CN102038934B - Application of cucurmosin in preparation of drug for treating breast cancer - Google Patents
Application of cucurmosin in preparation of drug for treating breast cancer Download PDFInfo
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Abstract
The invention provides application of cucurmosin in preparation of drugs. A ribosome-inactivating protein, namely the cucurmosin, can be separated from pumpkin flesh; and the protein well displays the good tumor resisting activity and can be used for preparing antineoplastic drugs. The cucurmosin can strikingly restrain gastric cancer cells SGC7901 and hepatoma cells HepG2 Bel7404, tiny lung cancer cells A549, breast cancer cells MCF-7 and melanoma cells B16 which are cultured in vitro, has little inhibitory action on normal liver cells and PBLC of a person and displays obvious selection, and can strikingly restrain animal transplanted tumors, such as cervical cancer U14, melanoma cells B16, lung cancer Lewis and the like. Furthermore, the application proves that the induction apoptosis and the induction differentiation of the cucurmosin on the tumor resisting activity serve as an important mechanism.
Description
The application is a patent of invention: the application (applying date: 2005 year November 3 day of Cucurmosin in pharmacy; Application number: dividing an application 200510119741.2).
Technical field
The present invention relates to field of antineoplastic medicaments, relate in particular to the application of Cucurmosin in the preparation antitumor drug.
Background technology
Malignant tumor is the healthy disease of serious threat human life, and clinical chemotherapeutics commonly used has also damaged normal structure and cell greatly in killing tumor cell at present, and this has just limited its application.Searching is efficient, the medicine of the treatment tumor of low toxicity has become current cancer therapy drug research direction and urgent task.From natural materials, seek antitumor drug and be considered to a kind of valid approach, natural active matter is carried out Antitumor Effects, especially, will help to obtain ideal antitumor drug exploring aspect inhibition propagation and apoptosis-induced and the differentiation.
(ribosome-inactivating protein RIP) extensively is present in the higher plant ribosome inactivating protein, kind surplus the plant RIP about 80 that is separated to so far.Plant RIP is divided into amphitypy by the structure difference usually: I type RIP is a single chain protein, and (Trichosanthin TCS), occupies the majority in plant RIP like trichosanthin; II type RIP is the double-stranded albumen that connects through disulfide bond, like Ricin (ricin).They are one type of RNA N-glycosidase or polynucleotide: the adenosine glycosidase, it is active to have various biological such as antifertility, antiviral and antitumor.The research of plant RIP anti-tumor aspect cause for a long time people's interest: RIP to the lethal effect of tumor cell more than to Normocellular strong, the immunotoxin that especially is cross-linked into monoclonal antibody has targeting property and High Fragmentation effect to tumor cell.And relevant RIP antineoplastic mechanism thinks that at first the tumor cell due to the cytotoxicity that is RIP is downright bad, finds afterwards to produce through inducing apoptosis of tumour cell.
CN 1263107A provides isolated Class1 RIP-Cucurmosin (Cucurmosin) from Fructus Cucurbitae moschatae, and discloses its method for preparing.SDS-PAGE shows that its molecular weight is 27kDa, and isoelectric point, IP pI＞9 have the synthetic activity of strong inhibition intracellular nucleic sugar body protein.Cucurmosin has grown the monocrystalline that can supply X-ray diffraction to use, and crystal structure analysis is the result point out, Cucurmosin and trichosanthin have structural homology [Chen et al.Acta Cryst.D562000,665-666; Shi etal:Chinese J.struct.chem.2003,22 (2), 165-168].CN 1603340A provides Cucurmosin to have the anti-tumor activity of RNA N glycosidase activity and vitro inhibition Leukemia Cell Proliferation.
The present invention is based on above-mentioned prior art basis; Through experiment confirm Cucurmosin the solid tumor cell (gastric cancer, hepatocarcinoma, pulmonary carcinoma, breast carcinoma and melanoma etc.) and the mice-transplanted tumor (melanoma, cervical cancer and pulmonary carcinoma etc.) of In vitro culture had significant inhibitory effect; And little to the influence of people's normal liver cell strain L02 and PBLC, show obvious selectivity.Discover that through analyze cellular morphology observation, cell generation cycle and agarose gel electrophoresis mensuration etc. Cucurmosin has apoptosis-induced effect to solid tumor cells such as gastric cancer, hepatocarcinoma and melanomas.In addition, be model with the melanin tumour b16 cell, discover that through cellular morphology observation, flow cytometry analysis and melanin content mensuration etc. Cucurmosin still has the effect of the differentiation of inducing to MC; Apoptosis-induced and induction of differentiation to tumor cell exists simultaneously, but during low concentration to be induced to differentiate into the master, then have significant apoptosis-induced effect during high concentration.We find that first Cucurmosin can break up by inducing tumor cell, and inducing differentiation is its antineoplastic new mechanism.Cucurmosin is the important mechanisms of its anti-tumor activity to the apoptosis-induced and induction of differentiation of tumor cell.
