CN103655613A - Application of arsenic trioxide and water-soluble object thereof in preparing medicine for treating pancreatic cancer - Google Patents
Application of arsenic trioxide and water-soluble object thereof in preparing medicine for treating pancreatic cancer Download PDFInfo
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- HJTAZXHBEBIQQX-UHFFFAOYSA-N 1,5-bis(chloromethyl)naphthalene Chemical compound C1=CC=C2C(CCl)=CC=CC2=C1CCl HJTAZXHBEBIQQX-UHFFFAOYSA-N 0.000 title claims abstract description 43
- 206010061902 Pancreatic neoplasm Diseases 0.000 title claims abstract description 31
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- 208000008443 pancreatic carcinoma Diseases 0.000 title claims abstract description 17
- 239000003814 drug Substances 0.000 title claims abstract description 13
- 201000002528 pancreatic cancer Diseases 0.000 title abstract description 11
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 36
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- 239000003752 hydrotrope Substances 0.000 claims description 11
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- 239000000890 drug combination Substances 0.000 claims description 10
- 229960005277 gemcitabine Drugs 0.000 claims description 9
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明属药物制药领域，具体涉及三氧化二砷及其水溶物亚砷酸作为SHH信号通路抑制剂在制备治疗癌胰腺癌药物的用途。本发明通过动物实验，将三氧化二砷以及联合给药干预荷人胰腺癌细胞株移植瘤裸鼠后，结果显示,三氧化二砷对胰腺癌移植瘤的产生具有显著的生长抑制作用，能下调胰腺癌细胞株移植瘤SHH末端成员GLI1蛋白及其靶基因的表达，下调肿瘤干细胞相关指标ALDH、CD24、CD44的表达，表明三氧化二砷在动物体内发挥SHH信号通路抑制剂的作用，并使GLI蛋白丧失活性，所述的三氧化二砷及其水溶物可作为SHH信号通路抑制剂用于制备治疗胰腺癌的药物。The invention belongs to the field of medicine and pharmacy, and specifically relates to the use of arsenic trioxide and its water-soluble product, arsenous acid, as an SHH signal pathway inhibitor in the preparation of medicines for treating cancer and pancreatic cancer. In the present invention, through animal experiments, arsenic trioxide and combined administration were used to intervene nude mice bearing transplanted tumors of human pancreatic cancer cell lines. The results showed that arsenic trioxide had a significant growth inhibitory effect on the generation of transplanted tumors of pancreatic cancer, and could down-regulate the growth of transplanted pancreatic cancer cell lines. The expression of GLI1 protein and its target genes, the terminal member of tumor SHH, down-regulated the expression of tumor stem cell-related indicators ALDH, CD24, and CD44, indicating that arsenic trioxide acts as an inhibitor of SHH signaling pathway in animals and inactivates GLI protein. The arsenic trioxide and its water solubles can be used as SHH signaling pathway inhibitors to prepare drugs for treating pancreatic cancer.
Description
Technical field
The invention belongs to medicine pharmaceutical field, relate to SHH signal pathway inhibitor, be specifically related to arsenic trioxide (chemical molecular formula: As
2o
3) and hydrotrope arsenious acid (chemical molecular formula H
3asO
3) as SHH signal pathway inhibitor, preparing the purposes for the treatment of cancer cancer of pancreas medicine.
Background technology
Studies show that, especially to neoplastic hematologic disorder, in the research of cerebroma and breast carcinoma, all confirmed the existence of tumor stem cell, also studies have found that a cell subsets of bringing into play main task in tumor occurs and develops, the expression CD44 that it is characterized in that peculiar property, CD24 and ESA(epithelial-specific antigen, the peculiar antigen of epithelial cell), studies show that, in pancreatic cancer cell, there is the cellular expression CD44+CD24+ESA+ of 0.2 – 0.8% that has an appointment, comparing it with other pancreatic cancer cell becomes cancer characteristic high 100 times, CD44+CD24+ESA+ pancreatic cancer cell can self replication, can break up daughter cell, performance stem cell characteristic, be considered to cancer of pancreas stem cell.High expressed Sonic Hedgehog (being called for short SHH, Chinese Chang Yizuo " Sonic hedgehog ") signal is the key character of cancer of pancreas stem cell.SHH signal path can or break up to maintain the stable of tissue by the regulation and control self replication of normal stem cell and the propagation of CFU-GM.The people such as Chenwei Li report that CD44+CD24+ESA+ cancer of pancreas stem cell approximately increases 46 times to the expression ratio Normal Pancreas cell of SHH mRNA, than the pancreatic cancer cell of CD44-CD24-ESA-or the somatic cell of pancreas carcinoma, approximately increase 4 times, prompting becomes tumor process all to have the participation of SHH signal path at the self replication of cancer of pancreas stem cell with cancer of pancreas, SHH signal plays a significant role at the self replication of cancer of pancreas stem cell and the forming process of tumor microenvironment.
