CN102600142B - New application of peiminine in manufacturing gastric cancer multidrug resistance reversing medicaments - Google Patents
New application of peiminine in manufacturing gastric cancer multidrug resistance reversing medicaments Download PDFInfo
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Abstract
The invention relates to new application of peiminine in manufacturing gastric cancer multidrug resistance reversing medicaments. The molecular formula and the molecular weight of peiminie are respectively C27H43NO3 and 429.63522. The beneficial effects provided by the invention are as follows: peiminine is used as a reserving agent; and cytotoxicity tests show that peiminine can obviously increase the sensitivity of drug resistance cells SGC7901/VCR on chemotherapeutics when being used together with commonly applied chemotherapeutics such as VCR (vincristine), ADR (adriamycin), CDDP (cis-platinum) and 5-Fu (5-fluorouracil). The result points out that when peiminie is applied with the chemotherapeutics to inhibit proliferation of the drug resistance cells, the proliferation capacity and the drug resistance level of the drug resistance cells are reduced, IC50 (half inhibitory concentration ) of the chemotherapeutics is reduced, and the cytotoxicity is increased. Therefore, peiminine can not only inhibit the proliferation of gastric cancer cells but also has the function of reserving gastric cancer multidrug resistance.
Description
Technical field
the invention belongs to peiminine in the technical field of preparing reversing stomach multidrug resistance medicine, is that a kind of peiminine is in the new purposes of preparing reversing stomach multidrug resistance medicine.
Background technology
demand and the medication effect of current cancer therapy drug medical market
along with social city, industrialized acceleration, environmental contaminants and novel chemical substance increasing, in addition bad life style and behavioural habits, as irregular, the psychentonia of living, anxiety, eating and drinking without temperance, smoking and drinking, short-tempered, the very few impact that waits of moving, tumor has become one of harm humans life and healthy major disease.Malignant tumor not only serious threat the mankind's life and health, and causes white elephant to family, society, country, disturbs economic construction and social development.Therefore, the research and development of antitumor specific medicament receive medicine and biotechnology worker's very big concern always, become one of focus of bio-pharmaceuticals research.
in the development history of antitumor drug, what find at first is microbiology class medicine.The eighties in 20th century, middle and late stage was rather active period of antitumor microbial medicine research and development work, but because its side effect is larger, though can adopt monoclonal antibody coupling target administration to reduce toxic and side effects, but still can not meet the demand of the mankind to more perfect medicine.
tumor plant amedica is the main body of antitumor medication, accounts for 41% the market share, and this is relatively little relevant with the toxic and side effects of such medicine.China is universally acknowledged natural drug big country, in the state-owned application Chinese herbal medicine long history of curing the disease, so screen PTS from Chinese herbal medicine, there is advantageous advantage.
in the process for the treatment of cancer, the selection of its Therapeutic Method is very important.Mainly contain at present the conventional therapeutic scheme such as operation, chemotherapy, radiotherapy.Chemotherapy is one of Main Means for the treatment of gastric cancer, and radical cure adjuvant chemotherapy of patients can reduce relapse rate, improves survival rate; For patients with terminal, chemotherapy is major measure, and some patients were can obtain the state of an illness to be alleviated, and extends life cycle, improves the quality of living, and the Comprehensive Treatment that the chemotherapy of take is master is the trend for the treatment of now late gastric cancer.Although new cancer therapy drug and chemotherapy regimen are constantly released in recent years, but chemotherapy to the therapeutic effect of gastric cancer still without significantly improving, most of antitumor drug are in inhibition or killing tumor cell, normal tissue, organ inevitably produce infringement or toxic action, toxic reaction is often the restrictive factor of chemotherapy of tumors, and its untoward reaction can be for a long time or temporary influence patient's quality of life, the both dosage of limit treatment and the course for the treatment of, affect the treatment, even cause death.
chemotherapy is exactly unsuccessfully the unchanged even progress of tumor after chemotherapy.We will cause some possible reason of chemotherapy failure to be summarized as follows: (1) tumor has drug resistance to chemotherapeutics.(2) medicament selection is improper, and dosage is too small, and the persistent period is not enough.(3) systemic situation is poor.(4) in chemotherapy process, occur that hemogram obviously reduces, serious liver, renal function injury, make chemotherapy Halfway Stopping.(5) patient, because reacting the overweight chemotherapy of ending without authorization, makes chemotherapeutics not reach effective dosage.And the multidrug resistance (multidrug resistance, MDR) that tumor cell produces chemotherapeutics by Chinese scholars be known as cause chemotherapy failure main cause.Therefore find the approach of effective reversion MDR, to improving the therapeutic effect of gastric cancer, there is important clinical meaning.
