CN109864991A - Cryptotanshinone is preparing the application in Ph+ acute lymphoblastic leukemia chemical therapy sensitivity-enhancing - Google Patents
Cryptotanshinone is preparing the application in Ph+ acute lymphoblastic leukemia chemical therapy sensitivity-enhancing Download PDFInfo
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- CN109864991A CN109864991A CN201910200083.1A CN201910200083A CN109864991A CN 109864991 A CN109864991 A CN 109864991A CN 201910200083 A CN201910200083 A CN 201910200083A CN 109864991 A CN109864991 A CN 109864991A
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- Prior art keywords
- cryptotanshinone
- inhibitor
- drug
- acute lymphoblastic
- lymphoblastic leukemia
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Classifications
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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Abstract
The invention discloses application of the Cryptotanshinone in preparation acute lymphoblastic leukemia chemical therapy sensitivity-enhancing；And the application of Cryptotanshinone and anticancer drug combination in the drug of the treatment of preparation acute lymphoblastic leukemia and/or prophylactic agent, drug resistance inversion drug and/or the recurrence of pre- rear defence.The research of the invention finds that, when by Cryptotanshinone and anticancer drug combined effect, Cryptotanshinone can greatly increase leukaemia cell to the sensibility of anticancer drug, explosion type improves a variety of anticancer drugs to the proliferation inhibiting effect of acute lymphoblastic leukemia cell, to make the usage amount of each drug be far below the drug usage amount of Present clinical, and realize the effect of explosion type synergy.Therefore, chemical therapy sensitivity-enhancing of the Cryptotanshinone as effective acute lymphoblastic leukemia in the present invention has important research meaning and broad application prospect in treatment acute lymphoblastic leukemia and in terms of solving acute lymphoblastic leukemia resistance problems.
Description
Technical field
The invention belongs to biomedicine technical fields, more particularly, to Cryptotanshinone in preparation Ph+ acute lymphoblastic
Application in leukemia chemotherapy hypersitization medicine.
Background technique
Leukaemia is commonly called as " leukemia ", is a kind of Hematological malignancies disease for deriving from candidate stem cell, it is thin to be divided into lymph
Born of the same parents' leukaemia and myelocytic leukemia.Lymphocytic leukemia is divided into acute lymphoblastic leukemia (ALL) and chronic lymphatic
Chronic myeloid leukemia (CLL), wherein the disease progression of Ph+ acute lymphoblastic leukemia (Ph+ALL) is rapid, grade malignancy is high,
Poor prognosis.For the drug-TKI inhibitor (such as Imatinib) of targeting Philadelphia chromosome (Philadelphia, Ph), suffer from
Curative effect when person takes in the early stage is good, but offer limited effectiveness, while will occur drug resistance phenomenon quickly.
It is often selected TKI inhibitor (such as above situation in clinical treatment Ph+ acute lymphoblastic leukemia
Imatinib) it is used in combination with the cytotoxic chemotherapy agents (such as: cyclophosphamide, methotrexate) of wide spectrum, with enhancing
Curative effect of medication postpones drug resistance phenomenon.However, there is also very big problems in the application for above-mentioned therapy: firstly, being hindered with the cell cycle
Although Common Chemotherapy scheme based on stagnant medicine prevents the abnormality proliferation of leukaemia cell, but it is thin also seriously to hinder normal body
The division of born of the same parents；Second, chemotherapeutics metabolic process is complicated, damages to vitals such as the heart of patient, liver, kidneys serious；Third, often
Though disease can be alleviated rapidly with chemotherapy, easily generation drug resistance and recurrence.
And the advantages such as native compound is significant in efficacy with its, cheap and easy to get, toxic side effect is low attract the sight of people, it will
The native compound and existing anticancer drug that cell chemosensitivity can be increased are used in combination, and can not only lower medicine significantly
The usage amount of object reduces toxic side effect, can also delay or even avoid the generation of drug resistance phenomenon.Therefore, thin in Ph+ acute lymphoblastic
Born of the same parents' leukemia treating field, need to develop one kind can greatly enhance Ph+ acute lymphoblastic leukemia cell chemosensitivity,
Reverse the lesser natural drug of drug resistance and toxic side effect to anticancer drug.
Summary of the invention
The technical problem to be solved by the present invention is to overcome the defect of the above-mentioned prior art and deficiencies, provide a kind of acute lymphoblastic
Chronic myeloid leukemia chemical therapy sensitivity-enhancing.The research of the invention finds that Cryptotanshinone (Cryptotanshinone, abbreviation CPT) can
With anti-cancer agent in combination compatible use, cause the cooperative synergism effect of explosion type.Such as Imatinib (Imatinib, abbreviation IM),
The research of the invention finds that Cryptotanshinone can greatly increase white blood with using Imatinib as the TKI inhibitor compatible use of representative
Sick cell can improve a variety of anticancer drugs to acute lymphoblastic leukemia cell to the sensibility of anticancer drug with explosion type
Proliferation inhibiting effect realizes synergistic effect, so that the usage amount of each drug be made to use far below the drug of Present clinical
Amount achievees the effect that low dosage, high efficiency kill Ph+ acute lymphoblastic leukemia cell.Simultaneously the study found that Cryptotanshinone
With with triptolide (Triptolide, abbreviation TRI) be representative high toxicity anticancer drug and with qinghaosu
(Artemisinin, abbreviation ATS) is that the inefficient anticancer drug of representative distinguishes compatibility, can reach similar synergistic function,
Low dosage, high efficiency kill the effect of Ph+ acute lymphoblastic leukemia cell.Simultaneously as Chinese herbal medicine Cryptotanshinone low toxicity
And abundance, material are easy to get, and can greatly reduce drug in therapeutic process to the toxic side effect of body, and significantly reduce treatment
Cost.Therefore, Cryptotanshinone is expected to be developed into the chemical therapy sensitivity-enhancing for Ph+ acute lymphoblastic leukemia, is applied to
Prepare acute lymphoblastic leukemia treatment and/or prophylactic agent, acute lymphoblastic leukemia drug resistance inversion drug and/or
The drug of pre- rear defence recurrence improves in the drug of immunity of organisms, and is applied to acute lymphoblastic leukemia clinic and base
In the correlative study of plinth.
The first purpose of the invention is to provide Cryptotanshinones in preparation acute lymphoblastic leukemia chemical therapy sensitivity-enhancing
In application.
