CN101991637B - Medicament for inducing apoptosis and application thereof - Google Patents
Medicament for inducing apoptosis and application thereof Download PDFInfo
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- CN101991637B CN101991637B CN 201010545659 CN201010545659A CN101991637B CN 101991637 B CN101991637 B CN 101991637B CN 201010545659 CN201010545659 CN 201010545659 CN 201010545659 A CN201010545659 A CN 201010545659A CN 101991637 B CN101991637 B CN 101991637B
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Abstract
The invention provides novel application of an astragalus mongholicus extract and a composition which comprises an astragalus mongholicus extract and a pharmaceutically acceptable vector and/or excipient. The composition can be used for treating tumors, especially for tumors in a blood system.
Description
The application be that March 9, application number in 2004 are 200410028632.5 the applying date, denomination of invention is the dividing an application of application for a patent for invention of " inducing cell is transferred medicine and the application thereof of dying ".
Technical field
The present invention relates to biomedicine field, particularly a kind of new purposes of the Radix Astragali and Radix Astragali extract.Radix Astragali extract can induce the hel cell programmatic dead, shows that Radix Astragali extract can be prepared into the treatment tumor, especially the medicine of hematological system tumor.
Background technology
Chinese herbal medicine is bright jewel in motherland's traditional medicine treasure-house.In recent years, caused Hesperian great attention.But relevant their molecular mechanism of action is still known little about it, and remains to be used the knowledge in modern age and technology to be illustrated.It is generally acknowledged that the Radix Astragali has the effect of enhancing human body immunity function, recently clinically, usually use it to alleviate chemotherapy and the caused toxic and side effects of radiotherapy.But relevant its definite Function and operation mechanism is not clear.
The Radix Astragali is a kind of Chinese medicine of tonifying Qi and lifting yang commonly used, now confirmed its have enhancing body non-specific, improve cardiac function, coronary artery dilator, inducing diuresis to remove edema, antibiotic, antiviral, promotion hemopoietic function, resisting fatigue, the anti-ageing effect of waiting for a long time.In order better to bring into play its effect and to make things convenient for clinical practice, its extracts active ingredients is out made injection, thereby improved curative effect, reduced untoward reaction, for bright prospects have been opened up in clinical practice.From present clinical practice, Radix Astragali injection reduces the aspects such as the respiratory system disease that causes and the nephrotic syndrome and shows preferably adjuvant treatment effect in cardiovascular disease, immunity.
The inventor is in the patent " medicine of induction-differential therapy and application thereof " of on October 29th, 1999 application, and application number 99119912.X discloses the Radix Astragali etc. and induced the eventually medicine of end differentiation of hematopoietic system cancer cell trend, has avirulence, the antineoplastic advantage.
The death of cell programmatic is an altitude mixture control process, and it and vegeto-animal growth promoter are closely related.Body is removed harmful cell by apoptosis, if make apoptosis process out of control because of various reasons, will cause the generation (for example, tumor, senile dementia etc.) of some diseases.So the research to the drug screening of inducing apoptosis of tumour cell and effect molecule mechanism thereof just seems very important, and to the design and development of newtype drug open a new approach.Have important theory significance and practice and be worth, also can bring larger economic benefit.
Summary of the invention
Purpose of the present invention just provides the Radix Astragali and the Radix Astragali extract new purposes in the medicine of preparation treatment tumor.
Another object of the present invention just provides a kind of pharmaceutical composition of new treatment tumor.
A first aspect of the present invention provides the application of the Radix Astragali in the medicine of preparation treatment tumor.Better, described tumor is hematological system tumor.
A second aspect of the present invention provides the application of Radix Astragali extract in the medicine of preparation treatment tumor.Better, described tumor is hematological system tumor.
A third aspect of the present invention provides a kind of compositions, it is characterized in that, described compositions comprises Radix Astragali extract and pharmaceutically acceptable carrier and/or the excipient of safe and effective amount.
Preferably, the dosage form of described compositions is tablet, capsule, oral liquid or injection.
As used herein, " Radix Astragali extract " refers to the Radix Astragali was boiled 30-180 minute with distilled water, removes block, filters to obtain Astragali Solution, with the Astragali Solution supernatant behind the high speed centrifugation at low temperatures.Then with the lyophilizing of gained supernatant, so that preserve.Usually be stored in about-20 ℃.