Summary of the invention
The objective of the invention is provides the application of Cucurmosin in the antitumor pharmacy through research Cucurmosin anti-tumor activity in vivo and in vitro
Adopt gentle isolation and purification method; Comprise that strong or weak cation gel media secondary ion displacement chromatographies such as saline solution extracting, the filtration of DEAE-cellulose, CM-cellulose or SP-agarose separate; Can from pumpkin fruit, be separated to Cucurmosin, SDS-PAGE detection molecules amount is 27kDa.Be used for experiment behind chromatographically pure Cucurmosin (purity＞97%) the process filtering bacterium.
The invention provides the application of Cucurmosin as preparation treatment hepatocarcinoma, gastric cancer, breast carcinoma, pulmonary carcinoma, cervical cancer, melanoma medicine.
The specific embodiment
The drug action and the beneficial effect of Cucurmosin are described with concrete embodiment below:
Embodiment 1: Cucurmosin reaches the influence to human normal cell line to the inhibited proliferation of the tumor cell of In vitro culture
Tumor cell (the stomach cancer cell SGC of trophophase takes the logarithm
7901, HCC HepG
2, Bel
7404, non-small cell lung cancer cell A
549, breast cancer cell MCF-7 and MC B16) and people's normal liver cell L02 be inoculated on 96 well culture plates, every hole inoculum concentration is respectively 3000～4000/100 μ L and 6000/100 μ L; Aseptic collection healthy blood donor's venous blood 15mL, anticoagulant heparin separates mononuclearcell with the Ficoll density, and with the outstanding night of RPMI1640 preparation individual cells that contains 10% hyclone, transferring cell concentration is 2 * 10
5Individual/mL, be inoculated in 96 well culture plates, every hole 100 μ L.Behind above-mentioned each culture plate cell culture 24h, experimental group adds the Cucurmosin 100 μ L of variable concentrations, and each concentration is done three multiple holes; Negative control group Ensure Liquid liquid 100 μ l, Ensure Liquid liquid 100 μ L in blank hole are used for the instrument zeroing.Behind the effect different time (48h and 72h), every hole adds the MTT20 μ L of 5mg/mL, continues to cultivate 4h, gets rid of supernatant, and every hole adds dimethyl sulfoxine 150 μ L.Measure the absorbance (A in each hole of 570nm with ELIASA (BIO-RAD product)
570), each group is averaged, and calculates suppression ratio: suppression ratio=(1-experimental group A
570/ control group A
570) * 100%.Carry out statistical analysis with SPSS12.0, and calculate IC
50The result: Cucurmosin all has tangible inhibited proliferation to above-mentioned gastric cancer, hepatocarcinoma, breast carcinoma, nonsmall-cell lung cancer and MC, and is dose dependent and time dependence, the IC of its 48h
50From 9.77 to 36.91 μ g/mL, the IC of 72h
50From 1.94 μ g/mL to 13.54 μ g/mL; And Cucurmosin is less to people's normal liver cell and PBLC inhibitory action, the IC of its 48h
50Difference＞80 μ g/mL and＞40 μ g/mL, the IC of 72h
50Be respectively 27.30 μ g/mL and＞40 μ g/mL (table 1).It is thus clear that Cucurmosin has the obvious selectivity inhibitory action to tumor cell.
Table 1 Cucurmosin is to tumor cell and Normocellular half-inhibition concentration
Embodiment 2: Cucurmosin is to SGC
7901, HepG
2, Bel
7404, A
549, MCF-7 and the effect of B16 induced apoptosis
(1) Cucurmosin is to the influence of above-mentioned tumor cell form
1. fluorescence microscope: above-mentioned tumor cell is inoculated in respectively on a plurality of coverslipes; The Cucurmosin processing 24,48 and the 72h that add variable concentrations behind the 12h; Behind acridine orange (AO)/bromine second pyridine (EB) mixing fluorescent dyeing; Back-off is on microscope slide, and the morphology of observation of cell becomes under fluorescence microscope.The result: above-mentioned cell all can be observed early, mid-term apoptotic cell nucleus or Cytoplasm in the dense fine and close graininess yellow-green fluorescence that dyes is arranged, nuclear chromatin concentrates, nucleorhexis, typical apoptotic morphologic such as apoptotic body release change; Apoptosis reaches dose-dependence if having time simultaneously.
