CN104031128B - A kind of interleukin-33 inhibitor polypeptide and application thereof - Google Patents
A kind of interleukin-33 inhibitor polypeptide and application thereof Download PDFInfo
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- CN104031128B CN104031128B CN201410281948.9A CN201410281948A CN104031128B CN 104031128 B CN104031128 B CN 104031128B CN 201410281948 A CN201410281948 A CN 201410281948A CN 104031128 B CN104031128 B CN 104031128B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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Abstract
The present invention relates to pharmaceutical field, be specifically related to that there is suppression interleukin-33, the polypeptide of carcinoma of the pancreas can be treated.Its sequence is KVLLSYYESQHPSNESGDDGG is brand-new sequence, and useful benefit of the present invention is that this polypeptide can suppress interleukin-33 to be expressed in body, treatment carcinoma of the pancreas.Suppress the propagation of human pancreatic cancer cell ASPC-1; Improve tumor-bearing mice survival rate in vivo; There is pharmaceutical use.
Description
Technical field:
The present invention relates to pharmaceutical field, being specifically related to for suppressing IL-33 to express, the interleukin-33 inhibitor polypeptide for the treatment of carcinoma of the pancreas.
Background technology:
Carcinoma of the pancreas is the digestive tract tumor that a kind of grade malignancy is very high, and prognosis is very poor.The histological type of carcinoma of the pancreas is a lot, and the duct adenocarcinoma wherein from conduit cuboidal epithelium is the most common, accounts for 99%, its is fine and close and hard, and wetting property is strong, and does not have obvious boundary, normal with fibrosis hyperplasia and inflammatory reaction, be difficult to distinguish with chronic inflammatory diseases lump, easily cause mistaken diagnosis.Although the cause of disease of carcinoma of the pancreas is still not clear, by the multifactor impact of h and E.But increasing evidence shows, certainly exists association between carcinoma of the pancreas and chronic inflammatory diseases.Pancreatic gland fibrosis is caused by too much extracellular matrix (ECM) deposits in pancreas, this is the pathologic characteristic that chronic pancreatitis and carcinoma of the pancreas have, a kind of flesh fibroblast-like cells similar to hepatic stellate cell (HSCs) on morphological and biological characteristics is there is in pancreatic tissue, be called pancreatic stellate cells (PSCs), this cell can express A-smooth muscle actin (A-SMA), synthesize too much collagen and ECM, play a significant role in pancreatic gland fibrosis process.Research shows, observes the high expression level of IL-33 in the myofibroblast of pancreas, pancreatic acini and ductal epithelial cell.Confirm that IL-33 take part in the pathologic, physiologic of pancreatic gland fibrosis and chronic pancreatitis, and can the propagation of stimulating pancreas myofibroblast and migration, and then participate in developing of carcinoma of the pancreas.
IL-33, in pancreatitis or carcinoma of the pancreas pathologic process, interacts with a lot of cytokine.(1) in chronic fibrosis process, IL-33 constantly promotes the propagation of endotheliocyte, migration and differentiation, and then promotes that blood vessel occurs, and reduces cell adhesion protein-interacting and improves vascular permeability, provides condition for tumour; (2) IL-33 can work in coordination with the secretion of raising IL-6 with IL-1 again.IL-6 is important close inflammatory mediator, plays the effect promoting tumor growth and inhibited apoptosis in multiple human tumor.Regulate NF-κ B mainly through JAK/STAT approach, NF-κ B regulates again tumor-blood-vessel growth and invasion and attack, and likely causes the generation of the specific tumor cells to chemotherapy resistance, comprising pancreatic cancer cell; (3) IL-33 can also stimulate separately the release of IL-8.In tumour cell and microenvironment thereof, IL-8 increases with the expression of its acceptor, promotes propagation and the survival of endotheliocyte and tumour cell, and strengthens the migration of cell at tumor locus.It is the important factor that carcinoma of the pancreas occurs that IL-33 function raises.Therefore, suppressing IL-33 to express, suppress carcinoma of the pancreas development, is the novel targets for the treatment of carcinoma of the pancreas.But, the medicine of the treatment carcinoma of the pancreas of the IL-33 inhibitor polypeptide not yet having exploitation ripe.