A second object of the present invention is to provide Cryptotanshinones and anticancer drug combination to prepare the white blood of acute lymphoblastic
The treatment and/or the application in prophylactic agent of disease.
Third object of the present invention is to provide Cryptotanshinones and anticancer drug combination to prepare the white blood of acute lymphoblastic
Application in sick drug resistance inversion drug and/or the drug of pre- rear defence recurrence.
Fourth object of the present invention is to provide a kind of therapeutic agent of acute lymphoblastic leukemia.
Above-mentioned purpose of the present invention is achieved through the following technical solutions:
The research of the invention finds that the Cryptotanshinone and anti-cancer agent in combination of denier (being greater than or equal to 1nmol/L) use
When, can make Cryptotanshinone itself and associated with anticancer drug dosage sharp fall, well below its be used alone IC50
Concentration (half-inhibitory concentration of cell Proliferation), and make acute lymphoblastic leukemia cell be proliferated inhibiting rate reach 66% with
On, cause the cooperative synergism effect of explosion type.Wherein, the effective activity of Cryptotanshinone is more than or equal to 1nmol/L.
Pass through research, it has been found that Cryptotanshinone is a kind of good acute lymphoblastic leukemia chemical therapy sensitivity-enhancing, be can be used for big
Width increases acute lymphoblastic leukemia cell to the drug susceptibility of anticancer drug；Using the preparation comprising Cryptotanshinone and/
Or Cryptotanshinone and anti-cancer agent in combination use and are applied to preparation acute lymphoblastic leukemia chemical therapy sensitivity-enhancing, can solve
The problem of weak curative effect as caused by drug is insensitive or drug resistance, recurrence or treatment failure.Wherein, due to Cryptotanshinone and
Imatinib is the drug of existing clinical application, and the drug combination mode of Cryptotanshinone and Imatinib can be rapidly in clinic
Mature application in acute lymphoblastic leukemia is treated, is no longer needed to by very long clinical stage, application prospect is very good.
Therefore, the following contents should all be within protection scope of the present invention:
The present invention provides application of the Cryptotanshinone in preparation acute lymphoblastic leukemia chemical therapy sensitivity-enhancing.
The chemical therapy sensitivity-enhancing is for increasing acute lymphoblastic leukemia cell to the sensibility of anticancer drug.
The Cryptotanshinone is as chemical therapy sensitivity-enhancing and anti-cancer agent in combination compatible use.
The present invention also provides Cryptotanshinone and anticancer drug combination preparation acute lymphoblastic leukemia treatment and/
Or the application in prophylactic agent；The Cryptotanshinone includes Cryptotanshinone, its pharmaceutical salt or ester, its derivative, its derivative
The combination of object pharmaceutically one or more of nano-grade matter of acceptable salt, its derivative.
The present invention also provides Cryptotanshinones and anticancer drug combination in preparation acute lymphoblastic leukemia drug resistance inversion
Application in drug and/or the drug of pre- rear defence recurrence；The Cryptotanshinone include Cryptotanshinone, its pharmaceutical salt or ester,
The combination of its derivative, its derivative pharmaceutically one or more of nano-grade matter of acceptable salt, its derivative.
The anticancer drug of this field routine is used equally in the present invention.
The anticancer drug can may be artificial synthesized anticancer drug for natural anti-cancer drugs, including but not limited to
One or more of anticancer chemotherapeutic agent, anti-inflammatory drug, immunostimulant, hormone medicine or small molecule targeted drug
Combination.
The anticancer drug includes but is not limited to antibody drug, anti-tumor Chinese medicine compound preparation, anti-tumor Chinese medicine extract
Or the combination of one or more of traditional Chinese medicine monomer and its derivative.
Particularly preferably, the anticancer drug be TKI inhibitor, c-Myc inhibitor, STAT5 phosphorylation inhibitor,
STAT3 phosphorylation inhibitor or Src inhibitor；The TKI inhibitor includes TKI inhibitor, its pharmaceutical salt or ester, it spreads out
The combination of biology, its derivative pharmaceutically one or more of nano-grade matter of acceptable salt, its derivative；It is described
C-Myc inhibitor includes that c-Myc inhibitor, its pharmaceutical salt or ester, its derivative, its derivative are pharmaceutically acceptable
Salt, its derivative one or more of nano-grade matter combination；The STAT5 phosphorylation inhibitor includes STAT5 phosphorus
Pharmaceutically acceptable salt, its derivative are received for acidification inhibitors, its pharmaceutical salt or ester, its derivative, its derivative
The combination of one or more of meter level substance；The STAT3 phosphorylation inhibitor include STAT3 phosphorylation inhibitor, its can
Medicinal salt or ester, its derivative, its derivative pharmaceutically one of nano-grade matter of acceptable salt, its derivative
Or several combination；The Src inhibitor includes that Src inhibitor, its pharmaceutical salt or ester, its derivative, its derivative exist
Pharmaceutically acceptable salt, its derivative one or more of nano-grade matter combination.
Preferably, the TKI inhibitor is Imatinib, Dasatinib, nilotinib or Ponatinib (ponatinib)
One or more of combination.
Preferably, the c-Myc inhibitor is the combination of one or both of triptolide or BET inhibitor.
Preferably, the STAT5 phosphorylation inhibitor is one in Imatinib, berberine, curcumin or tanshinone IIA
Kind or several combinations.
Preferably, the STAT3 phosphorylation inhibitor is qinghaosu, dihydroartemisinine, Artesunate, niclosamide
(Niclosamide), different Cryptotanshinone (Isocryptotanshinone), triptolide, vitexicarpin (Casticin)
Or the combination of one or more of Napabucasin.
Preferably, the Src inhibitor be saracatinib (Saracatinib), bosutinib (Bosutinib) or
The combination of one or more of Tirbanibulin.
Said medicine has the advantages that high-efficiency low-toxicity.
Preferably, ratio associated with the Cryptotanshinone and anticancer drug is 0.000025~100:1.
It is highly preferred that ratio associated with the Cryptotanshinone and anticancer drug is 0.000125~100:1.
It is further preferred that ratio associated with the Cryptotanshinone and anticancer drug is 0.00025~100:1.
Still further preferably, ratio associated with the Cryptotanshinone and anticancer drug is 0.0005~100:1.
Preferably, when Cryptotanshinone and TKI inhibitor are combined, ratio is 0.001~100:1.
It is highly preferred that ratio is 0.005~100:1 when Cryptotanshinone and TKI inhibitor are combined.
