CN111467478A - Application of polypeptide Kp-10 in preparation of medicine for treating and preventing osteosarcoma - Google Patents
Application of polypeptide Kp-10 in preparation of medicine for treating and preventing osteosarcoma Download PDFInfo
- Publication number
- CN111467478A CN111467478A CN202010291237.5A CN202010291237A CN111467478A CN 111467478 A CN111467478 A CN 111467478A CN 202010291237 A CN202010291237 A CN 202010291237A CN 111467478 A CN111467478 A CN 111467478A
- Authority
- CN
- China
- Prior art keywords
- osteosarcoma
- polypeptide
- medicament
- gpr54
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 201000008968 osteosarcoma Diseases 0.000 title claims abstract description 60
- 239000003814 drug Substances 0.000 title claims abstract description 37
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 31
- 102000004196 processed proteins & peptides Human genes 0.000 title claims abstract description 30
- 229920001184 polypeptide Polymers 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims description 11
- 125000003275 alpha amino acid group Chemical group 0.000 claims abstract 2
- VZUNGTLZRAYYDE-UHFFFAOYSA-N N-methyl-N'-nitro-N-nitrosoguanidine Chemical compound O=NN(C)C(=N)N[N+]([O-])=O VZUNGTLZRAYYDE-UHFFFAOYSA-N 0.000 claims description 16
- 230000002401 inhibitory effect Effects 0.000 claims description 7
- 206010061289 metastatic neoplasm Diseases 0.000 claims description 4
- 231100000673 dose–response relationship Toxicity 0.000 claims description 3
- 230000001394 metastastic effect Effects 0.000 claims description 3
- 230000001617 migratory effect Effects 0.000 claims description 3
- 230000002062 proliferating effect Effects 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000006187 pill Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims 7
- 230000002685 pulmonary effect Effects 0.000 claims 1
- 101001091205 Homo sapiens KiSS-1 receptor Proteins 0.000 abstract description 35
- 102100034845 KiSS-1 receptor Human genes 0.000 abstract description 31
- 238000013508 migration Methods 0.000 abstract description 14
- 230000005012 migration Effects 0.000 abstract description 14
- 230000035755 proliferation Effects 0.000 abstract description 14
- 210000004072 lung Anatomy 0.000 abstract description 13
- 229940079593 drug Drugs 0.000 abstract description 7
- 238000004393 prognosis Methods 0.000 abstract description 6
- 238000012546 transfer Methods 0.000 abstract description 6
- 238000011160 research Methods 0.000 abstract description 5
- 210000004027 cell Anatomy 0.000 description 40
- 210000001519 tissue Anatomy 0.000 description 12
- 206010027476 Metastases Diseases 0.000 description 10
- 230000009401 metastasis Effects 0.000 description 10
- MGSVBZIBCCKGCY-ZLUOBGJFSA-N Asp-Ser-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O MGSVBZIBCCKGCY-ZLUOBGJFSA-N 0.000 description 7
- 238000011161 development Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 150000001413 amino acids Chemical class 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 4
- 238000003197 gene knockdown Methods 0.000 description 4
- 238000011580 nude mouse model Methods 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 241000699660 Mus musculus Species 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- UOXHUUWVKCDOBO-BXRBKJIMSA-N (2s)-2-aminobutanedioic acid;(2s)-2-amino-3-hydroxypropanoic acid Chemical group OC[C@H](N)C(O)=O.OC(=O)[C@@H](N)CC(O)=O UOXHUUWVKCDOBO-BXRBKJIMSA-N 0.000 description 2
- RITKWYDZSSQNJI-INXYWQKQSA-N (2s)-n-[(2s)-1-[[(2s)-4-amino-1-[[(2s)-1-[[(2s)-1-[[2-[[(2s)-1-[[(2s)-1-[[(2s)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-2-oxoethyl]amino]-1-oxo-3-phenylpropan-2-yl]amino] Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 RITKWYDZSSQNJI-INXYWQKQSA-N 0.000 description 2
- OUYCCCASQSFEME-MRVPVSSYSA-N D-tyrosine Chemical compound OC(=O)[C@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-MRVPVSSYSA-N 0.000 description 2
- 102400001121 Kisspeptin-10 Human genes 0.000 description 2