The present invention also provides a kind of pharmaceutical composition, and it contains the Radix Astragali extract of the present invention of safe and effective amount, and pharmaceutically acceptable carrier and/or excipient.This class carrier comprises (but being not limited to): saline, buffer, glucose, water and combination thereof.Pharmaceutical preparation should be complementary with administering mode.Pharmaceutical composition of the present invention can be made into the injection form, for example is prepared by conventional method with normal saline or the aqueous solution that contains glucose and other adjuvant.Pharmaceutical composition such as Tablet and Capsula can be prepared by conventional method.Pharmaceutical composition such as injection, solution, Tablet and Capsula should be made under aseptic condition.The dosage of active component is the treatment effective dose, for example every day about 6.0 mg/kg body weight of 1 microgram/kg body weight-Yue.In addition, Radix Astragali extract of the present invention also can use with the other treatment agent.Certainly, concrete dosage also should be considered the factors such as route of administration, patient health situation, and these all are within the skilled practitioners skill.In addition, the example of carrier and compound method can be referring to " Remington pharmaceutical science " (Remington ' sPharmaceutical Science).
The present invention also provides the method for the medicine of a kind of screening treatment tumor, especially hematological system tumor or chemical compound etc., comprises step:
(a) under the condition that is fit to growth, culture of tumor cell is wherein added candidate substances in the culture medium of first group of tumor cell, do not add candidate substances in the culture medium of second group of tumor cell;
(b) measure the activity of the apoptotic proteins enzyme activity factor 1 (Apaf-1) of first group and second group tumor cell, wherein this enzymatic activity of first group of tumor cell or lysate is higher than second group and just represents this material standed for mass-energy inducing apoptosis of tumour cell.
Better, described tumor cell is hel cell.Better, described method also comprises the activity of the proteinase-3 (Caspase-3) of first group of mensuration and second group of tumor (HEL) cell, and wherein this enzymatic activity of first group of tumor (HEL) cell is higher than second group and just represents that this candidate substances is can induced tumor (hematological system tumor) apoptosis.
It is experimental model that the inventor adopts hel cell (human erythroleukemia).When the hel cell of cultivating, after the adding Radix Astragali (4.5mg/ml) is induced 3-5 days, can impel hel cell to produce programmatic dead.Dosage and the induction time of its apoptotic degree and medicine are relevant.
The Radix Astragali is induced the research aspect of the molecule mechanism of hel cell apoptosis, and the inventor obtains following experimental result:
A) after the Radix Astragali is induced hel cell, apoptotic proteins enzyme activity factor 1 in this cell (Apoptotic protease-acting factor 1, expression APAF1), and the formation of apoptotic body have been promoted.
Use the immunofluorescence analysis method, observe in the hel cell of inducing with the Radix Astragali, be the APAF1 positive staining, the hel cell of not induced by the Radix Astragali dyeing that then is negative.Show induce hel cell with the Radix Astragali after, make the up-regulated of APAF1, thereby promoted the formation of apoptotic body.
B) after the Radix Astragali is induced hel cell, activated the vigor of proteinase-3 (Caspase-3).The result of immunofluorescence analysis method shows, induce hel cell with the Radix Astragali after, in apoptotic cell, proteinase-3 (Caspase-3) is activated, the dyeing that is positive, and in the hel cell of non-apoptosis, the proteinase-3 non-activity, dyeing is negative.
The above results shows: after the Radix Astragali is induced hel cell, the expression of APAF1 in the cell is increased.APAF1 can combine with the cytochrome C that mitochondrion discharges, and forms apoptotic body, activates successively apoptosis pathway middle and lower reaches protease, finally makes apoptosis of tumor cells.
This experiment has proved that first the Radix Astragali induces in the hel cell apoptotic process, relates to the mitochondrial apoptotic pathway that an APAF1 dependent protein enzyme activates.
C) Radix Astragali promotes the activity of acetylcholine esterase (AChE) in the hel cell.
Use the acetylcholine esterase Cytochemical staining method to prove: in the hel cell of the apoptosis of inducing with the Radix Astragali, the vigor of AChE is activated, and presents positive staining, in the hel cell of not induced by the Radix Astragali staining reaction that then is negative.
Use the immunofluorescence dyeing method, further disclosed in the apoptotic cell of inducing with the Radix Astragali and present positive staining, the hel cell of not induced by the Radix Astragali reaction that then is negative.
Above-mentioned experimental result has hinted that the AChE enzyme has also played an active part in the apoptotic process of the hel cell that the Radix Astragali induces.