2. electron microscope observation: above-mentioned tumor cell uses 20 μ g/mL Cucurmosin effect 48h to be experimental group respectively, and the above-mentioned cell with normal cultured is a matched group simultaneously, and each organizes cell after 0.25% trypsinization; The centrifugal collecting cell deposition is fixed with the 2.5% glutaraldehyde-1% paraformaldehyde mixed liquor of 4 ℃ of pre-coolings, and is fixing behind 1% osmic acid; The epoxy resin embedding; Ultrathin section, the plumbous dyeing of acetic acid uranium and Fructus Citri Limoniae, transmission electron microscope (HITACHI Hu-12A type) is observed and is taken pictures.The result: the typical apoptotic morphological change all appears in above-mentioned tumor cell after the Cucurmosin effect, cell diminishes, and Cytoplasm concentrates, reticulum dilatation, and kernel disappears, and gather under nuclear membrane on the chromatin limit in the nucleus, visible karyopycnosis, karyorrhexis and apoptotic body; Apoptotic cell accounts for 15-20%.
(2) flow cytometry analysis: with 2 * 10
5After/mL is inoculated in and cultivates 12h in the culture bottle, add variable concentrations Cucurmosin solution and continue cultivation 24,48 and 72h, collecting cell, centrifugal 5 minutes of 2000r/min, after PBS washed 1 time, supernatant inclined.With 70% ethanol at 4 ℃ fixedly more than the 30min; The centrifugal fixative of removing; After PBS washes 1 time with propidium iodide (PI) solution (containing 0.005%PI, 0.1%Triton X-100,0.1mmol/L EDTA and 0.01%RNase A) in room temperature lucifuge dyeing 30min, last machine analysis.The result: above-mentioned tumor cell is behind processing 24,48 of variable concentrations Cucurmosin and 72h, at G
0/ G
1All there is highly different hypodiploid peaks the front at peak, and is tangible time and dose dependent.
(3) agarose gel electrophoresis detects cell DNA: collect the above-mentioned tumor cell of handling through 20 μ g/mL Cucurmosins 1～2 * 10 respectively
6Individual, the above-mentioned cell with normal cultured is contrast simultaneously.With PBS resuspension one time, add 200 μ L lysates (containing 10mmol/L Tris, 50mmol/L EDTA, 0.5%SDS), add 1 μ l E.C. 3.4.21.64 solution (20mg/mL) simultaneously; In 55 ℃ of digestion 4 hours, through phenol: chloroform: isoamyl alcohol (25: 24: 1) and chloroform: each extracting of isoamyl alcohol (24: 1) once, with dehydrated alcohol deposition, TE dissolving; Add RNase; 37 ℃ 30 minutes, add sample-loading buffer after, in 90V, 1.2% agarose gel electrophoresis 2h.Electrophoresis finishes, and on the ultraviolet visualization appearance, observes and takes pictures.The result: above-mentioned tumor cell is handled 72h through 20 μ g/mL Cucurmosins, all visible significantly DNA Ladder band.And the rarely seen genomic DNA band of matched group.
The result shows that Cucurmosin is to gastric cancer, and hepatocarcinoma, breast carcinoma, nonsmall-cell lung cancer and MC all have significant apoptosis-induced effect.
Embodiment 3: Cucurmosin is to the induction of differentiation (is model with the melanin tumour b16 cell) of tumor cell
(1) cellular morphology is observed: behind matched group and experimental group B16 cell culture 72h, respectively with phase contrast microscope and transmission electron microscope observation cellular morphology and take pictures.The result is following:
1. observation by light microscope: matched group B16 cell is the irregular growth of multilamellar, has eclipsed round cell; After the Cucurmosin effect, cell is certain polar growth, is arranged in parallel, and is not overlapping; Behind the 3d, Cucurmosin concentration is the above person of 2.5 μ g/mL, and cell polarity is obvious, and it is big that most cell volumes become, and has dendron shape structure, and iuntercellular is linked to be netted, poor growth, and cell number tails off.
2. electron microscopic observation: the visible more microvillus of matched group B16 cell surface, nucleus is most big and be oval, and nuclear is interior to be main with euchromatin, and the endochylema inner cell organ is less, and melanin granule is rare; After 20 μ g/mL Cucurmosins were handled 3d, the B16 cell volume is most to become big, and the surface is more smooth; Microvillus reduces; Nucleus reduces and is irregular, and heterochromatin increases in the nuclear, and the endochylema inner cell organ is abundant; It is thus clear that the melanosome in a large amount of different period of maturation, a large amount of melanosomes of part cell are assembled agglomerating.