- 101800001692 Kisspeptin-10 Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- OWIUPIRUAQMTTK-UHFFFAOYSA-N carbazic acid Chemical compound NNC(O)=O OWIUPIRUAQMTTK-UHFFFAOYSA-N 0.000 description 2
- 230000002596 correlated effect Effects 0.000 description 2
- 210000003414 extremity Anatomy 0.000 description 2
- 238000003209 gene knockout Methods 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 210000000963 osteoblast Anatomy 0.000 description 2
- 210000002997 osteoclast Anatomy 0.000 description 2
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108700042226 ras Genes Proteins 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- JIGIJNKESDREHJ-WOUDKVOTSA-N 374675-18-0 Chemical compound CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)CC1=CC=C(O)C=C1 JIGIJNKESDREHJ-WOUDKVOTSA-N 0.000 description 1
- DWBZEJHQQIURML-IMJSIDKUSA-N Asp-Ser Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CO)C(O)=O DWBZEJHQQIURML-IMJSIDKUSA-N 0.000 description 1
- 102000003951 Erythropoietin Human genes 0.000 description 1
- 108090000394 Erythropoietin Proteins 0.000 description 1
- 101500026282 Homo sapiens Metastin Proteins 0.000 description 1
- 102400001122 Kisspeptin-13 Human genes 0.000 description 1
- 101800005274 Kisspeptin-13 Proteins 0.000 description 1
- 102400001123 Kisspeptin-14 Human genes 0.000 description 1
- 101800005275 Kisspeptin-14 Proteins 0.000 description 1
- 102000013599 Kisspeptins Human genes 0.000 description 1
- 108010012048 Kisspeptins Proteins 0.000 description 1
- 206010027458 Metastases to lung Diseases 0.000 description 1
- 102400001124 Metastin Human genes 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 102000001742 Tumor Suppressor Proteins Human genes 0.000 description 1
- 108010040002 Tumor Suppressor Proteins Proteins 0.000 description 1
- 230000003262 anti-osteoporosis Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 230000005757 colony formation Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940105423 erythropoietin Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000003054 facial bone Anatomy 0.000 description 1
- 210000002454 frontal bone Anatomy 0.000 description 1
- 210000001214 frontal sinus Anatomy 0.000 description 1
- 230000002267 hypothalamic effect Effects 0.000 description 1
- 238000011532 immunohistochemical staining Methods 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- KAHDONZOCXSKII-NJVVDGNHSA-N kisspeptin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H]1N(CCC1)C(=O)[C@H]1N(CCC1)C(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)O)C1=CN=CN1 KAHDONZOCXSKII-NJVVDGNHSA-N 0.000 description 1
- KAHDONZOCXSKII-UHFFFAOYSA-N kisspeptin-54 Chemical compound C1CCC(C(=O)NC(C)C(=O)N2C(CCC2)C(=O)NC(CCC(N)=O)C(=O)NCC(=O)NC(C)C(=O)NC(C(C)C)C(=O)NC(CC(C)C)C(=O)NC(C(C)C)C(=O)NC(CCC(N)=O)C(=O)NC(CCCNC(N)=N)C(=O)NC(CCC(O)=O)C(=O)NC(CCCCN)C(=O)NC(CC(O)=O)C(=O)NC(CC(C)C)C(=O)N2C(CCC2)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C3=CC=CC=C3NC=2)C(=O)NC(CC(N)=O)C(=O)NC(CO)C(=O)NC(CC=2C=CC=CC=2)C(=O)NCC(=O)NC(CC(C)C)C(=O)NC(CCCNC(N)=N)C(=O)NC(CC=2C=CC=CC=2)C(N)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C(CCCNC(N)=N)NC(=O)C(CO)NC(=O)C(NC(=O)C1N(CCC1)C(=O)C(C)NC(=O)C(CO)NC(=O)C(CC(C)C)NC(=O)CNC(=O)C1N(CCC1)C(=O)C(CCC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C(CCCNC(N)=N)NC(=O)C(CO)NC(=O)CNC(=O)C(CO)NC(=O)C(CO)NC(=O)C(CCC(O)=O)NC(=O)C1N(CCC1)C(=O)C1N(CCC1)C(=O)C1N(CCC1)C(=O)C(CO)NC(=O)C(CC(C)C)NC(=O)C(CO)NC(=O)C(NC(=O)CN)C(C)O)CC1=CNC=N1 KAHDONZOCXSKII-UHFFFAOYSA-N 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 210000004373 mandible Anatomy 0.000 description 1
- 210000002050 maxilla Anatomy 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 210000000537 nasal bone Anatomy 0.000 description 1
- 238000011227 neoadjuvant chemotherapy Methods 0.000 description 1
- 210000000103 occipital bone Anatomy 0.000 description 1
- 208000029513 osteogenic neoplasm Diseases 0.000 description 1
- 230000001936 parietal effect Effects 0.000 description 1