refer to when tumor cell develops immunity to drugs to a kind of antitumor drug other structures antitumor drug different with the mechanism of action also produced to cross-resistance.
the overview of peiminine
(1) peiminine (PMI) is a kind of alkaloid being extracted from Bulbus Fritillariae Uninbracteatae, English name: Peiminine; Molecular formula: C
27
h
43
nO
3
; Molecular weight: 429.63522, No. CAS: 18059-10-4.Its structural formula is as follows:
(2) peiminine is extensively present in Bulbus Fritillariae Uninbracteatae class plant.Bulbus Fritillariae Cirrhosae, Bulbus Fritillariae Thunbergii, Bulbus Fritillariae Pallidiflorae, Bulbus Fritillariae Ussuriensis and Fritillaria wabuensis are all included by < < Chinese Pharmacopoeia > >.Bulbus Fritillariae Uninbracteatae derives from the bulb of Liliaceae Fritillaria various plants, has clearing heat and moistening lung, the effect of preventing phlegm from forming and stopping coughing.Alkaloid kind in Bulbus Fritillariae Uninbracteatae is many, is the effective ingredient of Bulbus Fritillariae Uninbracteatae cough-relieving, resolve phlegm effect.Bulbus Fritillariae Uninbracteatae is herbaceos perennial, and leaf is microscler, like fragrant-flowered garlic, and brightly yellowish green, sagging picture clock, its bulb hyoscine, has the merit of relieving cough and resolving phlegm, heat clearing away eliminating stagnation, originates in the ground such as Sichuan, Yunnan, Gansu, Xinjiang.Bulbus Fritillariae Uninbracteatae is rare medicinal herbs, can be rated as the treasured in medicine.After founding of New, once classify state plan management kind as, within 1980, changed market regulation production and marketing product later into.Over 40 years, the production of Bulbus Fritillariae Uninbracteatae has larger development, and annual production is by more than 40 ton of 2000 tons of left and right of developing into 2000 of early 1950s, and 2009 annual production estimations approach 3000 tons, the output value approaches 9,000 ten thousand yuan, possesses larger market supply ability and potentiality to be exploited.
(3) the extraction and purification method of peiminine:
the extracting method of peiminine roughly has 3 classes, and the one, traditional shaking table extraction, in order to improve alkaloidal extraction ratio, people are auxiliary microwave method and the ultrasonic method of having added also; The 2nd, percolation, the hydrochloric acid of available variable concentrations extracts; The 3rd, alcohol extracting method, methanol or the ethanol of conventional 80%-95% extract, and people also use cellulase pretreatment before alcohol extraction process, and the cellulose in degradation of cell wall promotes effective ingredient stripping, improves extraction ratio.
conventional purification process has: two kinds of purification by macroporous resin method and abstraction purification methods.
Summary of the invention
the invention provides a kind of peiminine in the new purposes of preparing reversing stomach multidrug resistance medicine.
technical scheme of the present invention realizes by following measures: a kind of peiminine is being prepared the new purposes of reversing stomach multidrug resistance medicine, and the molecular formula of this peiminine is C
27
h
43
nO
3
, molecular weight is 429.63522, its structural formula is as follows:
useful technique effect of the present invention: take peiminine as inversion agent, find peiminine and Common Chemotherapy medicine VCR through cytotoxicity experiment, ADR, CDDP, when 5-Fu share, can significantly improve the sensitivity of mdr cell SGC7901/VCR to chemotherapeutics.This results suggest, when peiminine and chemotherapy drugs in combination application suppress mdr cell propagation, the multiplication capacity of mdr cell declines, and resistance levels reduces, the IC of chemotherapeutics
50
value reduces, and the toxic action of cell is strengthened.Prove thus, peiminine can not only suppress the propagation of stomach cancer cell, also has Multidrug Resistance of Gastric Cancer reverse effect.