(2) Cucurmosin is to the MC influence of proliferating cycle: collect the B16 cell of handling through 10 μ g/mL Cucurmosins 24 hours; The centrifugal 10min of 1500r/min; Deposition is fixed 12 hours through 70% ethanol, and PBS is resuspended after washing 2 times, with 300 order nylon net filters; With propidium iodide (PI) solution at room temperature lucifuge dyeing 30min, flow cytometry analysis.The result: the B16 cell after 10 μ g/mL Cucurmosins are handled 24h, G
2/ M phase cell reduces, and S phase cell obviously reduces, and G
0/ G
1The phase cytosis.The prompting Cucurmosin can stop the B16 cell by G
1Thereby the phase stagnates in G to S phase transition
1Phase.
(3) Cucurmosin is to the influence of MC melanin content: B16 cell to 6 orifice plate of inoculation exponential phase, every hole 1.5 * 10
5, every group 3 hole, d2 adds Cucurmosin; Final concentration is respectively 1.25,2.5,5 and 10 μ g/mL, washs 3 times 0.25% trypsinization, counting with PBS behind the effect 72h; The centrifugal 10min of 1000r/min; Cell precipitation is dissolved among the 1M NaOH-10%DMSO solution 1mL, and room temperature is placed 30min, measures trap value (A in the 400nm wavelength
400), the result is converted into 10
6The trap of cell.The result: matched group B16 cell melanin content is 0.040 ± 0.002 (A
400/ 10
6And 1.25,2.5,5 and 10 μ g/mL Cucurmosin group melanin contents are respectively 0.088 ± 0.007,0.165 ± 0.003,0.225 ± 0.006 and 0.309 ± 0.008 (A cell),
400/ 10
6Cell).It is thus clear that B16 cell melanin content obviously increases after Cucurmosin is handled.
The result shows that Cucurmosin has tangible induction of differentiation to MC.
Embodiment 4: Cucurmosin is to the inhibitory action of animal-transplanted tumor
(1) Cucurmosin is to the inhibitory action of cervical cancer U14: select that tumor growth is good, general body state tumor-bearing mice preferably; The cervical vertebra dislocation is put to death; Fixing back iodine tincture alcohol disinfecting, aseptic condition takes out the tumor piece down, with tumor (g) and normal saline (mL) with ratio homogenate in 1: 4 after; In subcutaneous vaccination ICR mice (quality certification SCXK (Fujian) 2004-0002), every 0.2mL.With the animal random packet and in inoculation 24h pneumoretroperitoneum drug administration by injection, establish 0.25,0.5 and three dose groups of 1mg/kg, establish cyclophosphamide group and normal saline matched group simultaneously, administration was 1 time in per 2 days, and after totally 5 times, the cervical vertebra dislocation is put to death, and takes by weighing body weight and tumor weight respectively.Calculate inhibition rate of tumor growth (%): inhibition rate of tumor growth %=(the average tumor of the average tumor weight/matched group of 1-administration group is heavy) * 100; And the result carried out statistical procedures.
The result: Cucurmosin 0.25,0.5 and 1mg/kg are to cervical cancer U
14All have the obvious suppression effect, suppression ratio is respectively 22.57%, 41.17% and 58.26% (table 2).
(2) Cucurmosin is to the inhibitory action of melanin tumour b16: melanin tumour b16 is measured the inhibitory action of Cucurmosin to melanin tumour b16 as stated above in subcutaneous vaccination mouse inbred lines C57 (quality certification SCXK (Shanghai) 2003-0003).
The result: Cucurmosin 0.25,0.5 and 1mg/kg all have the obvious suppression effect to melanin tumour b16, and suppression ratio is respectively 22.26%, 36.55% and 52.21% (table 3).
(3) Cucurmosin is to the inhibitory action of lung cancer Lewis: lung cancer Lewis is measured the inhibitory action of Cucurmosin to lung cancer Lewis as stated above in subcutaneous vaccination mouse inbred lines C57 (quality certification SCXK (Shanghai) 2003-0003).