Then, the inventor adopts the plastidogenetic nude mice entity tumor of K562, observes tumor and significantly dwindle behind the injection Radix Astragali, and the tumor of matched group is then without significant change.
1。After the present invention has proved first and induced hel cell with the Radix Astragali, cause that this cell produces programmatic dead.
2. the Radix Astragali is induced the hel cell apoptosis, has related at least the approach of the proteinase activated mitochondrion apoptosis of an APAF1 dependence.
3. have the function that suppresses tumor growth by the zoopery proof Radix Astragali, to reach the purpose for the treatment of tumor, particularly neoplastic hematologic disorder, more more remarkable than the curative effect of medication of inventor original application, clear and definite.The Radix Astragali also has and improves immunity of organisms and alleviate chemotherapy and the function such as the caused toxic and side effects of radiotherapy, has more shown the superiority of the Radix Astragali in oncotherapy.
Description of drawings
Fig. 1. the Radix Astragali is induced the hel cell apoptosis
(A) flow cytometry analysis: a and c are the hel cell of not inducing, and b and d are the apoptosis result of Radix Astragali extract induce respectively hel cell 3 days and 5 days.
(B) hel cell of transmission electron microscope analysis: a for not inducing amplifies 7040 times; B is the apoptotic cell that the Radix Astragali was induced three days, amplifies 7200 times.
(C) TUNEL analyzes: the hel cell of a for not inducing; B is the apoptotic cell that the Radix Astragali was induced three days.It is green that the cell of the TUNEL positive is.(gray in the accompanying drawing)
Fig. 2. the Radix Astragali is induced the up-regulated (cell amplifies 400 times) of Apaf-1 in the hel cell
(a) the Hoechst 33258 dyeing hel cell of not inducing;
The hel cell of (b) not inducing, the Apaf-1 immunostaining is negative;
(c) Hoechst 33258 dyeing Radix Astragali extracts are induced three days hel cell;
(d) Radix Astragali extract is induced three days hel cell, Apaf-1 immunostaining positive (arrow, (gray in the accompanying drawing) takes on a red color).
Fig. 3. the Radix Astragali induces the activity of caspase-3 in the hel cell to raise (cell amplifies 1000 times)
(a) the apoptosis-induced hel cell of Radix Astragali extract, caspase-3 dyeing are positive (long arrow indication is green (gray in the accompanying drawing)); Apoptotic cell is not negative;
(b) the apoptosis-induced hel cell (long arrow indication) of Hoechst 33258 dyeing Radix Astragali extracts dyes with Hoechst 33258, and genome is cracked; Apoptosis hel cell (arrow indication) nucleus is not complete;
(c) the optical microphotograph Microscopic observation Radix Astragali extract hel cell of inducing.The hel cell of apoptosis (long arrow indication) and the hel cell of apoptosis (arrow indication) not.
Fig. 4. the Radix Astragali is induced the detection (cell amplifies 400 times) of AChE in the hel cell
(A) according to the Karnovsky-Roots method hel cell is carried out CYTOCHEMICAL ANALYSIS:
The hel cell of (a) not inducing dyes with Hoechst 33258;
The hel cell of (b) not inducing, AChE dyeing is negative;
(c) Radix Astragali extract is induced three days hel cell, with Hoechst 33258 dyeing, amplifies 600 times;
(d) Radix Astragali extract is induced three days hel cell, AChE dyeing, and the apoptotic cell dyeing positive (sepia (gray in the accompanying drawing)) of arrow indication is amplified 600 times;
(e) Radix Astragali extract is induced five days hel cell, with Hoechst 33258 dyeing;
(f) Radix Astragali extract is induced five days hel cell, AChE dyeing, arrow indication apoptotic cell dyeing positive (sepia (gray in the accompanying drawing)).
(B) AChE immuning fluorescent dyeing analysis:
The hel cell of (a) not inducing is with Hoechst 33258 dyeing;
The hel cell of (b) not inducing, the AChE immunostaining is negative;
(c) Radix Astragali extract is induced three days hel cell, with Hoechst 33258 dyeing;
(d) Radix Astragali extract is induced three days hel cell, AChE immunostaining, apoptotic cell dyeing positive (green (gray in the accompanying drawing));
The tumor suppression analysis on animal model of Fig. 5, Radix Astragali extract
The A matched group is not injected Radix Astragali extract (solid tumor on average is about 1.1 centimetres);
The B experimental group, the injection Radix Astragali two weeks of extract (solid tumor on average is about 0.2,0.5 centimetre).