Summary of the invention:
The invention provides brand-new sequence, this sequence IL-33 inhibitor polypeptide, has good curative effect to carcinoma of the pancreas.
Technical scheme
Technical solution of the present invention is to provide a kind of interleukin-33 inhibitor polypeptide 2, and its sequence is KVLLSYYESQHPSNESGDDGG, and the application in treatment pancreatic cancer drug.
Beneficial outcomes:
Interleukin-33 inhibitor polypeptide 2 sequence KVLLSYYESQHPSNESGDDGG in the present invention, can express by targeted inhibition interleukin-33, suppresses the effect of IL-33, reach the effect for the treatment of carcinoma of the pancreas.
Through great many of experiments, contriver knows that interleukin-33 inhibitor polypeptide 2 has brand-new sequence, this polypeptide can suppress interleukin-33 to be expressed in body, treatment carcinoma of the pancreas.Suppress the propagation of human pancreatic cancer cell ASPC-1; Improve tumor-bearing mice survival rate in vivo; There is potential new drug development value.
Embodiment
The present invention relates to polypeptide (KVLLSYYESQHPSNESGDDGG) to be synthesized by gill biochemistry (Shanghai).
Embodiment 1
The effect that interleukin-33 inhibitor polypeptide is bred human pancreatic cancer cell ASPC-1.
Adopt MTT colorimetry.By the ASPC-1 cell of logarithmic growth, add in 96 well culture plates with 1.0 × 105, cultivate 24h, experimental port, positive drug control hole add Experimental agents interleukin-33 inhibitor polypeptide and the positive control medicine vincristine(VCR) of different concns respectively; Blank group adds the solvent of same volume.Five multiple holes are established in every hole, and cultivate 48h, every hole adds MTT, after effect 4h, add DMSO, hatch 30min, absorbance A value is measured, by formula growth of tumour cell inhibiting rate=(1-experimental group light absorption value/control group light absorption value) × 100% at microplate reader 620nm place.The IC50 calculating Experimental agents is 7.43 μMs.When concentration is 7.43 μMs, be 70.32% to ASPC-1 proliferation inhibition rate.
Embodiment 2
The inhibition test that interleukin-33 inhibitor polypeptide grows human pancreatic cancer cell ASPC-1 nude mouse xenograft tumor
The human pancreatic cancer cell ASPC-1 cell strain of taking the logarithm vegetative period, is aseptically prepared into 5 × 10
7/ ml cell suspension, is inoculated in armpit on the right side of nude mice with 0.1ml subcutaneous.With vernier caliper measurement transplanted tumor in nude mice diameter, treat that tumor growth is to 100-200mm
3after by animal random packet.Use the method measuring knurl footpath, dynamically observe the antitumous effect of tested polypeptide.The pendulous frequency of diameter of tumor is survey 1 time for every 2 days.Administering mode all adopts tail vein injection.Negative control group injection normal saline, every day 1 time; Taxol group 10mg/kg, Per-Hop behavior 1 time; RhEndostatin group 2.5mg/kg, administration every day 1 time;
High, normal, basic group of polypeptide respectively with 20mg/kg, 10mg/kg, 5mg/kg, administration every day 1 time.After off-test, sacrifice, operation strips knurl block and weighs.
The restraining effect that table 1 polypeptide grows human pancreatic cancer cell ASPC-1 nude mouse xenograft tumor
Therefore, polypeptide shows human pancreatic cancer cell ASPC-1 transplanted tumor in nude mice growth inhibition test result, compared with negative control group, the growth of polypeptide 20mg/kg, 10mg/kg and 5mg/kg group to human pancreatic cancer cell ASPC-1 transplanted tumor all has the restraining effect of pole significance.Compared with positive controls taxol, the body weight of polypeptide to laboratory animal does not have a significant effect, and has no obvious toxic side effects, and survival rate improves.