- 238000011248 postoperative chemotherapy Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 210000003625 skull Anatomy 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 210000002303 tibia Anatomy 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Rheumatology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- Oncology (AREA)
- Orthopedic Medicine & Surgery (AREA)
Abstract
The invention discloses an application of a polypeptide Kp-10 in preparing a medicine for treating and preventing osteosarcoma, wherein the amino acid sequence of the polypeptide Kp-10 is DSSDSSDSSDSSDSSDSSYNWNSFG L RF., researches show that the expression of GPR54/KiSS-1 in osteosarcoma tissues is obviously lower than that of paraneoplastic normal tissues, and the polypeptide Kp-10 and a receptor GPR54 thereof are highly related to clinical prognosis, and can inhibit the proliferation and migration capacity and lung transfer capacity of osteosarcoma cells, so that the polypeptide Kp-10 can be used for preparing the medicine for treating and preventing osteosarcoma, and a new thought is provided for the search of targeted medicines for osteosarcoma.
Description
Technical Field
The invention relates to the field of biological medicine, in particular to application of a polypeptide Kp-10 in preparing a medicine for treating and preventing osteosarcoma.
Background
Osteosarcoma is the most common one of bone malignancies, a malignant osteogenic tumor derived from mesenchymal cells. The patients are adolescents and males. It is best seen in the skull, where the frontal bone is the most, followed by the parietal, temporal, occipital bones, and in the facial bones, most located in the maxilla, mandible, zygomatic, nasal bones, followed by the frontal sinus, orbit, etc., and 1/3 in the anterior side of the tibia. The tumor grows slowly and has light symptoms, and the tumor mostly appears in children, the development of the body gradually grows, and the tumor usually attracts attention due to the occurrence of lumps after years of 10-20 years of age and the course of disease of decades or decades. Moreover, lung metastases usually occur in 80% of cases when osteosarcoma is diagnosed.
At present, the treatment of osteosarcoma is mainly based on large-dose individualized neoadjuvant chemotherapy (preoperative chemotherapy) and operative treatment, and is assisted by drug treatment. The survival rate of the patient in 5 years is greatly improved by combining the development of the new auxiliary chemotherapy with the postoperative chemotherapy, and the limb protection operation is carried out on the patient with limb protection finger syndrome under the cooperation of a scientific and reasonable chemotherapy scheme, so that the life cycle of the patient is prolonged, and the life quality of the patient is also greatly improved. In addition, the development and research of new effective targeted drugs are also very necessary for the generation and development of osteosarcoma and the inhibition of lung metastasis, so that the pain of patients can be reduced, and the reasonable allocation of medical resources can be realized.
The KiSS-1 gene is found as a tumor suppressor in melanoma and encodes a protein of 145 amino acids, which is cleaved by proteasomes to yield a biologically active secreted peptide consisting of 54 amino acids, KiSSpeptin-54, which is further cleaved to KiSSpeptin-14, KiSSpeptin-13, KiSSpeptin-10, which specifically binds to GPR54 and exerts a biological effect, which is a natural ligand of GPR54, wherein KiSSpeptin-10 is abbreviated Kp-10, which is the shortest KiSSpeptin in active form, which is the smallest of these biological peptides, which consists of 10 amino acids, and clinical analysis of patients shows that, by gene knockout, mouse and clinical analysis, KiSS-1 is a natural ligand of GPR54, the hypothalamic erythropoietin (Kp) regulates the secretion of various bioactive peptides, and thus the whole-cycle secretion of GnH 2 can be regulated and regulated in the same species.