Studies confirm that arsenic trioxide (chemical molecular formula: As
2o
3) contained arsenic element can be directly combined with the cysteine of " zinc refers to " structure of cancer protein PML end, induced protein occurred conformation changes and multimerization, Sumoization, ubiquitination occur then and degraded by proteasome, this is the leukemic main mechanism of the acute children's grain of arsenic trioxide in treatment.The end member GLI of SHH signal path has and PML protein similar zinc fingers, arsenic trioxide also can with GLI protein binding, cause GLI proteins lose transduction activity, blocking-up SHH signal, suppress the expression of its target gene, also can become a kind of SHH signal pathway inhibitor.
Summary of the invention
The object of the invention, for the new purposes of a kind of SHH signal pathway inhibitor in pharmacy is provided, is specifically related to arsenic trioxide and the hydrotrope thereof and in preparation, treats the purposes in cancer of pancreas medicine as SHH signal pathway inhibitor.
The present invention is by zoopery, using arsenic trioxide as SHH signal pathway inhibitor administration lotus human pancreas cancer cell strain transplanted tumor nude mice 5mg/Kg, the next day once, on this basis, give again low dose of gemcitabine, 15mg/Kg, weekly, after administering drug combinations is intervened, measure gross tumor volume, result shows, as the arsenic trioxide of SHH signal pathway inhibitor, the generation of cancer of pancreas transplanted tumor had to significant growth inhibited effect, and tumour inhibiting rate is 60.9% (P=0.004); Meanwhile, arsenic trioxide and the gemcitabine coupling as SHH signal pathway inhibitor, used, have no the untoward reaction that increases animal, and nude mice body weight does not show significant attenuating; Animal-transplanted tumor sample is carried out to immunohistochemistry and Western blot analysis, result shows the expression that arsenic trioxide can be lowered pancreas cancer cell strain transplanted tumor SHH end member's GLI1 albumen and target gene thereof, lower the expression of tumor stem cell index of correlation ALDH, CD24, CD44, show that arsenic trioxide brings into play the effect of SHH signal pathway inhibitor in animal body.
The present invention adopts laser co-focusing and Adenovirus Transfection to cross expression technology, observe the combination containing arsenic dyestuff and GLI1 albumen, and this cohesive process can be weakened by arsenic trioxide, first show that arsenic trioxide can be combined with GLI by contained arsenic element, cause GLI proteins lose active, meet the fundamental mechanism that suppresses SHH signal transduction activity.
Arsenic trioxide of the present invention and the hydrotrope thereof can be used as SHH signal pathway inhibitor for the preparation of the medicine for the treatment of cancer of pancreas.
Figure of description
Fig. 1 is each experimental group transplanted tumor in nude mice growth curve chart of the present invention.
Fig. 2 is each experimental group nude mice body weight change curve of the present invention.
Fig. 3 is each experimental group of the present invention Liu Yang immuning tissue fractional analysis representative graph.
Fig. 4 is that each experimental group tumor sample of the present invention Western Blot analyzes representative graph.
Fig. 5 is that the present invention tests Green fluorescent labeling GLI1 albumen and As2O3 interaction laser co-focusing observation figure.
Fig. 6 is after the SW1990 cell of GFP-GLI1 adenovirus expression carrier transfection during the present invention tests adopts arsenic trioxide to cultivate, then the observation figure that adopts ReAsH to process.
The specific embodiment
The present invention tests reagent and the raw material of employing:
RPMI 1640 culture medium (RPMI 1640+10% hyclone); Colleague CCK-8(chemical company product); ReAsH-EDT
2fluorescent dye (Invitrogen company product).