It is further preferred that ratio is 0.01~100:1 when Cryptotanshinone and TKI inhibitor are combined.
Still further preferably, when Cryptotanshinone and TKI inhibitor are combined, ratio is 0.02~100:1.
Preferably, when Cryptotanshinone and c-Myc inhibitor are combined, ratio is 0.01~50:1.
It is highly preferred that ratio is 0.05~50:1 when Cryptotanshinone and c-Myc inhibitor are combined.
It is further preferred that ratio is 0.1~50:1 when Cryptotanshinone and c-Myc inhibitor are combined.
Preferably, when Cryptotanshinone and STAT5 phosphorylation inhibitor are combined, ratio is 0.001~100:1.
It is highly preferred that ratio is 0.005~100:1 when Cryptotanshinone and STAT5 phosphorylation inhibitor are combined.
It is further preferred that ratio is 0.01~100:1 when Cryptotanshinone and STAT5 phosphorylation inhibitor are combined.
Still further preferably, when Cryptotanshinone and STAT5 phosphorylation inhibitor are combined, ratio is 0.02~100:1.
Preferably, when Cryptotanshinone and STAT3 phosphorylation inhibitor are combined, ratio is 0.000025~100:1.
It is highly preferred that ratio is 0.000125~100:1 when Cryptotanshinone and STAT3 phosphorylation inhibitor are combined.
It is further preferred that when Cryptotanshinone and STAT3 phosphorylation inhibitor are combined, ratio is 0.00025~
100:1.
Still further preferably, when Cryptotanshinone and STAT3 phosphorylation inhibitor are combined, ratio is 0.0005~100:
1。
The active constituent that synergism and attenuation is played in above-mentioned joint compatibility program is Cryptotanshinone.
Result of study shows, when Cryptotanshinone is more than or equal to 20nmol/L, Cryptotanshinone and TKI inhibitor (such as her horse
For Buddhist nun) pharmaceutical composition of compatibility, 76% or more may be up to the proliferation inhibition rate of Ph+ acute lymphoblastic leukemia cell；
When Cryptotanshinone is more than or equal to 10nmol/L, the medicine group of Cryptotanshinone and c-Myc inhibitor (such as triptolide) compatibility
Object is closed, 72% or more may be up to the proliferation inhibition rate of Ph+ acute lymphoblastic leukemia cell；When Cryptotanshinone is more than or equal to
When 20nmol/L, the pharmaceutical composition of Cryptotanshinone and STAT5 phosphorylation inhibitor (such as Imatinib) compatibility is acute to Ph+
The proliferation inhibition rate of lymphocytic leukemia cell may be up to 66% or more；It is hidden when Cryptotanshinone is more than or equal to 10nmol/L
The pharmaceutical composition of tanshinone and STAT3 phosphorylation inhibitor (such as qinghaosu) compatibility, it is thin to Ph+ acute lymphoblastic leukemia
The proliferation inhibition rate of born of the same parents may be up to 72% or more.The usage amount of above-mentioned Cryptotanshinone and anticancer drug compatibility mode is well below working as
The usage amount of preceding clinic, being not belonging to can be to the range that body damages.
The present invention also provides a kind of therapeutic agent of acute lymphoblastic leukemia, comprising a effective amount of Cryptotanshinone and
Anticancer drug；The Cryptotanshinone include Cryptotanshinone, its pharmaceutical salt or ester, its derivative, its derivative pharmaceutically
Acceptable salt, its derivative one or more of nano-grade matter combination.
Preferably, the anticancer drug is TKI inhibitor, c-Myc inhibitor, STAT5 phosphorylation inhibitor, STAT3 phosphorus
Acidification inhibitors or Src inhibitor；The TKI inhibitor include TKI inhibitor, its pharmaceutical salt or ester, its derivative, its
The combination of derivative pharmaceutically one or more of nano-grade matter of acceptable salt, its derivative；The c-Myc suppression
Preparation include c-Myc inhibitor, its pharmaceutical salt or ester, its derivative, its derivative pharmaceutically acceptable salt, it spreads out
The combination of one or more of the nano-grade matter of biology；The STAT5 phosphorylation inhibitor includes STAT5 inhibition of phosphorylation
The nano-grade matter of agent, its pharmaceutical salt or ester, its derivative, its derivative pharmaceutically acceptable salt, its derivative
One or more of combination；The STAT3 phosphorylation inhibitor includes STAT3 phosphorylation inhibitor, its pharmaceutical salt
Or ester, its derivative, its derivative pharmaceutically one or more of nano-grade matter of acceptable salt, its derivative
Combination；The Src inhibitor includes that Src inhibitor, its pharmaceutical salt or ester, its derivative, its derivative pharmaceutically may be used
The salt of receiving, its derivative one or more of nano-grade matter combination.
Preferably, the TKI inhibitor is Imatinib, Dasatinib, nilotinib or Ponatinib (ponatinib)
One or more of combination.
Preferably, the c-Myc inhibitor is the combination of one or both of triptolide or BET inhibitor.
Preferably, the STAT5 phosphorylation inhibitor is one in Imatinib, berberine, curcumin or tanshinone IIA
Kind or several combinations.
The STAT3 phosphorylation inhibitor is qinghaosu, dihydroartemisinine, Artesunate, niclosamide
(Niclosamide), different Cryptotanshinone (Isocryptotanshinone), triptolide, vitexicarpin (Casticin)
Or the combination of one or more of that parkacine (Napabucasin).
Preferably, the Src inhibitor be saracatinib (Saracatinib), bosutinib (Bosutinib) or
The combination of one or more of Tirbanibulin.
From another perspective, the anticancer drug can may be artificial synthesized anticarcinogen for natural anti-cancer drugs
Object, including but not limited to anticancer chemotherapeutic agent, anti-inflammatory drug, immunostimulant, hormone medicine or small molecule targeted drug
One or more of combination.
The anticancer drug includes but is not limited to antibody drug, anti-tumor Chinese medicine compound preparation, anti-tumor Chinese medicine extract
Or the combination of one or more of traditional Chinese medicine monomer and its derivative.
Particularly preferably, the anticancer chemotherapeutic agent can be below one or more for (but being not limited to): etoposide,
5 FU 5 fluorouracil, adriamycin, daunorubicin, epirubicin, cytarabine, isatin, cis-platinum, carboplatin, relies on pool at cyclophosphamide
Glycosides, topotecan, Irinotecan etc..