Accompanying drawing explanation
accompanying drawing 1 is with peiminine, to process the growth curve chart of rear SGC7901 and SGC7901/VCR cell.
accompanying drawing 2 is the affect figure of peiminine on P-gp expression.
accompanying drawing 3 is induced SGC7901/VCR apoptosis figure for flow cytometer detects peiminine associating 5-Fu.
accompanying drawing 4 is the variation diagram of caspase-3 expression after the medication of Western-Blot analysis joint.
accompanying drawing 5 is the apoptotic detection figure of peiminine associating 5-Fu inducible resistance, wherein, and a:5-Fu, b:PMI 20ug/ml, c:5-Fu+PMI 10ug/ml, d:5-Fu+PMI 15ug/ml, e:5-Fu+PMI 20ug/ml.
The specific embodiment
the present invention is not subject to the restriction of following embodiment, can determine concrete embodiment according to the technical scheme of the invention described above and practical situation.
below by embodiment, the invention will be further described:
embodiment 1, and this peiminine is being prepared the new purposes of reversing stomach multidrug resistance medicine, and the molecular formula of this peiminine is C
27
h
43
nO
3
, molecular weight is 429.63522, its structural formula is as follows:
the medical usage that this peiminine is new: the multidrug resistance that 20ug/ml peiminine can reversing stomach cell, significantly improves the sensitivity of mdr cell to Common Chemotherapy medicine.The inhibitory action that peiminine has gastric cancer parental cell and mdr cell, its related experiment data are as follows:
(1) toxicity test of peiminine to SGC7901 and SGC7901/VCR cell
by MTT colorimetry, detect the inhibitory action of peiminine to parental cell SGC7901 and mdr cell SGC7901/VCR growth.Along with the increase of peiminine concentration, two kinds of cells survival rate reduce gradually.The results show, the growth that peiminine not only can suppress parental cell also can suppress the growth of mdr cell, as shown in the figure, the half-inhibition concentration (IC of peiminine to two kinds of cell lines
50
) be respectively 76.71 ± 3.01ug/ml and 65.98 ± 2.27ug/ml; Under the effect of 20ug/ml peiminine, the cell survival rate of drug resistance and parental cell is all greater than 90%.So concentration is when being less than 20ug/ml, we think that peiminine is to the effect of two kinds of cell no cytotoxicities, are the non-toxic dosage of peiminine to two kinds of cell lines.Can avoid like this can not tolerating because of cytotoxic effect or the excessive body causing of dosage.Refer to accompanying drawing 1.
(2) peiminine of non-toxic dosage can make mdr cell strengthen the sensitivity of Common Chemotherapy medicine
in at present conventional chemotherapeutics, we select 4 kinds of vincristine (VCR), amycin (ADR), cisplatin (CDDP) and 5-fluorouracil (5-Fu) etc. to test, after peiminine and chemotherapy drugs in combination medication, the survival rate of mdr cell reduces greatly, chemotherapeutics is obviously strengthened, with the half-inhibition concentration (IC of medicine to the toxic action of cell
50
) be judge index.As shown in subordinate list 1: IC when A is alone chemotherapeutics
50
value, B is the IC after drug combination
50
value, B value, lower than A value, illustrates that peiminine can reduce the IC of chemotherapeutics
50
, make chemotherapeutics enhanced sensitivity, the reversal index of VCR, ADR, CDDP and 5-Fu is respectively: 16.61,6.27,6.40,7.18 times, reach the effect of reversing drug resistance.
(3) flow cytometer detects the impact that peiminine is accumulated ADR in cell
increase drug efflux, reducing accumulating of medicine in cell is the one of the main reasons that causes multidrug resistance.Detect ADR in cell and accumulate, reflected intracellular drug level.ADR is a kind of antitumor drug with spontaneous red fluorescence characteristic, by flow cytometer, can detect ADR relative amount in cell, and sensitive, accurate, can be quantitatively.By flow cytometer, detect and can find out, cultivate altogether after 1h with 5ug/ml amycin, in SGC790l/ VCR cell, the average fluorescent strength of ADR is compared with 6.02 times of SGC790l Leukopenias, add PMI and the ADR of variable concentrations to cultivate altogether after 1h, along with the intracellular ADR fluorescence intensity of increase of peiminine concentration increases gradually, more alone ADR has increased respectively 1.94,2.38,3.23 times, and has obvious dose dependent.Illustrate that peiminine can increase the savings of ADR in SGC7901/VCR mdr cell, reduce drug efflux, reach the effect of reversing drug resistance.As shown in subordinate list 2.