Human pancreas cancer SW1990, PANC-1 cell culture is in 1640+10%FBS culture fluid, 5%CO, 37 ℃ of cellar cultures.96 well culture plates, 5000 cells are implanted in every hole, and preculture, after 24 hours, adopts the above-mentioned M at 0-50 μ, the As of containing
2o
3the 1640+10%FBS culture fluid cellar culture of concentration range, after 24,48,72 hours, adds CCK-8 reagent, continues to hatch 2 hours microplate reader 450nm wavelength and detects every hole absorbance (OD), calculates as follows growth of tumour cell suppression ratio and cell viability.
Growth of tumour cell suppression ratio=(OD
blank-OD
experiment)/OD
blank* 100%
Cell viability=OD
experiment/ OD
blank* 100%
Result shows, As
2o
3can effectively suppress SW1990, the propagation of two kinds of human pancreas cancer cell strains of PANC-1, and with incubation time close association, the IC50 value that the IC50 value of 24 hours is respectively 27.3uM, 41.5uM.48 hour is respectively 15.1uM, 21.4uM, the IC50 value of 72 hours is respectively 7.2uM, 13.4uM, along with the prolongation of drug treating time, the effect that suppresses cell proliferation strengthens (as shown in Figure 1).
Embodiment 2 zooperies
Female nude mouse in 5 week age (purchased from Chinese science academy), SPF environment is raised, and first gets 5 nude mices, the subcutaneous injection of right side omoplate SW1990 cell 1 * 10
7/ only, after 3 weeks, tumor growth is to～500mm
3, conventional treatment nude mice, gets tumor piece, chooses eugonic two tumor pieces, is cut into the square fragment of 1mm * 1mm * 1mm, implants other 32 nude mices. and as grow to～200mm of nude mice lotus tumor
3during size (2 weeks), be divided at random 4 groups, 8 every group, specifically grouping and medication: (1) matched group: lumbar injection and drug combination group equal-volume normal saline; (2) gemcitabine group: lumbar injection gemcitabine hydrochloride, 15mg/kg, (3) arsenic trioxide group once in a week: lumbar injection arsenic trioxide, 5mg/Kg, the next day once, (4) drug combination group: lumbar injection gemcitabine hydrochloride, 15mg/kg, weekly, add lumbar injection arsenic trioxide, 5mg/Kg, the next day once.
Within every three days, by following formula, measure gross tumor volume:
Gross tumor volume computing formula: V=(L * W
2) * 0.5
In formula, L is tumor major diameter, and W is tumor minor axis.
Nude mice was treated after three weeks, at the 22nd day, all processed routinely, took out tumor piece, took pictures, and retained tumor tissues and carried out immunohistochemistry and Western Blot analysis of protein.
Gross tumor volume measurement result according to the 21st day, compare with matched group, gemcitabine group, arsenic trioxide group, drug combination group are respectively 23.6% (P=0.189), 22.8% (P=0.205) to the suppression ratio of tumor growth, with 60.9% (P=0.004), tumor growth curve as shown in Figure 2; Wherein drug combination group and the comparison of gemcitabine group, nude mice body weight does not significantly lower, and prompting adds with arsenic trioxide does not significantly increase the untoward reaction of gemcitabine group nude mice, and body weight change curve is as shown in Figure 3.
Get above-mentioned tumor sample and carry out immunohistochemical analysis, result shows, compares the coloured differently that gemcitabine, arsenic trioxide group and drug combination group all can be to CD24, CD44 and ALDH1A1 with matched group, but gemcitabine group difference is the lightest, drug combination group difference is the heaviest; In addition, ALDH1A1 is the Major Members of stem cell index ALDH, it is the most obvious to the expression difference of this albumen that each organizes tumor sample, wherein, arsenic trioxide group and drug combination group all have lowers the trend (as shown in Figure 4) that ALDH1A1 expresses, and shows that arsenic trioxide in treatment can reduce the ratio of cancer of pancreas stem cell in tumor tissue;
Get above-mentioned tumor sample and carry out Western Blot analysis, result shows, the expression of arsenic trioxide group and drug combination group SHH signal path end member GLI1 albumen all has downward, the target gene of while GLI1 albumen, PATCHED, the expression of WNT1 is obviously reduced (as shown in Figure 5), has verified that arsenic trioxide has the GLI of causing protein active and loses, the effect of blocking-up SHH signal path.
