 24 hours；
5 μMs of rubescensine A and cryptotanshinone drug combination group: every hole adds each concentration cryptotanshinone solution diluted in the 0.5mM rubescensine A solution and 1 μ LB diluted in 1 μ LA, rubescensine A 0 μM of control wells of 5 μMs of cryptotanshinones is add the 0.5mM rubescensine A solution and 1 μ LDMSO solution that have diluted in 1 μ LA, rock culture plate with mixing, it is placed in 37 DEG C, 5%CO2Incubator is cultivated 24 hours；
10 μMs of rubescensine A and cryptotanshinone drug combination group: every hole adds each concentration cryptotanshinone solution diluted in the 1mM rubescensine A solution and 1 μ LB diluted in 1 μ LA, rubescensine A 0 μM of control wells of 10 μMs of cryptotanshinones is add the 1mM rubescensine A solution and 1 μ LDMSO solution that have diluted in 1 μ LA, rock culture plate with mixing, it is placed in 37 DEG C, 5%CO2Incubator is cultivated 24 hours；
(3) in each porocyte suspension, add 15 μ LMTT solution (MTT test kit is purchased from Promega company, USA), be placed in 37 DEG C, 5%CO2Incubator is cultivated 4 hours；
(4) in (3), in each hole, add 100 μ LSTOP solution, be placed in 37 DEG C, 5%CO2Incubator is cultivated 24 hours；
(5) take out 96 well culture plates, under the exciting light of 570nm wavelength and 630nm wavelength, detect the light absorption value in each hole, A570-A630, it being the real light absorption value in each hole, reaction is the survival rate of cell in each hole, can calculate each porocyte Proliferation Ability situation under medicine effect accordingly.
5, experimental result
As shown in Figure 1, rubescensine A and being used in combination of cryptotanshinone can play significant synergistic function to result.
This drug regimen can substantially reduce and make leukaemia reach medicine total concentration corresponding during half proliferation inhibition rate: 5 μMs of compatibility cryptotanshinones of rubescensine A 7.5 μMs (as shown in Figure 1) or rubescensine A 10 μMs of compatibility cryptotanshinones 3 μMs (as shown in Figure 1), and the consumption that makes of these two kinds of compatibility modes is not admitted to the scope that can body be damaged.
Embodiment 2 rubescensine A and the research in acute myeloid leukemia cells in children strain of the cryptotanshinone drug combination
The rubescensine A selecting finite concentration gradient processes acute myeloid leukaemia HL60 cell 24 hours respectively with cryptotanshinone, the concentration simultaneously fixing cancer therapy drug rubescensine A, the cryptotanshinone that different gradient concentration is used in combination process leukemia HL60 cell 24 hours, calculate cell respective Proliferation Ability intensity under drug treating pattern three kinds different by MTT colorimetry.
Concrete research method is as follows:
1, experimental cell strain
HL60 acute myeloid leukemia cells in children takes from Zhongshan University's bio-engineering research center (Guangdong, Guangzhou).
2, cell is cultivated:
HL60 cell complete medium (containing the RPMI-1640 culture medium that 10%FBS and 1% is dual anti-) carries out regular growth cultivation, adopts 37 DEG C of constant temperature, 5%CO during cultivation2Condition carry out.
3, mother liquid medicine preparation experiment:
Take purchased from Henan benefit mankind pharmaceutical Co. Ltd rubescensine A powder and purchased from the cryptotanshinone powder of SelleckChemicals company, weigh, and dissolve with DMSO solution, respectively to final concentration of 40mM(Ori) and 5mM(CPT).