The previous research proves that GPR54 is deficient to activate osteoclast and cause osteoporosis, and the natural ligand Kp-10 of GPR54 has an anti-osteoporosis effect by inhibiting the formation and the function of osteoclast. However, whether KiSS-1/GPR54 plays a role in inhibiting osteosarcoma has not been reported, and development and research of the role in preparing drugs for inhibiting the development of osteosarcoma and lung metastasis are also urgently needed.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides the application of the polypeptide Kp-10 in preparing the medicine for treating and preventing osteosarcoma.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the invention provides a use of a polypeptide Kp-10 in the preparation of a medicament for treating and preventing osteosarcoma, wherein the amino acid sequence of the polypeptide Kp-10 is DSSDSSDSSDSSDSSDSSYNWNSFG L R F, specifically (Asp-Ser-Ser)6- (D-Tyr) -Asn- (D-Trp) -Asn-Ser-Phe- (azaGly) -L eu-Arg (Me) -Phe-NH2 (abbreviated as (AspSerSer) 6-Kp-10). The (AspSerSer)6-Kp-10 in the invention is formed by connecting 6 repeated serial aspartic acid-serine sequences (AspSerSer)6 to the N-terminal of Kp-10.
Further, the medicine also comprises a pharmaceutically acceptable carrier or excipient.
Further, the administration route of the drug is oral, transdermal, intramuscular, subcutaneous or intravenous injection.
Further, the medicine can be tablets, pills, granules, capsules or injections.
Further, the medicine can inhibit proliferation ability and migration ability of osteosarcoma cells.
Further, the drug is dose-dependent on the proliferative and migratory capacity of osteosarcoma cells.
Further, the medicine can inhibit lung metastasis ability of osteosarcoma cells.
Further, the osteosarcoma cell line is MNNG/HOS, ZOS or 143B cell line.
By adopting the technical scheme, compared with the prior art, the invention has the following technical effects:
the application of the polypeptide Kp-10 in the preparation of the medicine for treating and preventing osteosarcoma, provided by the invention, discovers that the expression of GPR54/KiSS-1 in osteosarcoma tissues is obviously lower than that of paraneoplastic normal tissues and is highly negatively related to clinical prognosis through research, and the genes Kp-10 and GPR54 can inhibit the proliferation and migration capacity and lung transfer capacity of osteosarcoma cells, so that the polypeptide Kp-10 can be used for preparing the medicine for treating and preventing osteosarcoma, and a new thought is provided for the search of targeted medicines for osteosarcoma.
Drawings
FIG. 1 is a graph showing the expression results of GPR54/KiSS-1 in one embodiment of the present invention; wherein, the graph A is a graph of the immunohistochemistry results of GPR54/KiSS-1 in osteosarcoma patient tissues and paraneoplastic normal tissues, and the graph B is a graph of the expression WB results in a plurality of osteosarcoma cell lines;
FIG. 2 is a graph showing the relationship between the expression level of GPR54/KiSS-1 and the clinical prognosis of osteosarcoma patients in accordance with one embodiment of the present invention;
FIG. 3 is a graph of Kp-10 polypeptide and its concentration as a function of proliferation and migration capacity of the osteosarcoma cell lines MNNG/HOS and ZOS cells in accordance with an embodiment of the present invention; wherein, the graph A is a graph of the relationship between the Kp-10 polypeptide and the proliferation and migration capacity of an osteosarcoma cell line MNNG/HOS, and the graph B is a graph of the relationship between the Kp-10 polypeptide and the proliferation and migration capacity of an osteosarcoma cell line ZOS;
FIG. 4 is a graph showing the results of changes in the proliferation and migration abilities of MNNG/HOS and ZOS cells after knocking down the GPR54 gene in accordance with one embodiment of the present invention; wherein, the graph A is a graph of expression WB of GPR54 in ZOS cells and MNNG/HOS cells of the control group and the knockdown group, and the graph B is a graph of the influence of the control group and the knockdown group on the proliferation and migration capacity of the ZOS cells and the MNNG/HOS cells;
FIG. 5 is a graph showing the results of lung metastasis of MNNG/HOS cells in mice after knocking down the GPR54 gene according to one embodiment of the present invention;
FIG. 6 is a graph showing the results of lung metastasis of 143B cells stimulated with Kp-10(100nM/Kg) exogenously administered in one embodiment of the present invention.