The specific embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used for explanation the present invention and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually according to people such as normal condition such as Sambrook, molecular cloning: laboratory manual (New York:ColdSpring Harbor Laboratory Press, 1989) condition described in, or the condition of advising according to manufacturer.
Embodiment 1 Radix Astragali is induced the experiment of hel cell apoptosis
Cell culture and cell death inducing: HEL and K562 cell (available from Shanghai life science institute of Chinese Academy of Sciences cell bank) contain 5%CO with the RPMI-1640 culture medium (GIBCO-BRL) that contains 10% calf serum at 37 ℃
2Cell culture incubator in cultivate.The Radix Astragali (Inner Mongol, the place of production) was boiled 60-90 minute with distilled water, remove block, filter and obtain Astragali Solution.With Astragali Solution high speed centrifugation at low temperatures, the supernatant lyophilizing is obtained Radix Astragali extract, and deposits in-20 ℃ for subsequent use.When inducing, in the hel cell of cultivating, press 4.5mg/ml and add Radix Astragali extract, cultivated 3-5 days.
Flow cytometry analysis: will induce with the centrifugal collection of hel cell of not inducing, be resuspended in the citrate solution with Radix Astragali extract.With suspension cell-20 ℃ freeze 20 minutes after, melt fast and centrifugal at 40 ℃.With cell dyeing, use the FACS flow cytometry analysis.Flow cytometry analysis is the result show: after hel cell is induced 5 days with the Radix Astragali (4.5mg/ml), have obvious apoptosis peak (～54.79%) to occur and see Figure 1A d, and the hel cell of not inducing does not detect apoptotic peak (Figure 1A c).
Transmission electron microscope analysis: will fix with the hel cell that Radix Astragali extract is induced and do not induced, dehydration, coated with Epon 812 resins.Sample dyes routinely and uses transmission electron microscope observing.Hel cell has produced change at morphocytology after inducing 3 days with the Radix Astragali: such as chromatic agglutination, (Figure 1B b) such as the formation of apoptotic body; And in the hel cell of non-apoptosis, (Figure 1B a) not detect change on the morphocytology.
B) detect apoptosis: TUNEL (Terminaldeoxynucleotidyl-transferase-mediated dUTP nick-end labeling) test kit available from Boehringer Mannheim company with the TUNEL test kit, according to the said firm's description operation, detect the apoptosis of cell.Result with fluorescence microscope record TUNEL detection.The TUNEL reaction detection is positive, and proves hel cell after the Radix Astragali is induced, and can cause that the hel cell programmatic is dead.Experimental result is seen Fig. 1 C.It is green that the cell of the TUNEL positive is.(gray point-like among the accompanying drawing 1Cb)
Embodiment 2 Radixs Astragali are induced the up-regulated experiment of Apaf-1 in the hel cell
Nuclei dyeing normal complexion morphologic observation: collect hel cell and fixing, be resuspended in Hoechst 33258 solution and dye, behind the smear, with fluorescence microscope and take pictures.
Immunofluorescence dyeing: will induce and the centrifugal collection of hel cell of not inducing with Radix Astragali extract, fixedly rear enclosed is 45 minutes, (the Apaf-1 polyclonal antibody is available from Santa Cruz company to add first primary antibodie, sc-8339) reaction is 30 minutes, two anti-(anti-rabbit is available from Rockland companies) that add again the Rhodamine labelling after the cleaning reacted 30 minutes.Fluorescence microscope after cleaning.After the Radix Astragali is induced hel cell, apoptotic proteins enzyme activity factor 1 in this cell (Apoptotic protease-acting factor 1, expression APAF1), and the formation (seeing Fig. 2 c, cell gray point-like) of apoptotic body have been promoted.
Use the immunofluorescence analysis method, observe in the hel cell of inducing with the Radix Astragali, the dyeing that is positive (redness (gray among the accompanying drawing 2d)), the hel cell of not induced by the Radix Astragali dyeing (Fig. 2 b) that then is negative.Show induce hel cell with the Radix Astragali after, make the up-regulated of APAF1, thereby promoted the formation of apoptotic body.