The result: Cucurmosin 0.25,0.5 and 1mg/kg all have the obvious suppression effect to lung cancer Lewis, and suppression ratio is respectively 30.80%, 50.76% and 65.54% (table 4)
The influence (x+s) that table 2 Cucurmosin is heavy to mice U14 tumor
Annotate: compare with matched group,
*P＜0.01
The influence (x+s) that table 3 Cucurmosin is heavy to mice B16 tumor
Annotate: compare with matched group,
*P＜0.01;
* *P＜0.001
The influence (x+s) that table 4 Cucurmosin is heavy to the Mice Bearing Lewis tumor
Annotate: compare with matched group,
*P＜0.01;
* *P＜0.001
Can draw from above-mentioned experimental result, the beneficial effect of Cucurmosin of the present invention is: Cucurmosin significantly suppresses the stomach cancer cell SGC of In vitro culture
7901, HCC HepG
2, Bel
7404, non-small cell lung cancer cell A
549The propagation of breast cancer cell MCF-7 and MC B16; And less to people's normal liver cell and PBLC inhibitory action, show obvious selectivity, Cucurmosin also can obviously suppress animal-transplanted tumors such as cervical cancer U14, melanin tumour b16 and lung cancer Lewis in vivo.Therefore, the present invention confirms the inside and outside solid tumor resisting effect that the Cucurmosin tool is good.Cross cell morphologic observation, analysis cell generation cycle and agarose gel electrophoresis mensuration etc. and discover that Cucurmosin has apoptosis-induced effect to solid tumor cells such as gastric cancer, hepatocarcinoma and melanomas; In addition, be model with the melanin tumour b16 cell, discover that through cellular morphology observation, flow cytometry analysis and melanin content mensuration etc. Cucurmosin still has the effect of the differentiation of inducing to MC.Apoptosis-induced and induction of differentiation to tumor cell exists simultaneously, but during low concentration to be induced to differentiate into the master, then have significant apoptosis-induced effect during high concentration.Therefore, the present invention confirms that Cucurmosin has inducing tumor cell differentiation and effect of apoptosis mechanism.
Embodiment 5: Cucurmosin and trichosanthin are to the comparison of the inhibited proliferation of gastric cancer, hepatocarcinoma and MC
The gastric cancer SGC of trophophase takes the logarithm respectively
7901, hepatocarcinoma Bel
7404With the melanin tumour b16 cell, be inoculated on 96 well culture plates every hole inoculum concentration 3000～4000/100 μ l.Cultivate overnight after, experimental group adds the Cucurmosin or the trichosanthin 100 μ l of variable concentrations, each concentration is done three multiple holes; Negative control group Ensure Liquid liquid 100 μ l, Ensure Liquid liquid 100 μ l in blank hole are used for the instrument zeroing.Behind the effect different time (24,48,72 hours), every hole adds the MTT20 μ l of 5mg/ml, continues to cultivate 4 hours, gets rid of supernatant, and every hole adds dimethyl sulfoxine 150 μ l.With the absorbance in each hole of ELIASA (BIO-RAD product) mensuration 570nm, each group is averaged, and calculates suppression ratio.Suppression ratio=(1-experimental group OD value/matched group OD value) * 100%
The result sees table 5:
Table 5
Claims (1)
1. the application of Cucurmosin in preparation treatment breast cancer medicines.
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| CN1263107A (en) * | 1999-02-11 | 2000-08-16 | 中国科学院福建物质结构研究所 | Ribosome deactivated protein-pumpkin protein |
| CN1263106A (en) * | 1999-02-11 | 2000-08-16 | 中国科学院福建物质结构研究所 | Small molecule ribosome deactivated protein |
| CN1603339A (en) * | 2003-09-29 | 2005-04-06 | 中国科学院福建物质结构研究所 | Polypeptide ---N-terminal sequence polypeptide with squash protein |
| CN1603340A (en) * | 2003-09-29 | 2005-04-06 | 中国科学院福建物质结构研究所 | Antitumor activity of squash protein and use thereof |
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2005
- 2005-11-03 CN CN 201010166686 patent/CN102038934B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1263107A (en) * | 1999-02-11 | 2000-08-16 | 中国科学院福建物质结构研究所 | Ribosome deactivated protein-pumpkin protein |
| CN1263106A (en) * | 1999-02-11 | 2000-08-16 | 中国科学院福建物质结构研究所 | Small molecule ribosome deactivated protein |
| CN1603339A (en) * | 2003-09-29 | 2005-04-06 | 中国科学院福建物质结构研究所 | Polypeptide ---N-terminal sequence polypeptide with squash protein |
| CN1603340A (en) * | 2003-09-29 | 2005-04-06 | 中国科学院福建物质结构研究所 | Antitumor activity of squash protein and use thereof |
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| Title |
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