Detailed Description
The invention provides application of a polypeptide Kp-10 in preparing a medicine for treating and preventing osteosarcoma, wherein the amino acid sequence of the polypeptide Kp-10 is DSSDSSDSSDSSDSSDSSYNWNSFG L RF, in particular to (Asp-Ser-Ser)6- (D-Tyr) -Asn- (D-Trp) -Asn-Ser-Phe- (azaGly) -L eu-Arg (Me) -Phe-NH2 (short for (AspSer) 6-Kp-10), and the (AspSerSer)6-Kp-10 is formed by connecting 6 repeated aspartic acid-serine serial sequences (AspSerSer)6 to the N end of the Kp-10.
The present invention will be described in detail and specifically with reference to the following examples to facilitate better understanding of the present invention, but the following examples do not limit the scope of the present invention.
Example one
This example demonstrates that GPR54/KiSS-1 is expressed in osteosarcoma tissue significantly lower than paraneoplastic normal tissue, and the specific experimental contents and results are as follows:
the collected human osteosarcoma tissue specimens were stained by immunohistochemical staining using human osteoblast line HFOB1.19 as a normal control, and the results are shown in FIG. 1. Wherein, 143B and MNNG/HOS cell line are from osteosarcoma TE85 cell line, 143B cell has stronger transfer activity by transferring ki-ras gene; ZOS and ZOSM cell lines are derived from the same patient from both in situ and distant metastatic lesions. As can be seen from FIG. 1, GPR54/KiSS-1 was expressed in the tissues of osteosarcoma patients significantly lower than in paraneoplastic normal tissues; and the expression level of KiSS-1 and GPR54 in an osteosarcoma cell line is reduced by taking a human osteoblast cell line HFOB1.19 as a normal control, wherein 143B cells have stronger transfer activity by introducing a ki-ras gene, the expression level of KiSS-1 and GPR54 is lower, the expression level of ZOSM has stronger transfer capability, and the expression level of KiSS-1 and GPR54 is lower.
Example two
This example demonstrates that GPR54/KiSS-1 expression is highly correlated with the clinical prognosis of osteosarcoma patients, and the specific experimental contents and results are as follows:
by counting the expression of GPR54/KiSS-1, the results shown in FIG. 2 were obtained in combination with the clinical follow-up data of patients. As can be seen from FIG. 2, the expression of GPR54/KiSS-1 is highly correlated with the clinical prognosis of osteosarcoma patients, i.e., a lower expression of GPR54/KiSS-1 is indicative of a shorter survival of the patients.
EXAMPLE III
This example demonstrates the inhibitory effect of GPR54/KiSS-1 on the proliferation and migration ability of the osteosarcoma cell line MNNG/HOS and ZOS cells, and the specific experimental contents and results are as follows:
the effect of Kp-10, the shortest polypeptide with activity in the KiSS protein, on the proliferation and migration capacity of the osteosarcoma cell line MNNG/HOS and ZOS cells was investigated by colony formation and transwell experiments and the results are shown in FIG. 3. The GPR54 gene was knocked down to study changes in the proliferation and migration abilities of MNNG/HOS and ZOS cells, and the results are shown in FIG. 4.
As can be seen from FIG. 3, Kp-10 was able to significantly inhibit the proliferation and migration ability of the MNNG/HOS and ZOS cells, which are osteosarcoma cell lines, and both were dose-dependent. As seen in FIG. 4A, the expression level of GPR54 was decreased in the knockdown group; as can be seen from FIG. 4B, the clone number and cell number in the knock-down group (shGPR54-1 and shGPR54-2) were significantly higher than those in the blank control group (Ctrl) and the empty control group (shCtrl), i.e., the proliferation and migration ability of MNNG/HOS and ZOS cells were significantly enhanced after knocking down the GPR54 gene.