The anti-inflammatory drug can be below one or more for (but being not limited to): aspirin, sulindac, Tuo Mei
Spit of fland, Indomethacin etc..
The immunostimulant can be below one or more for (but being not limited to): interferon, cyclic adenosine monophosphate (c-
AMP), globulin etc..
The hormone medicine can for (but being not limited to) it is below one or more: glucocorticoid, estrogen, it is pregnant swash
Element etc..
The small molecule targeted drug can be below one or more for (but being not limited to): Imatinib
(Imatinib), Dasatinib (Dasatinib), nilotinib (Nilotinib), bosutinib (Bosutinib), Buddhist nun of relaxing replace
Buddhist nun (Sutent, Sunitinib), Sorafenib (Nexavar, Sorafenib), Lapatinib (Lapatinib), Iressa
(Gefitinib) etc..
The antibody drug can be below one or more for (but being not limited to): Mabthera (Rituximab,
Rituxan), He Saiting (Trastuzumab, Herceptin), Erbitux (Cetuximab, Erbitux), bevacizumab
(Bevacizumab, Avastin), Victibix (Panitumumab), Buddhist nun's trastuzumab (Nimotuzumab) etc..
The anti-tumor Chinese medicine compound preparation can be below one or more for (but being not limited to): arsenic tetrasulfide-tanshinone-indirubin, maple Siberian cocklebur are closed
Agent, dried venom of toads spirit etc..
The anti-tumor Chinese medicine extract can be below one or more for (but being not limited to): Ganodenna Lucidum P.E, rainbow conk
Extract, tuckahoe extracts, Semen Coicis extract etc..
The traditional Chinese medicine monomer and its derivative can be below one or more for (but being not limited to): taxol, camptothecine,
Homoharringtonine, isoflavones, ginsenoside, vincristine, colchicin, naringenin, rheum emodin, matrine, cucurbit
Element, aconine, baicalein, berberine, curcumin, qinghaosu, triptolide and derivative of above-mentioned all monomers etc.
Deng.
Preferably, the drug is oral preparation or ejection preparation.
Further, the drug may also include acceptable pharmaceutical carrier and/or pharmaceutically acceptable excipient；It can
Various pharmaceutically acceptable preparations, including tablet (controlled release tablet, sustained release tablets), granule, capsule (hard capsule, flexible glue is made
Capsule), pill, the oral preparations such as decoction, the injections such as freeze-dried powder.
Preferably, the pharmaceutical carrier includes that (but being not limited to) is below one or more: salt water, buffer, grape
Sugar, water, glycerol, ethyl alcohol, low molecular weight dextran, polyethylene glycol 400, Macrogol 6000, mannitol, lactose, glucose,
Sucrose, sodium chloride, sorbierite.
The preparation method of the drug of Cryptotanshinone and anticancer drug compatibility composition of the present invention does not do stringent limitation.In sterile item
Under part, injection can be made into, such as the aqueous solution with physiological saline or containing glucose and other adjuvants is prepared by a conventional method
It obtains；It can be made into tablets and capsules, be prepared by a conventional method to obtain.
, easily drug resistance and easy to recur problem insensitive to anticancer drug for acute lymphoblastic leukemia cell, this
Invention, which is proposed, is used to prepare acute lymphoblastic leukemia for the lesser Chinese herbal medicine effective ingredients Cryptotanshinone of toxic side effect
Hypersitization medicine is treated, specifically presses down Cryptotanshinone and TKI inhibitor (such as Imatinib), c-Myc inhibitor, STAT5 phosphorylation
The anticancer drugs such as preparation, STAT3 phosphorylation inhibitor or Src inhibitor carry out the drug combination of compatibility, and give specific
The inhibition situation of cell Proliferation under proportion compatibility and corresponding dosage.The research of the invention finds that the compatibility mode can greatly improve
Anticancer drug is to the proliferation inhibiting effect of acute lymphoblastic leukemia cell, under Cryptotanshinone participation effect, cell Proliferation
Rate declines in explosion type.
In addition, Cryptotanshinone provided by the invention and anticancer drug combination are in preparation prevention acute lymphoblastic leukemia
Application in drug, the drug for improving immunity of organisms, health medicine or health food；In enhanced sensitivity and/or kill acute lymphoblastic
The analytical reagent of cell leukemia cell, biochemical reagents, the application in detection reagent；Composition analyzed assessment and related pharmacology,
Application in drug effect and clinical research；Answering in the basic research of the related disciplines such as cell biology, molecular biology, medicine
With should all be within protection scope of the present invention.
In the present invention, it is preferable that the acute lymphoblastic leukemia is Ph+ acute lymphoblastic leukemia.
It is highly preferred that the Ph+ acute lymphoblastic leukemia is the acute lymphoblastic comprising BCR-ABL antigen-4 fusion protein gene
Leukaemia.
It is further preferred that the acute lymphatic leukaemia comprising BCR-ABL antigen-4 fusion protein gene is the acute leaching of Ph+
Bar cell leukemia cell line Sup-B15 cell.
Compared with prior art, the invention has the following advantages:
The present invention provides application of the Cryptotanshinone in preparation acute lymphoblastic leukemia chemical therapy sensitivity-enhancing, will be hidden
Tanshinone and anticancer drug carry out quantitative combined effect, can explosion type raising Cryptotanshinone and anticancer drug (Imatinib etc.
TKI inhibitor, c-Myc inhibitor, STAT5 phosphorylation inhibitor, STAT3 phosphorylation inhibitor or Src inhibitor) effect effect
Fruit with high-efficiency low-toxicity treats acute lymphoblastic leukemia；And the drug usage amount of above-mentioned compatibility mode is well below current
Clinical drug usage amount, being not belonging to can be to the range that body damages.In addition, Cryptotanshinone is a kind of natural diterpene
Quinones is mainly derived from Chinese tradition herbal medicine Radix Salviae Miltiorrhizae, and easily prepared and lower to human toxicity, application is strong.
Therefore, the chemical therapy sensitivity-enhancing that prepared by present invention Cryptotanshinone not only high-efficiency low-toxicity, and specificity is strong, takes effect
Fastly；And Cryptotanshinone and anticancer drug combination are in preparation acute lymphoblastic leukemia therapeutic agent, drug resistance inversion drug or pre-
Have great importance and broad application prospect in the drug of rear defence recurrence, is mentioned for targeted therapy acute lymphoblastic leukemia
Thinking is supplied, and for clinically efficiently treatment acute lymphoblastic leukemia provides new technology, new method and new tool.