A) immunofluorescence dyeing: will induce and the centrifugal collection of hel cell of not inducing with Radix Astragali extract, fixedly rear enclosed is 45 minutes, add primary antibodie (Caspase 3 monoclonal antibodies are available from Santa Cruz company) reaction 30 minutes, two anti-(anti-Mus is available from Rockland companies) that add again the FITC labelling after the cleaning reacted 30 minutes.Fluorescence microscope after cleaning.After the Radix Astragali is induced hel cell, activated the vigor of proteinase-3 (Caspase-3).The result of immunofluorescence analysis method shows, after inducing hel cell with the Radix Astragali, in apoptotic cell, protease 1 (Caspase-3) is activated, the dyeing (green, in the accompanying drawing among the 3a gray) that is positive, and in the hel cell of non-apoptosis, proteinase-3 active, dyeing (Fig. 3) is negative.
The above results shows: after the Radix Astragali is induced hel cell, the expression of APAF1 in the cell is increased.APAF1 can combine with the cytochrome C that mitochondrion discharges, and has formed apoptotic body, activates successively apoptosis pathway middle and lower reaches protease, finally makes apoptosis of tumor cells.
The detection that embodiment 4 Radixs Astragali are induced AChE in the hel cell
AChE cytochemical staining: carry out the AChE cytochemical staining according to the method (J.Histochem.Cytochem.12:219-222,1964) of Karnovsky-Roots and analyze.Brown precipitate thing (gray in the accompanying drawing) represents the zone that the AChE enzyme is activated.The results show: in the hel cell of the apoptosis of inducing with the Radix Astragali, the vigor of AChE is activated, and presents the positive staining of brown (Fig. 4 Ad, gray among Fig. 4 Af), in the hel cell of not induced by the Radix Astragali staining reaction that then is negative.
Immunofluorescence dyeing: will induce and the centrifugal collection of hel cell of not inducing with Radix Astragali extract, fixedly rear enclosed is 45 minutes, (the AChE polyclonal antibody is available from Santa Cruz company to add first primary antibodie, sc-6431) reaction is 30 minutes, two anti-(anti-goat is available from Rockland companies) that add again the FITC labelling after the cleaning reacted 30 minutes.Fluorescence microscope after cleaning.Use the immunofluorescence dyeing method, further disclosed and in the apoptotic cell of inducing with the Radix Astragali, present green positive staining (gray among Fig. 4 Bd), the hel cell of not induced by the Radix Astragali reaction that then is negative.
Above-mentioned experimental result has hinted that the AChE enzyme has also played an active part in the apoptotic process of the hel cell that the Radix Astragali induces.
The tumor suppression analysis of embodiment 5 Radix Astragali extracts on animal model
Set up the nude mice solid tumor models with the K562 cell: with 1 * 10
6～10
7K562 injection cell to 4～5 nude mice by subcutaneous in all ages formed solid tumor about 10 days.Solid tumor is taken out homogenate, the homogenate cell is injected into the nude mice by subcutaneous in 4～5 ages in week, when treating tumor body length to a certain size about 10 days, injection Chinese medicine astragalus extract (10mg/g body weight), twice of a week.After two weeks, the nude mice of injection Radix Astragali extract, the tumor body obviously dwindles (Fig. 5 B); And nude mice of control group, tumor body continue to grow up (Fig. 5 A).
Embodiment 6 pharmaceutical compositions
First with Radix Astragali water rinse, after in vial, adding tri-distilled water and decocting, to remove slag, filtration, centrifugal, sterilization is mixed with injection with normal saline according to a conventional method, can be used for intramuscular injection or intravenous drip with the treatment leukaemic.
All quote in this application as a reference at all documents that the present invention mentions, just as each piece document is quoted separately as a reference.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.
Claims (1)
1. the application of Radix Astragali water extract in the medicine of the solid tumor that preparation inhibition human body erythroleukemia cell K562 forms.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1217207A (en) * | 1997-11-17 | 1999-05-26 | 王树民 | Shengxuebao-medicine for improving hematopoitic function |
| CN1302657A (en) * | 1999-10-29 | 2001-07-11 | 中国科学院上海细胞生物学研究所 | Medicine for induction-differential therapy and its application |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1217207A (en) * | 1997-11-17 | 1999-05-26 | 王树民 | Shengxuebao-medicine for improving hematopoitic function |
| CN1302657A (en) * | 1999-10-29 | 2001-07-11 | 中国科学院上海细胞生物学研究所 | Medicine for induction-differential therapy and its application |
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