Example four
This example demonstrates the inhibitory effect of GPR54/KiSS-1 on lung metastatic capacity of osteosarcoma cells, and the specific experimental contents and results are as follows:
an osteosarcoma tail vein lung metastasis model is constructed by injecting MNNG/HOS and a GPR54 knockout cell strain into the tail vein of a nude mouse, and the metastasis condition of the osteosarcoma in the mouse is detected by IVIS (in vivo animal imaging system) on 21 th, 28 th, 35 th and 42 th days respectively, and the result is shown in figure 5. 143B cells were injected into the tail vein of nude mice and stimulated with Kp-10(100nM/Kg) exogenously, and the transfer of osteosarcoma in mice was examined by IVIS (in vivo animal imaging System) on days 14, 21, and 28, respectively, and the results are shown in FIG. 6.
As shown in fig. 5, compared to the control group (nude mice injected with MNNG/HOS cell strain alone), the nude mice injected with GPR54 knockout cell have stronger in vivo fluorescence signal and significantly stronger and wider range of lung metastasis foci, i.e., the GPR54 gene knockout group has significantly enhanced lung metastasis ability. As can be seen from FIG. 6, the fluorescence signal of lung was significantly reduced in the Kp-10 group of mice as compared with the control group, and thus Kp-10 inhibited the lung-metastatic ability of 143B cells.
In conclusion, the expression of GPR54/KiSS-1 in osteosarcoma tissues is obviously lower than that of paraneoplastic normal tissues, the tissue is highly negatively related to clinical prognosis, and the polypeptide Kp-10 and the receptor GPR54 thereof can inhibit the proliferation and migration of tumor cells and the lung metastasis capacity, so that a target is expected to be provided for preparing a medicament for treating osteosarcoma.
The embodiments of the present invention have been described in detail, but the embodiments are merely examples, and the present invention is not limited to the embodiments described above. Any equivalent modifications and substitutions to those skilled in the art are also within the scope of the present invention. Accordingly, equivalent changes and modifications made without departing from the spirit and scope of the present invention should be covered by the present invention.
Claims (8)
1. The application of the polypeptide Kp-10 in preparing the medicine for treating and preventing osteosarcoma is characterized in that the amino acid sequence of the polypeptide Kp-10 is DSSDSSDSSDSSDSSDSSYNWNSFG L RF.
2. The use of the polypeptide Kp-10 according to claim 1 for the preparation of a medicament for the treatment and prevention of osteosarcoma, wherein said medicament further comprises a pharmaceutically acceptable carrier or excipient.
3. The use of the polypeptide Kp-10 according to claim 1 for the preparation of a medicament for the treatment and prevention of osteosarcoma, wherein said medicament is administered orally, transdermally, intramuscularly, subcutaneously or intravenously.
4. The use of the polypeptide Kp-10 according to claim 1 for the preparation of a medicament for the treatment and prevention of osteosarcoma, wherein said medicament can be in the form of tablets, pills, granules, capsules or injections.
5. The use of the polypeptide Kp-10 according to claim 1 for the preparation of a medicament for the treatment and prevention of osteosarcoma, wherein said medicament is capable of inhibiting the proliferative and migratory capacity of osteosarcoma cells.
6. The use of the polypeptide Kp-10 according to claim 5 for the preparation of a medicament for the treatment and prevention of osteosarcoma, wherein said medicament is dose-dependent on the proliferative and migratory capacity of osteosarcoma cells.
7. The use of the polypeptide Kp-10 according to claim 1 for the preparation of a medicament for the treatment and prevention of osteosarcoma, wherein said medicament is capable of inhibiting the pulmonary metastatic capacity of osteosarcoma cells.