Embodiment 3 laser co-focusing experiments
In order further to confirm the interaction of arsenic trioxide and SHH signal path GLI albumen, the present invention adopts green fluorescent protein (GFP) and GLI and adenovirus vector restructuring (entrusting Shanghai Sheng Bo medical biotechnology Science and Technology Ltd.), form GFP-GLI1 adenovirus expression carrier, transfection SW1990 human pancreatic cancer cell, adopt and there is no the protein bound GPF adenovirus expression carrier of GLI1 transfection SW1990 cell as negative control simultaneously, after transfection 24 hours, choosing wherein one group of replacing contains 2.5 μ M arsenic trioxide, all the other are replaced by fresh culture medium, continue to cultivate after 24 hours, employing contains 2.5 μ M ReAsH-EDT
2(be called for short: under 37 ° of C conditions of Opti-MEM ReAsH) (Invitrogen) culture medium, transfection, after 30 minutes, by ReAsH-EDT2 guide for use, adopts 250 μ M BAL buffer solution to rinse well, and laser co-focusing is observed,
Result shows, in SW1990 cell after GFP-GLI1 adenovirus expression carrier and the transfection of GFP adenovirus expression carrier, all can be seen green fluorescence, but in the cell of GFP-GLI1 adenovirus expression carrier transfection, can observe the red fluorescence sending of ReAsH simultaneously, green fluorescence is identical with red fluorescence position, becomes yellow after overlapping; And in the cell of GFP adenovirus expression carrier transfection, can not observe red fluorescence; Simultaneously, after the SW1990 cell of GFP-GLI1 adenovirus expression carrier transfection adopts arsenic trioxide to cultivate, adopt again ReAsH to process, red fluorescence has the phenomenon (as shown in Figure 6) being reduced, show that arsenic trioxide is combined with GFP-GLI1 albumen in SW1990 cell, the fluorescent dye ReAsH that contains arsenic and the combination of GLI1 have been weakened, further confirm arsenic trioxide can by with GLI protein binding, performance, as the effect of SHH pathway inhibitor, is further used for the medicine of preparation treatment cancer of pancreas.
Claims (7)
1. arsenic trioxide and hydrotrope arsenious acid thereof are treated the purposes in cancer of pancreas medicine in preparation.
2. by the purposes of claim 1, it is characterized in that, described arsenic trioxide and hydrotrope arsenious acid thereof are as SHH signal pathway inhibitor.
3. by the purposes of claim 1, it is characterized in that, described arsenic trioxide and hydrotrope arsenious acid thereof suppress SW1990, the propagation of PANC-1 human pancreas cancer cell strain.
4. by the purposes of claim 1, it is characterized in that, described arsenic trioxide and hydrotrope arsenious acid thereof suppress pancreatic tumour growth.
5. by the purposes of claim 1, it is characterized in that, described arsenic trioxide and hydrotrope arsenious acid thereof reduce the ratio of cancer of pancreas stem cell in tumor tissue.
6. by the purposes of claim 1, it is characterized in that, described arsenic trioxide and hydrotrope arsenious acid thereof are lost GLI protein active, blocking-up SHH signal path.
7. by the purposes of claim 1, it is characterized in that described arsenic trioxide and hydrotrope arsenious acid thereof and gemcitabine drug combination.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104997807A (en) * | 2015-01-23 | 2015-10-28 | 复旦大学附属华山医院 | Application of arsenic trioxide in preparation of tumour immunomodulator |
| CN105535978A (en) * | 2016-01-30 | 2016-05-04 | 新乡医学院第一附属医院 | Tumor stem cell optional killing agent and application thereof |
| CN108670977A (en) * | 2018-07-23 | 2018-10-19 | 广西大学 | A kind of drug inhibiting tumor cell proliferation |
| CN110092765A (en) * | 2019-05-16 | 2019-08-06 | 上海交通大学医学院附属第九人民医院 | A kind of trivalent Arsenic-bearing gold ore and its preparation method and application |
| CN110101713A (en) * | 2019-05-16 | 2019-08-09 | 上海交通大学医学院附属第九人民医院 | A kind of application of arsenic trioxide composition |
| CN115990191A (en) * | 2022-11-04 | 2023-04-21 | 中山大学孙逸仙纪念医院 | A kind of antitumor pharmaceutical composition |
| WO2023070815A1 (en) * | 2021-11-01 | 2023-05-04 | 深圳先进技术研究院 | Method for inducing sumoylation of g1/s-specific cyclin-d1, use and preparation |
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