4, cell growth inhibition assay:
(1) cell is obtained
Taking the leukemia HL60 cell being cultured to exponential phase, 750rpm is centrifugal to be collected for 3 minutes, with the RPIM1640 culture medium re-suspended cell containing 10% hyclone, and the concentration of cell suspension is adjusted to 3 × 105Individual/ml, accesses above-mentioned cell suspension in 96 orifice plates with the amount in 98 μ L/ holes, is placed in 37 DEG C, 5%CO2Incubator is cultivated 24 hours；
(2) agent-feeding treatment
A. the 40mM rubescensine A mother solution DMSO solution dilution for preparing is taken to 100 times of working concentration (1 μM and 2.5 μMs), therefore compound concentration respectively 0.1mM and 0.25mM, piping and druming mixing；
B. the 5mM cryptotanshinone mother solution DMSO solution dilution for preparing is taken to 100 times of working concentration (2.5 μMs, 5 μMs and 7.5 μMs), therefore compound concentration respectively 0.25mM, 0.5mM and 0.75mM, piping and druming mixing；
C. in (1) the every porocyte suspension in 96 orifice plates adds medicine dilute, is divided into the independent medication group of cryptotanshinone, 1 μM of rubescensine A and cryptotanshinone drug combination group, 2.5 μMs of rubescensine A and cryptotanshinone drug combination group:
Cryptotanshinone independent medication group: every hole adds each concentration cryptotanshinone solution and 1 μ LDMSO solution that have diluted in 1 μ LB, 0 μM of control wells of cryptotanshinone, for only to add 2 μ LDMSO solution, is rocked culture plate with mixing, is placed in 37 DEG C, 5%CO2Incubator is cultivated 24 hours；
1 μM of rubescensine A and cryptotanshinone drug combination group: every hole adds each concentration cryptotanshinone solution diluted in the 0.1mM rubescensine A solution and 1 μ LB diluted in 1 μ LA, rubescensine A 0 μM of control wells of 1 μM of cryptotanshinone is add the 0.1mM rubescensine A solution and 1 μ LDMSO solution that have diluted in 1 μ LA, rock culture plate with mixing, it is placed in 37 DEG C, 5%CO2Incubator is cultivated 24 hours；
2.5 μMs of rubescensine A and cryptotanshinone drug combination group: every hole adds each concentration cryptotanshinone solution diluted in the 0.25mM rubescensine A solution and 1 μ LB diluted in 1 μ LA, rubescensine A 0 μM of control wells of 2.5 μMs of cryptotanshinones is add the 0.25mM rubescensine A solution and 1 μ LDMSO solution that have diluted in 1 μ LA, rock culture plate with mixing, it is placed in 37 DEG C, 5%CO2Incubator is cultivated 24 hours；
(3) in each porocyte suspension, add 15 μ LMTT solution (MTT test kit is purchased from Promega company, USA), be placed in 37 DEG C, 5%CO2Incubator is cultivated 4 hours；
(4) in (3), in each hole, add 100 μ LSTOP solution, be placed in 37 DEG C, 5%CO2Incubator is cultivated 24 hours；
(5) take out 96 well culture plates, under the exciting light of 570nm wavelength and 630nm wavelength, detect the light absorption value in each hole, A570-A630, it being the real light absorption value in each hole, reaction is the survival rate of cell in each hole, can calculate each porocyte Proliferation Ability situation under medicine effect accordingly.
5, experimental result
As shown in Figure 2, rubescensine A and being used in combination of cryptotanshinone can play significant synergistic function to result.
This drug regimen can substantially reduce and make leukaemia reach medicine total concentration corresponding during half proliferation inhibition rate: 1 μM of compatibility cryptotanshinone of rubescensine A 5 μMs (as shown in Figure 2) or rubescensine A 2.5 μMs of compatibility cryptotanshinones 2.5 μMs (as shown in Figure 2), and the consumption that makes of these two kinds of compatibility modes is not admitted to the scope that can body be damaged.
Claims (10)
1. Rabdosia rubescens associating Radix Salviae Miltiorrhizae application in the medicine of preparation leukemia prevention, treatment, auxiliary treatment and/or pre-rear defence recurrence.