(4) peiminine can be lowered the expression of SGC7901/VCR cell P-glycoprotein (P-gp)
transmembrane transporter P-gp causes in the outer row of medicine and cell that drug accumulation reduces and causes tumor cell to produce MDR, is to cause the one of the main reasons for the treatment of unsuccessfully with cancer return.P-gp is the main target spot of reversing tumor as classical drug resistance-associated proteins, and genus ATP is a kind of in conjunction with boxlike transmembrane protein superfamily.Can directly combine with chemotherapeutics, power consumption outside Concentraton gradient transporte to cells, reduces chemotherapeutics at the lethal effect of the slightly weak many tumor cells of intracellular valid density by medicine in cell.Protein immunoblot (Western Blot) experimental result shows, when the definite applied sample amount of internal reference (β-actin) is identical, the peiminine of 10ug/ml and 20ug/ml acts on SGC7901/VCR cell 48h and compares with matched group, and the expression of P-gp albumen has obvious downward trend.Medicine-resistant cell line SGC7901/VCR high expressed P-gp(gray value is high), the low expression of parental cell line SGC7901 P-gp(gray value is low); Peiminine under non-toxic dosage is alone or share the equal P-gp expressing quantity of medicine-resistant cell line SGC7901/VCR that can make with ADR and lower.As shown in Figure 2.
(5) flow cytometer detects peiminine associating 5-Fu induction SGC7901/VCR apoptosis
the anti-apoptosis capacity that reduces tumor cell is also another important channel of reverse multiple drug resistance of tumor, flow cytometer can be quantitative the total cell number of detection in the number of apoptosis cell, apoptosis is divided into early apoptosis (Ru Tu Q4 district) and apoptosis in late period (Ru Tu Q2 district).Experiment is divided into 5 groups, a negative control group: use separately chemotherapeutics 5-fluorouracil (5-Fu), b blank group: use separately non-toxic dosage peiminine PMI 20ug/ml, c experimental group one: chemotherapeutics and peiminine drug combination 5-Fu+PMI 10ug/ml d experimental group two: chemotherapeutics and peiminine drug combination 5-Fu+PMI 15ug/ml e experimental group three: chemotherapeutics and peiminine drug combination 5-Fu+PMI 20ug/ml.Testing result as shown in the figure, when alone 5-Fu and PMI (as Fig. 4 a, 4b), percentage of cell apoptosis is less than 15%, but when 5-Fu combines variable concentrations peiminine, percentage of cell apoptosis increases gradually (as Fig. 4 c, 4d, 4e), be respectively: 17.8%, 29.5%, 44.5%.Proof thus, peiminine associating 5-Fu can inducible resistance apoptosis, reaches the effect of reversing drug resistance.As shown in Figure 3.
(6) Western-Blot method detects caspase-3 and expresses variation
caspase family belongs to the special cysteine proteinase of aspartic acid, closely related with apoptosis.Most important a member in Caspase-3 Shi Qi family, on apoptotic co-route, one of apoptotic crucial executor, in apoptosis, play irreplaceable effect, caspase-3 can be activated by many factors, after activation, will become Cleaved-caspase-3, the latter is the former activated form.By Western-Blot method, detect caspase-3 and Cleaved-caspase-3 expression variation, experiment is divided into 5 groups, a negative control group: use separately chemotherapeutics 5-fluorouracil (5-Fu), b blank group: use separately non-toxic dosage peiminine PMI 20ug/ml, c experimental group one: chemotherapeutics and peiminine drug combination 5-Fu+PMI 10ug/ml d experimental group two: chemotherapeutics and peiminine drug combination 5-Fu+PMI 15ug/ml e experimental group three: chemotherapeutics and peiminine drug combination 5-Fu+PMI 20ug/ml.Experimental result explanation, after drug combination along with the increase of drug dose, the expression of caspase-3 increases (as shown in Figure 4) gradually, when heavy dose is induced, the caspase-3(35kd of total length) be activated as cleaved caspase-3(17kd and 19kd), proof thus, drug combination really can cell death inducing, and it may be with to activate caspase-3 apoptosis pathway relevant.