Detailed description of the invention
Fig. 1 is that 20nmol/L, 100nmol/L, 500nmol/L and 1 μm of ol/L Cryptotanshinone combination her horse of various concentration are replaced
The compatibility of drugs mode of Buddhist nun, to the Proliferation Ability situation of Ph+ acute lymphoblastic leukemia cell strain Sup-B15 cell.
Fig. 2 is that the combination of 10nmol/L, 50nmol/L, 100nmol/L, 250nmol/L and 500nmol/L Cryptotanshinone is different
The compatibility of drugs mode of concentration triptolide presses down the proliferation of Ph+ acute lymphoblastic leukemia cell strain Sup-B15 cell
Situation processed.
Fig. 3 is the compatibility of drugs of 20nmol/L, 100nmol/L, 500nmol/L Cryptotanshinone combination various concentration qinghaosu
Mode, to the Proliferation Ability situation of Ph+ acute lymphoblastic leukemia cell strain Sup-B15 cell.
Specific embodiment
Further illustrate the present invention below in conjunction with specific embodiment, but embodiment the present invention is not done it is any type of
It limits.Unless stated otherwise, the present invention uses reagent, method and apparatus is the art conventional reagents, method and apparatus.
Unless stated otherwise, following embodiment agents useful for same and material are commercially available.
1 Cryptotanshinone of embodiment grinding in Ph+ acute lymphoblastic leukemia cell strain with Imatinib drug combination
Study carefully
The Cryptotanshinone and Imatinib for selecting a certain concentration gradient handle Ph+ acute lymphoblastic leukemia cell respectively
Strain Sup-B15 cell for 24 hours, while the concentration of fixed Cryptotanshinone, the Imatinib processing that different gradient concentrations are used in combination
It is strong that Sup-B15 cell calculates cell respective Proliferation Ability under five kinds of different drug-treated modes for 24 hours, with MTT colorimetric method
Degree.
Specific research method is as follows:
1, experimental cell strain
Sup-B15Ph+ acute lymphoblastic leukemia cell strain is purchased from U.S. ATCC cell bank.
2, cell culture:
Sup-B15 cell is carried out conventional with complete medium (containing the dual anti-RPMI-1640 culture medium of 10%FBS and 1%)
Cell culture uses 37 DEG C of constant temperature, 5%CO when culture2Condition carry out.
3, mother liquid medicine preparation experiment:
Take the Cryptotanshinone powder purchased from Selleck Chemicals company and the Imatinib powder purchased from Sigma company
End, weighing, and dissolved with DMSO solution, respectively to final concentration of 5mmol/L (CPT) and 30mmol/L (IM).
4, cell growth inhibition assay:
(1) cell is obtained
Take culture to the Sup-B15 cell of logarithmic growth phase, 1000rpm centrifugation 3min is collected, with containing 10% tire ox
Cell is resuspended in 1640 culture medium of RPIM of serum, and the concentration of cell suspension is adjusted to 3 × 105A/mL, with the amount in 98 holes μ L/
Above-mentioned cell suspension is accessed in 96 orifice plates, is placed in 37 DEG C, 5%CO2It is cultivated for 24 hours in incubator；
(2) agent-feeding treatment
A. take the 5mmol/L Cryptotanshinone mother liquor prepared with DMSO solution be diluted to working concentration (20nmol/L,
100nmol/L, 500nmol/L and 1 μm of ol/L) 100 times, therefore compound concentration be respectively 2 μm of ol/L, 10 μm of ol/L,
0.05mmol/L and 0.1mmol/L, piping and druming mix；
B. take the 30mmol/L Imatinib mother liquor prepared with DMSO solution be diluted to working concentration (10nmol/L,
50nmol/L, 100nmol/L, 500nmol/L and 1 μm of ol/L) 100 times, therefore compound concentration is respectively 1 μm of ol/L, 5 μm of ol/
L, 10 μm of ol/L, 0.05mmol/L and 0.1mmol/L, piping and druming mix；
C. the drug diluted is added in every hole cell suspension in step (1) in 96 orifice plates, is divided into Imatinib list
Private medicine group, 20nmol/L Cryptotanshinone are combined with Imatinib drug combination group, 100nmol/L Cryptotanshinone with Imatinib
Medication group, 500nmol/L Cryptotanshinone combine use with Imatinib with Imatinib drug combination group and 1 μm of ol/L Cryptotanshinone
Medicine group:
Imatinib independent medication group: each concentration Imatinib solution and 1 μ L diluted in 1 μ L step B is added in every hole
DMSO solution, Imatinib 0nmol/L control wells are that 2 μ L DMSO solutions are only added, and shake culture plate to mix, are placed in 37 DEG C,
5%CO2It is cultivated for 24 hours in incubator；
20nmol/L Cryptotanshinone and Imatinib drug combination group: the 2 μm of ol/ diluted in 1 μ L step A are added in every hole
Each concentration Imatinib solution diluted in L Cryptotanshinone solution and 1 μ L step B, Cryptotanshinone 20nmol/L Imatinib
0nmol/L control wells are that the 2 μm of ol/L Cryptotanshinone solution diluted in 1 μ L step A and 1 μ L DMSO solution is added, and shake training
Plate is supported to mix, is placed in 37 DEG C, 5%CO2It is cultivated for 24 hours in incubator；
100nmol/L Cryptotanshinone and Imatinib drug combination group: 10 μ diluted in 1 μ L step A are added in every hole
Each concentration Imatinib solution diluted in mol/L Cryptotanshinone solution and 1 μ L step B, her horse of Cryptotanshinone 100nmol/L
It is that the 10 μm of ol/L Cryptotanshinone solution diluted in 1 μ L step A and 1 μ L DMSO solution is added for Buddhist nun 0nmol/L control wells,
Culture plate is shaken to mix, is placed in 37 DEG C, 5%CO2It is cultivated for 24 hours in incubator；
500nmol/L Cryptotanshinone and Imatinib drug combination group: it has been diluted in 1 μ L step A of every hole addition
Each concentration Imatinib solution diluted in 0.05mmol/L Cryptotanshinone solution and 1 μ L step B, Cryptotanshinone 500nmol/
L Imatinib 0n mol/L control wells are that the 0.05mmol/L Cryptotanshinone solution and 1 μ L diluted in 1 μ L step A is added
DMSO solution shakes culture plate to mix, is placed in 37 DEG C, 5%CO2It is cultivated for 24 hours in incubator；
1 μm of ol/L Cryptotanshinone and Imatinib drug combination group: it has been diluted in 1 μ L step A of every hole addition
Each concentration Imatinib solution diluted in 0.1mmol/L Cryptotanshinone solution and 1 μ L step B, 1 μm of ol/L of Cryptotanshinone she
Imatinib 0nmol/L control wells are that the 0.1mmol/L Cryptotanshinone solution diluted in 1 μ L step A of addition and 1 μ L DMSO are molten
Liquid shakes culture plate to mix, is placed in 37 DEG C, 5%CO2It is cultivated for 24 hours in incubator；
(3) 15 μ LMTT solution (MTT kit is purchased from Promega company, USA) is added in each hole cell suspension, is placed in
37 DEG C, 5%CO24h is cultivated in incubator；
(4) 100 μ L STOP solution are added in each hole in step (3), are placed in 37 DEG C, 5%CO2It is cultivated in incubator
24h；
(5) 96 well culture plates are taken out, respectively at the extinction for detecting each hole under the exciting light of 570nm wavelength and 630nm wavelength
Value, A570-A630, as each true light absorption value in hole, reaction be cell in each hole survival rate, each hole cell can be calculated accordingly
Proliferation Ability situation under drug effect.