8. The use of the polypeptide Kp-10 according to any of claims 5 to 7 for the preparation of a medicament for the treatment and prevention of osteosarcoma, wherein said osteosarcoma cell is a MNNG/HOS, ZOS or 143B cell line.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010291237.5A CN111467478A (en) | 2020-04-14 | 2020-04-14 | Application of polypeptide Kp-10 in preparation of medicine for treating and preventing osteosarcoma |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010291237.5A CN111467478A (en) | 2020-04-14 | 2020-04-14 | Application of polypeptide Kp-10 in preparation of medicine for treating and preventing osteosarcoma |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111467478A true CN111467478A (en) | 2020-07-31 |
Family
ID=71751926
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010291237.5A Pending CN111467478A (en) | 2020-04-14 | 2020-04-14 | Application of polypeptide Kp-10 in preparation of medicine for treating and preventing osteosarcoma |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111467478A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110172461A (en) * | 2019-06-03 | 2019-08-27 | 上海长征医院 | A kind of construction method of novel osteosarcoma Lung metastases model and its application |
| CN112457371A (en) * | 2020-11-29 | 2021-03-09 | 北京泽勤生物医药有限公司 | Bone formation promoting polypeptide and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100160241A1 (en) * | 2006-04-26 | 2010-06-24 | Kyoto University | Novel compound having gpr54 agonistic activity |
| CN109111506A (en) * | 2018-01-17 | 2019-01-01 | 上海长征医院 | A kind of polypeptide and its preparation method and application for treating osteoporosis |
-
2020
- 2020-04-14 CN CN202010291237.5A patent/CN111467478A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100160241A1 (en) * | 2006-04-26 | 2010-06-24 | Kyoto University | Novel compound having gpr54 agonistic activity |
| CN109111506A (en) * | 2018-01-17 | 2019-01-01 | 上海长征医院 | A kind of polypeptide and its preparation method and application for treating osteoporosis |
Non-Patent Citations (1)
| Title |
|---|
| 王冬生: "KiSSl/GPR54在骨肉瘤转移和增殖中的作用及机制研究", 中国博士学位论文全文数据库医药卫生科技辑 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110172461A (en) * | 2019-06-03 | 2019-08-27 | 上海长征医院 | A kind of construction method of novel osteosarcoma Lung metastases model and its application |
| CN112457371A (en) * | 2020-11-29 | 2021-03-09 | 北京泽勤生物医药有限公司 | Bone formation promoting polypeptide and application thereof |
| CN112457371B (en) * | 2020-11-29 | 2021-12-10 | 北京泽勤生物医药有限公司 | Bone formation promoting polypeptide and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105338977B (en) | Eribulin and the happy purposes cut down for Buddhist nun as the conjoint therapy for the treatment of cancer | |
| JP6367950B2 (en) | Prostate cancer treatment composition | |
| WO2021027704A1 (en) | Application of polypeptide or derivative thereof | |
| MX2007009012A (en) | Methods for treating renal cell carcinoma. | |
| WO2016034081A1 (en) | Methods and compositions for treating c-met associated cancers | |
| CN111467478A (en) | Application of polypeptide Kp-10 in preparation of medicine for treating and preventing osteosarcoma | |
| US20210379143A1 (en) | Drug containing recombinant mistletoe lectins for treating | |
| CN112641775B (en) | Application of brucea javanica picrol and analogues thereof in treatment of pituitary adenoma | |
| US20230226140A1 (en) | Ang (1-7) derviative oligopeptides for the treatment of pain | |
| KR102003422B1 (en) | Integrin blocker polypeptide and use thereof | |
| US20100330093A1 (en) | Treatment of melanoma with alpha thymosin peptides in combination with antibodies against cytotoxic t lymphocyte-associated antigen 4 (ctla4) | |
| EA019738B1 (en) | Prophylactic/therapeutic agent for cancer | |
| KR102206017B1 (en) | Pharmaceutical composition for treating skin fibrosis comprising PARP1 inhibitor | |
| CN101735314A (en) | Osteopontin and purpose of protecting liver thereof | |
| CN111569046B (en) | Application of polypeptide in preparation of medicine for treating pancreatitis and medicine containing polypeptide | |
| EP0890361A1 (en) | Antitumor agent | |
| US7507401B2 (en) | Anti-cancer agent | |
| AU2016297311A1 (en) | Novel peptide and use thereof | |
| CN114835776B (en) | Small molecule polypeptide for targeting Smad4/PELO interaction and resisting tumor metastasis and application thereof | |
| CN113842466B (en) | Molecular-coated nafamomus and application thereof in treating triple negative breast cancer | |
| RU2597795C2 (en) | Inhibitor of liquid in cavities of body accumulation | |
| CN111574590B (en) | Polypeptide with anti-tumor function and application thereof | |
| KR100274172B1 (en) | A synthetic peptide derived from TIMP-2 inhibiting the activity of type Ⅳ collagenase | |
| US20180036366A1 (en) | Adminstration of recombinant collagen 7 for the treatment of age related disorders | |
| CN110064046B (en) | Application of mini-peptide YY1BM in treating cancer |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20200731 |