(7) cellular immunofluorescence method detects the expression variation of cleaved caspase-3
the fluorescence staining difference that detects peiminine drug combination cell death inducing with the Caspase 3 Activation test kits of Cellomics company, operates imaging under laser confocal microscope after dyeing according to test kit description.After Hoechst dyeing, Normocellular nucleus is normal blueness, and the nucleus of apoptotic cell can be fine and close dense dying, or is fine and close dense the dying of chunky shape, and color is a bit shinny.Experiment is divided into 5 groups, a negative control group: use separately chemotherapeutics 5-fluorouracil (5-Fu), b blank group: use separately non-toxic dosage peiminine PMI 20ug/ml, c experimental group one: chemotherapeutics and peiminine drug combination 5-Fu+PMI 10ug/ml d experimental group two: chemotherapeutics and peiminine drug combination 5-Fu+PMI 15ug/ml e experimental group three: chemotherapeutics and peiminine drug combination 5-Fu+PMI 20ug/ml.As shown in the figure, a, b group nucleus is normal blueness, proves acellular apoptosis phenomenon.C, d, e organize karyopyknosis, and color is shinny, prove thus, and drug combination can make apoptosis.Cleaved caspase-3 be a kind of when apoptosis the albumen of endochylema high expressed, utilize immunofluorescence method to make its fluorescence redly, as shown in Figure 5, a, b group redfree fluorescence bright spot, proves acellular apoptosis phenomenon.C, d, e group have red fluorescence bright spot in corresponding Hoechst fluorescence bright spot position, and the expression that Cleaved caspase-3 can be detected in the cell that apoptosis occurs is described.So can prove, drug combination really can cell death inducing, and its mechanism is with to activate the apoptosis pathway such as caspase-3, generation spliced body Cleaved caspase-3 relevant.
in sum, we take peiminine as inversion agent, through cytotoxicity experiment, find, and peiminine and Common Chemotherapy medicine VCR, ADR, CDDP, when 5-Fu share, can significantly improve the sensitivity of mdr cell SGC7901/VCR to chemotherapeutics.This results suggest, when peiminine and chemotherapy drugs in combination application suppress mdr cell increment, the competence for added value of mdr cell declines, and resistance levels reduces, the IC of chemotherapeutics
50
value reduces, and the toxic action of cell is strengthened.Prove thus, peiminine can not only suppress the propagation of stomach cancer cell, also has Multidrug Resistance of Gastric Cancer reverse effect.Increase drug efflux, reducing intracellular drug accumulation is the one of the main reasons that causes MDR.With flow cytometry, directly measure the average fluorescent strength of ADR in cell, peiminine makes drug-resistant cell strain greatly recover ADR picked-up and accumulating capability.Western Blot detects the expression of P-gp albumen and finds: the P-gp protein expression that peiminine is processed rear mdr cell is starkly lower than not medication group and vincristine processed group, and peiminine concentration is larger, and difference is more obvious.This proof, peiminine can, by regulating P-gp protein expression, suppress the effect that drug efflux reaches its reversing drug resistance.The anti-apoptosis capacity that reduces tumor cell is also another important channel of reversion MDR.Experimentation proves, the inducible resistance apoptosis that peiminine can dose dependent.Along with the increase of drug dose, apoptosis is more obvious, illustrates that chemotherapeutics is significantly strengthened the lethality of mdr cell, its mechanism with activate caspase-3, to produce the apoptosis pathway such as spliced body Cleaved caspase-3 relevant, have nothing to do with BAX/bcl-2.In vivo in animal experiment study, the peiminine of finding 1.5mg/ ml is safety non-toxic to Babl/c mice.
Claims (1)
1. peiminine improves the purposes of mdr cell SGC7901/VCR to chemotherapy drug susceptibility medicine in preparation, and described chemotherapeutics is vincristine, amycin, cisplatin and 5-fluorouracil; The molecular formula of this peiminine is C
27h
43nO
3, molecular weight is 429.63522, its structural formula is as follows:
。
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| CN1245057A (en) * | 1998-08-19 | 2000-02-23 | 中国人民解放军军事医学科学院百环生物医学研究中心 | Reversing agent for multi-medicine resistance of tumor cells |
| CN102327571A (en) * | 2011-09-30 | 2012-01-25 | 四川大学 | New cancer-resisting use of fritillaria cirrhosa total alkaloids and compounds contained in fritillaria cirrhosa total alkaloids |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1245057A (en) * | 1998-08-19 | 2000-02-23 | 中国人民解放军军事医学科学院百环生物医学研究中心 | Reversing agent for multi-medicine resistance of tumor cells |
| CN102327571A (en) * | 2011-09-30 | 2012-01-25 | 四川大学 | New cancer-resisting use of fritillaria cirrhosa total alkaloids and compounds contained in fritillaria cirrhosa total alkaloids |
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