5, experimental result
As a result as shown in Fig. 1, the synergy that can play explosion type is used in combination in Cryptotanshinone and Imatinib
Effect, when 20nmol/L Cryptotanshinone compatibility 10nmol/L Imatinib, the survival rate of cell is only 24%, that is, be can inhibit
76% cell Proliferation, the usage amount of this compatibility mode well below the usage amount of current clinic, be not belonging to can be to body
The range damaged.
2 Cryptotanshinone of embodiment and triptolide drug combination are in Ph+ acute lymphoblastic leukemia cell strain
Research
The Cryptotanshinone of a certain concentration gradient is selected to handle Ph+ acute lymphoblastic leukemia respectively with triptolide thin
Born of the same parents' strain Sup-B15 for 24 hours, while fixing the concentration of anticancer drug triptolide, the hidden Radix Salviae Miltiorrhizae of different gradient concentrations is used in combination
Ketone handles Sup-B15 cell for 24 hours, calculates cell respective proliferation under four kinds of different drug-treated modes with MTT colorimetric method
Inhibition strength.
Specific research method is as follows:
1, experimental cell strain
Sup-B15Ph+ acute lymphoblastic leukemia cell strain is purchased from U.S. ATCC cell bank.
2, cell culture:
Sup-B15 cell is carried out conventional with complete medium (containing the dual anti-RPMI-1640 culture medium of 10%FBS and 1%)
Cell culture uses 37 DEG C of constant temperature, 5%CO when culture2Condition carry out.
3, mother liquid medicine preparation experiment:
Take the Cryptotanshinone powder purchased from Selleck Chemicals company and the triptolide purchased from Sigma company
Powder, weighing, and dissolved with DMSO solution, respectively to final concentration of 5mmol/L (CPT) and 20mmol/L (TRI).
4, cell growth inhibition assay:
(1) cell is obtained
Take culture to the Sup-B15 cell of logarithmic growth phase, 1000rpm centrifugation 3min is collected, with containing 10% tire ox
Cell is resuspended in 1640 culture medium of RPIM of serum, and the concentration of cell suspension is adjusted to 3 × 105A/ml, with the amount in 98 holes μ L/
Above-mentioned cell suspension is accessed in 96 orifice plates, is placed in 37 DEG C, 5%CO2It is cultivated for 24 hours in incubator；
(2) agent-feeding treatment
A. take the 5mmol/L Cryptotanshinone mother liquor prepared with DMSO solution be diluted to working concentration (10nmol/L,
50nmol/L, 100nmol/L, 250nmol/L and 500nmol/L) 100 times, therefore compound concentration is respectively 1 μm of ol/L, 5 μ
Mol/L, 10 μm of ol/L, 25 μm of ol/L and 50 μm of ol/L, piping and druming mix；
B. take the 20mmol/L triptolide mother liquor prepared with DMSO solution be diluted to working concentration (10nmol/L,
50nmol/L and 100nmol/L) 100 times, therefore compound concentration is respectively 1 μm of ol/L, 5 μm of ol/L and 10 μm of ol/L, and piping and druming is mixed
It is even；
C. the drug diluted is added in every hole cell suspension in step (1) in 96 orifice plates, is divided into triptolide
Independent medication group, 10nmol/L Cryptotanshinone and triptolide drug combination group, 50nmol/L Cryptotanshinone and tripterygium wilfordii first
Plain drug combination group and 100nmol/L Cryptotanshinone and triptolide drug combination group, 250nmol/L Cryptotanshinone and Thunder God
Rattan A prime drug combination group, 500nmol/L Cryptotanshinone and triptolide drug combination group:
Triptolide independent medication group: every hole be added each concentration triptolide solution for having been diluted in 1 μ L step B with
1 μ L DMSO solution, triptolide 0nmol/L control wells are that 2 μ L DMSO solutions are only added, and shake culture plate to mix, set
In 37 DEG C, 5%CO2It is cultivated for 24 hours in incubator；
10nmol/L Cryptotanshinone and triptolide drug combination group: 1 μ diluted in 1 μ L step A is added in every hole
Each concentration triptolide solution diluted in mol/L Cryptotanshinone solution and 1 μ L step B, Cryptotanshinone 10nmol/L thunder
Public rattan A prime 0nmol/L control wells are that the 1 μm of ol/L Cryptotanshinone solution diluted in 1 μ L step A of addition and 1 μ L DMSO are molten
Liquid shakes culture plate to mix, is placed in 37 DEG C, 5%CO2It is cultivated for 24 hours in incubator；
50nmol/L Cryptotanshinone and triptolide drug combination group: 5 μ diluted in 1 μ L step A are added in every hole
Each concentration triptolide solution diluted in mol/L Cryptotanshinone solution and 1 μ L step B, Cryptotanshinone 50nmol/L thunder
Public rattan A prime 0nmol/L control wells are that the 5 μm of ol/L Cryptotanshinone solution diluted in 1 μ L step A of addition and 1 μ L DMSO are molten
Liquid shakes culture plate to mix, is placed in 37 DEG C, 5%CO2It is cultivated for 24 hours in incubator；
100nmol/L Cryptotanshinone and triptolide drug combination group: 10 μ diluted in 1 μ L step A are added in every hole
Each concentration triptolide solution diluted in mol/L Cryptotanshinone solution and 1 μ L step B, Cryptotanshinone 100nmol/L thunder
Public rattan A prime 0nmol/L control wells are that the 10 μm of ol/L Cryptotanshinone solution diluted in 1 μ L step A of addition and 1 μ L DMSO are molten
Liquid shakes culture plate to mix, is placed in 37 DEG C, 5%CO2It is cultivated for 24 hours in incubator；
250nmol/L Cryptotanshinone and triptolide drug combination group: 25 μ diluted in 1 μ L step A are added in every hole
Each concentration triptolide solution diluted in mol/L Cryptotanshinone solution and 1 μ L step B, Cryptotanshinone 250nmol/L thunder
Public rattan A prime 0nmol/L control wells are that the 25 μm of ol/L Cryptotanshinone solution diluted in 1 μ L step A of addition and 1 μ L DMSO are molten