Embodiment 3
Detecting interleukin-33 with tumor model suppresses polypeptide on the impact of interleukin-33 expression in tumour.
Tumor tissues after Example 2 execution carries out the experiment of interleukin-33 immune result, adopt MoticImagesAdvanced3.2 image analyzer, under 200 times of mirrors, Continuous Observation 5 visuals field are detected, measure gray-scale value, the height of interleukin-33 positive expression is represented with gray-scale value, gray-scale value is less, illustrates that interleukin-33 positive expression is lower; Gray-scale value is larger, illustrates that interleukin-33 positive expression is higher.As a result, interleukin-33 suppression polypeptide has the effect that Tumor suppression interleukin-33 is expressed in vain.
SEQUENCELISTING
Pu Luoda bio tech ltd, <110> Suzhou
<120> interleukin-33 inhibitor polypeptide and application thereof
<130>
<160>1
<170>PatentInversion3.3
<210>1
<211>19
<212>PRT
<213> artificial sequence
<400>1
GluThrIleArgArgAlaTyrProAspAlaAlaAsnLeuLeuAsnAsp
151015
ArgValLeu
Claims (4)
1. interleukin-33 inhibitor polypeptide, is characterized in that its sequence is KVLLSYYESQHPSNESGDDGG.
2. a pharmaceutical composition, is characterized in that it comprises polypeptide and more than one pharmaceutically acceptable vehicle, weighting agent, tackiness agent, lubricant, disintegrating agent or stablizer as claimed in claim 1.
3. pharmaceutical composition as claimed in claim 2, it is characterized in that, described composition is injection.
4. the application of interleukin-33 inhibitor polypeptide as claimed in claim 1 in preparation treatment pancreatic cancer drug.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410281948.9A CN104031128B (en) | 2014-06-23 | 2014-06-23 | A kind of interleukin-33 inhibitor polypeptide and application thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410281948.9A CN104031128B (en) | 2014-06-23 | 2014-06-23 | A kind of interleukin-33 inhibitor polypeptide and application thereof |
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| Publication Number | Publication Date |
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| CN104031128A CN104031128A (en) | 2014-09-10 |
| CN104031128B true CN104031128B (en) | 2016-03-30 |
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| CN111150748A (en) * | 2019-12-27 | 2020-05-15 | 杭州荣谷生物科技有限公司 | Application of recombinant oncolytic virus in preparation of medicine for treating digestive tract cancer |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004022718A3 (en) * | 2002-09-06 | 2005-12-01 | Amgen Inc | Therapeutic human anti-il-1r1 monoclonal antibody |
| CN102146413A (en) * | 2011-01-17 | 2011-08-10 | 中国科学院广州生物医药与健康研究院 | Method for expressing and purifying human recombinant interleukin-3 |
-
2014
- 2014-06-23 CN CN201410281948.9A patent/CN104031128B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004022718A3 (en) * | 2002-09-06 | 2005-12-01 | Amgen Inc | Therapeutic human anti-il-1r1 monoclonal antibody |
| CN102146413A (en) * | 2011-01-17 | 2011-08-10 | 中国科学院广州生物医药与健康研究院 | Method for expressing and purifying human recombinant interleukin-3 |
Non-Patent Citations (1)
| Title |
|---|
| 白介素-33在疾病中的作用;刘晓萃等;《生命的化学》;20111231;第31卷(第5期);第751页-755页 * |
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Inventor after: Xu Yongjun Inventor before: Luo Ruixue |
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Effective date of registration: 20160301 Address after: 314000, room 8, building 778, 1205 Asia Pacific Road, Nanhu District, Jiaxing, Zhejiang, Jiaxing Applicant after: Yuan Tai bio tech ltd, Zhejiang Address before: High tech Zone Suzhou city Jiangsu province 215000 Chuk Yuen Road No. 209 Applicant before: Suzhou Pu Luo Da Biotechnology Co., Ltd. |
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