2. rubescensine A associating cryptotanshinone application in the medicine of preparation leukemia prevention, treatment, auxiliary treatment and/or pre-rear defence recurrence, it is characterized in that, described rubescensine A or cryptotanshinone include rubescensine A or cryptotanshinone, and the combination of its pharmaceutically useful salt and ester, analog that selectivity replaces or one or more aforesaid compounds；Also include the derivant of the two or the solvate of the two and derivant thereof pharmaceutically acceptable salt or salt.
3. apply according to claim 2, it is characterised in that the molar concentration rate of rubescensine A and cryptotanshinone is 0.1～15:0.1～20.
4. apply according to claim 3, it is characterised in that when preparation is for the medicine of chronic myelogenous leukemia, the molar concentration rate of rubescensine A and cryptotanshinone is 5～10:3～7.5；When preparation is for the medicine of acute myeloid leukaemia, the molar concentration rate of rubescensine A and cryptotanshinone is 1～2.5:2.5～5.
5. apply according to claim 2, it is characterised in that the concentration of rubescensine A and cryptotanshinone coupling is respectively as follows: the concentration of rubescensine A compatibility less than 15 μMs, and the concentration of cryptotanshinone compatibility is less than 20 μMs.
6. treat leukemic pharmaceutical composition for one kind, it is characterized in that, comprise Rabdosia rubescens and the Radix Salviae Miltiorrhizae of effective dose, or comprise rubescensine A and the cryptotanshinone of effective dose, or comprise rubescensine A described in claim 2 or cryptotanshinone derivant and pharmaceutically acceptable salt thereof and ester, the compositions of analog that selectivity replaces or one or more aforesaid compounds.
7. pharmaceutical composition according to claim 6, it is characterized in that, described medicine Orally-administrable or drug administration by injection, also include acceptable pharmaceutical carrier and make various pharmaceutically acceptable preparation, including pin or freeze-dried powder, pill, decoction, tablet, granule, hard capsule, soft capsule, controlled release, slow releasing preparation, injection or oral formulations.
8. pharmaceutical composition according to claim 6, it is characterised in that also include more than one pharmaceutically acceptable excipient.
9. pharmaceutical composition according to claim 6, it is characterized in that, may also include other chemotherapeutics or antitumor and anticancer agent, anti-inflammatory drug or immunostimulant, hormone medicine, little molecular targeted agents, antibody drug, compound Chinese medicinal preparation and Chinese medicine extract and/or Chinese medicine monomer and derivant thereof.
10. the pharmaceutical composition described in claim 6 preparing the antileukemie medicine of attenuation synergistic, prevent leukemic medicine, improve the medicine of immunity of organisms, health care medicine or health food in application.
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| CN106635641A (en) * | 2016-12-22 | 2017-05-10 | 阜阳市殿兴农业科技有限公司 | Nutritional health care green tea/strawberry fruit wine |
| CN109864991A (en) * | 2019-03-15 | 2019-06-11 | 中山大学 | Cryptotanshinone is preparing the application in Ph+ acute lymphoblastic leukemia chemical therapy sensitivity-enhancing |
| CN111467367A (en) * | 2020-05-22 | 2020-07-31 | 陈炯 | Plant monomer composition for inhibiting tumor cell growth and preparation method and application thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106635641A (en) * | 2016-12-22 | 2017-05-10 | 阜阳市殿兴农业科技有限公司 | Nutritional health care green tea/strawberry fruit wine |
| CN109864991A (en) * | 2019-03-15 | 2019-06-11 | 中山大学 | Cryptotanshinone is preparing the application in Ph+ acute lymphoblastic leukemia chemical therapy sensitivity-enhancing |
| CN109864991B (en) * | 2019-03-15 | 2021-07-09 | 中山大学 | Application of cryptotanshinone in preparation of Ph + acute lymphocytic leukemia chemotherapy sensitization drug |
| CN111467367A (en) * | 2020-05-22 | 2020-07-31 | 陈炯 | Plant monomer composition for inhibiting tumor cell growth and preparation method and application thereof |
| CN111467367B (en) * | 2020-05-22 | 2021-08-17 | 陈炯 | Plant monomer composition for inhibiting tumor cell growth and preparation method and application thereof |
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