Liquid shakes culture plate to mix, is placed in 37 DEG C, 5%CO2It is cultivated for 24 hours in incubator；
500nmol/L Cryptotanshinone and triptolide drug combination group: 50 μ diluted in 1 μ L step A are added in every hole
Each concentration triptolide solution diluted in mol/L Cryptotanshinone solution and 1 μ L step B, Cryptotanshinone 500nmol/L thunder
Public rattan A prime 0nmol/L control wells are that the 50 μm of ol/L Cryptotanshinone solution diluted in 1 μ L step A of addition and 1 μ L DMSO are molten
Liquid shakes culture plate to mix, is placed in 37 DEG C, 5%CO2It is cultivated for 24 hours in incubator；
(3) 15 μ L MTT solution (MTT kit is purchased from Promega company, USA) is added in each hole cell suspension, sets
In 37 DEG C, 5%CO24h is cultivated in incubator；
(4) 100 μ L STOP solution are added in each hole in step (3), are placed in 37 DEG C, 5%CO2It is cultivated in incubator
24h；
(5) 96 well culture plates are taken out, respectively at the extinction for detecting each hole under the exciting light of 570nm wavelength and 630nm wavelength
Value, A570-A630, as each true light absorption value in hole, reaction be cell in each hole survival rate, it is thin that each hole can be calculated accordingly
Proliferation Ability situation of the born of the same parents under drug effect.
5, experimental result
As a result as shown in Fig. 2, Cryptotanshinone and triptolide be used in combination can play explosion type cooperate with increasing
Effect effect, as Cryptotanshinone 10nmol/L compatibility triptolide 10nmol/L, that is, can inhibit 72% cell Proliferation, this matches
The usage amount of 5 modes well below the usage amount of current clinic, be not belonging to can be to the range that body damages.
3 Cryptotanshinone of embodiment and research of the qinghaosu drug combination in Ph+ acute lymphoblastic leukemia cell strain
The Cryptotanshinone and qinghaosu for selecting a certain concentration gradient handle Ph+ acute lymphoblastic leukemia cell strain respectively
Sup-B15 for 24 hours, while the concentration of fixed anticancer drug Cryptotanshinone, the qinghaosu processing that different gradient concentrations are used in combination
It is strong that Sup-B15 cell calculates cell respective Proliferation Ability under four kinds of different drug-treated modes for 24 hours, with MTT colorimetric method
Degree.
Specific research method is as follows:
1, experimental cell strain
Sup-B15Ph+ acute lymphoblastic leukemia cell strain is purchased from U.S. ATCC cell bank.
2, cell culture:
Sup-B15 cell is carried out conventional with complete medium (containing the dual anti-RPMI-1640 culture medium of 10%FBS and 1%)
Cell culture uses 37 DEG C of constant temperature, 5%CO when culture2Condition carry out.
3, mother liquid medicine preparation experiment:
The Cryptotanshinone powder purchased from Selleck Chemicals company and the qinghaosu powder purchased from Sigma company are taken,
Weighing, and dissolved with DMSO solution, respectively to final concentration of 5mmol/L (CPT) and 80mmol/L (ATS).
4, cell growth inhibition assay:
(1) cell is obtained
Take culture to the Sup-B15 cell of logarithmic growth phase, 1000rpm centrifugation 3min is collected, with containing 10% tire ox
Cell is resuspended in 1640 culture medium of RPIM of serum, and the concentration of cell suspension is adjusted to 3 × 105A/ml, with the amount in 98 holes μ L/
Above-mentioned cell suspension is accessed in 96 orifice plates, is placed in 37 DEG C, 5%CO2It is cultivated for 24 hours in incubator；
(2) agent-feeding treatment
A. take the 5mmol/L Cryptotanshinone mother liquor prepared with DMSO solution be diluted to working concentration (20nmol/L,
100nmol/L and 500nmol/L) 100 times, therefore compound concentration is respectively 2 μm of ol/L, 10 μm of ol/L and 50 μm of ol/L, piping and druming
It mixes；
B. the 80mmol/L artemisinine mother solution prepared is taken to be diluted to working concentration (2.5 μm of ol/L, 5 μm of ol/ with DMSO solution
L, 10 μm of ol/L, 20 μm of ol/L and 40 μm of ol/L) 100 times, therefore compound concentration be respectively 0.25mmol/L, 0.5mmol/L,
1mmol/L, 2mmol/L and 4mmol/L, piping and druming mix；
C. the drug diluted is added in every hole cell suspension in step (1) in 96 orifice plates, it is independent to be divided into qinghaosu
Medication group, 20nmol/L Cryptotanshinone and qinghaosu drug combination group, 100nmol/L Cryptotanshinone and qinghaosu drug combination group
With 500nmol/L Cryptotanshinone and qinghaosu drug combination group:
Qinghaosu independent medication group: each concentration qinghaosu solution and 1 μ L DMSO diluted in 1 μ L step B is added in every hole
Solution, 0 μm of ol/L control wells of qinghaosu are that 2 μ L DMSO solutions are only added, and shake culture plate to mix, are placed in 37 DEG C, 5%CO2
It is cultivated for 24 hours in incubator；
20nmol/L Cryptotanshinone and qinghaosu drug combination group: the 2 μm of ol/L diluted in 1 μ L step A are added in every hole
Each concentration qinghaosu solution diluted in Cryptotanshinone solution and 1 μ L step B, 0 μm of ol/ of Cryptotanshinone 20nmol/L qinghaosu
L control wells are that 2 μm of ol/L Cryptotanshinone solution having diluted and 1 μ L DMSO solution in 1 μ L step A is added, shaking culture plate with
It mixes, is placed in 37 DEG C, 5%CO2It is cultivated for 24 hours in incubator；
100nmol/L Cryptotanshinone and qinghaosu drug combination group: the 10 μm of ol/ diluted in 1 μ L step A are added in every hole
Each concentration qinghaosu solution diluted in L Cryptotanshinone solution and 1 μ L step B, 0 μ of Cryptotanshinone 100nmol/L qinghaosu
Mol/L control wells are that the 10 μm of ol/L Cryptotanshinone solution diluted in 1 μ L step A and 1 μ L DMSO solution is added, and shake training
Plate is supported to mix, is placed in 37 DEG C, 5%CO2It is cultivated for 24 hours in incubator；
500nmol/L Cryptotanshinone and qinghaosu drug combination group: the 50 μm of ol/ diluted in 1 μ L step A are added in every hole
Each concentration qinghaosu solution diluted in L Cryptotanshinone solution and 1 μ L step B, 0 μ of Cryptotanshinone 500nmol/L qinghaosu
Mol/L control wells are that the 50 μm of ol/L Cryptotanshinone solution diluted in 1 μ L step A and 1 μ L DMSO solution is added, and shake training
Plate is supported to mix, is placed in 37 DEG C, 5%CO2It is cultivated for 24 hours in incubator；
(3) 15 μ L MTT solution (MTT kit is purchased from Promega company, USA) is added in each hole cell suspension, sets
In 37 DEG C, 5%CO2It is cultivated 4 hours in incubator；
(4) 100 μ L STOP solution are added in each hole in step (3), are placed in 37 DEG C, 5%CO2It is cultivated in incubator
24h；
(5) 96 well culture plates are taken out, respectively at the extinction for detecting each hole under the exciting light of 570nm wavelength and 630nm wavelength
Value, A570-A630, as each true light absorption value in hole, reaction be cell in each hole survival rate, it is thin that each hole can be calculated accordingly
Proliferation Ability situation of the born of the same parents under drug effect.
5, experimental result
As a result as shown in Fig. 3, being used in combination for Cryptotanshinone and qinghaosu can play the synergistic of explosion type and make
With as Cryptotanshinone 20nmol/L compatibility 2.5 μm of ol/L of qinghaosu, that is, can inhibit 66% cell Proliferation, this compatibility mode
Usage amount well below the usage amount of current clinic, be not belonging to can be to the range that body damages.
The preferred embodiment that the above specific embodiment is of the invention for ease of understanding and illustrates, but the invention is not limited to
Above-described embodiment does not mean that the present invention must rely on above-described embodiment and could implement.Person of ordinary skill in the field
It is the addition of equivalence replacement and auxiliary element to raw material selected by the present invention, specific it will be clearly understood that any improvement in the present invention
The selection etc. of mode, all of which fall within the scope of protection and disclosure of the present invention.
Claims (10)
1. application of the Cryptotanshinone in preparation acute lymphoblastic leukemia chemical therapy sensitivity-enhancing.
2. Cryptotanshinone and anticancer drug combination answering in the treatment of preparation acute lymphoblastic leukemia and/or prophylactic agent
With.
3. Cryptotanshinone and anticancer drug combination are multiple in preparation acute lymphoblastic leukemia drug resistance inversion drug and/or pre- rear defence
Application in the drug of hair.
4. application according to claim 2 or 3, which is characterized in that the anticancer drug is TKI inhibitor, c-Myc inhibition
Agent, STAT5 phosphorylation inhibitor, STAT3 phosphorylation inhibitor or Src inhibitor.
5. application according to claim 4, which is characterized in that the TKI inhibitor is Imatinib, Dasatinib, Buddhist nun
Replace the combination of one or more of Buddhist nun or Ponatinib in Lip river；The c-Myc inhibitor is in triptolide or BET inhibitor
One or two kinds of combinations；The STAT5 phosphorylation inhibitor is in Imatinib, berberine, curcumin or tanshinone IIA
One or more of combinations；The STAT3 phosphorylation inhibitor be qinghaosu, dihydroartemisinine, Artesunate, niclosamide,
The combination of one or more of different Cryptotanshinone, triptolide or vitexicarpin；The Src inhibitor is saracatinib
Or the combination of one or both of bosutinib.
6. any application according to claim 1~3, which is characterized in that the acute lymphoblastic leukemia is Ph+ anxious
Property lymphocytic leukemia.
7. application according to claim 2 or 3, which is characterized in that ratio associated with Cryptotanshinone and anticancer drug is
0.000025~100:1.
8. application according to claim 7, which is characterized in that ratio associated with Cryptotanshinone and anticancer drug is
0.000125~100:1.
9. application according to claim 4, which is characterized in that when Cryptotanshinone and TKI inhibitor are combined, ratio is
0.001~100:1；When Cryptotanshinone and c-Myc inhibitor are combined, ratio is 0.001~50:1；When Cryptotanshinone and
When STAT5 phosphorylation inhibitor is combined, ratio is 0.001~100:1；When Cryptotanshinone and STAT3 phosphorylation inhibitor are combined
When, ratio is 0.000025~100:1.
10. a kind of therapeutic agent of acute lymphoblastic leukemia, which is characterized in that include a effective amount of Cryptotanshinone and anticancer
Drug；The anticancer drug is TKI inhibitor, c-Myc inhibitor, STAT5 phosphorylation inhibitor, STAT3 phosphorylation inhibitor
Or Src inhibitor.
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| CN111000850A (en) * | 2019-12-23 | 2020-04-14 | 中山大学 | Application of cryptotanshinone in preparation of drug for overcoming drug resistance of EGFR-TKI used for treating NSCLC |
| CN112089842A (en) * | 2020-09-10 | 2020-12-18 | 中国医学科学院医学生物学研究所 | Target point c-FOS related to leukemia treatment and application thereof |
| WO2023246464A1 (en) * | 2022-06-24 | 2023-12-28 | 澳门大学 | Use of cryptotanshinone substance and combined composition thereof |
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| CN110433290A (en) * | 2019-03-15 | 2019-11-12 | 中山大学 | Cryptotanshinone and the combination of TKI inhibitor are preparing the application in Ph+ acute lymphoblastic leukemia chemotherapeutics |
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