CN115624627B - 靶向cd226分子的抑制剂在抗肿瘤转移中的应用 - Google Patents
靶向cd226分子的抑制剂在抗肿瘤转移中的应用 Download PDFInfo
- Publication number
- CN115624627B CN115624627B CN202211066187.6A CN202211066187A CN115624627B CN 115624627 B CN115624627 B CN 115624627B CN 202211066187 A CN202211066187 A CN 202211066187A CN 115624627 B CN115624627 B CN 115624627B
- Authority
- CN
- China
- Prior art keywords
- tumor
- inhibitor
- metastasis
- platelets
- tumor metastasis
- 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.)
- Active
Links
- 206010027476 Metastases Diseases 0.000 title claims abstract description 57
- 230000009401 metastasis Effects 0.000 title claims abstract description 54
- 102100038077 CD226 antigen Human genes 0.000 title claims abstract description 53
- 101000884298 Homo sapiens CD226 antigen Proteins 0.000 title claims abstract description 53
- 239000003112 inhibitor Substances 0.000 title claims abstract description 51
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 50
- 210000004881 tumor cell Anatomy 0.000 claims abstract description 45
- 230000008685 targeting Effects 0.000 claims abstract description 16
- 230000010118 platelet activation Effects 0.000 claims description 11
- 230000000259 anti-tumor effect Effects 0.000 claims description 9
- 210000004027 cell Anatomy 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 8
- 201000001441 melanoma Diseases 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 6
- SNKFFCBZYFGCQN-UHFFFAOYSA-N 2-[3-[3-[1-carboxy-2-(3,4-dihydroxyphenyl)ethoxy]carbonyl-2-(3,4-dihydroxyphenyl)-7-hydroxy-2,3-dihydro-1-benzofuran-4-yl]prop-2-enoyloxy]-3-(3,4-dihydroxyphenyl)propanoic acid Chemical compound C=1C=C(O)C=2OC(C=3C=C(O)C(O)=CC=3)C(C(=O)OC(CC=3C=C(O)C(O)=CC=3)C(O)=O)C=2C=1C=CC(=O)OC(C(=O)O)CC1=CC=C(O)C(O)=C1 SNKFFCBZYFGCQN-UHFFFAOYSA-N 0.000 claims description 4
- SNKFFCBZYFGCQN-VWUOOIFGSA-N Lithospermic acid B Natural products C([C@H](C(=O)O)OC(=O)\C=C\C=1C=2[C@H](C(=O)O[C@H](CC=3C=C(O)C(O)=CC=3)C(O)=O)[C@H](OC=2C(O)=CC=1)C=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 SNKFFCBZYFGCQN-VWUOOIFGSA-N 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 4
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- STCJJTBMWHMRCD-UHFFFAOYSA-N salvianolic acid B Natural products OC(=O)C(Cc1ccc(O)c(O)c1)OC(=O)C=Cc2cc(O)c(O)c3OC(C(C(=O)OC(Cc4ccc(O)c(O)c4)C(=O)O)c23)c5ccc(O)c(O)c5 STCJJTBMWHMRCD-UHFFFAOYSA-N 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 13
- 238000000034 method Methods 0.000 abstract description 8
- 230000003993 interaction Effects 0.000 abstract description 6
- 150000003384 small molecules Chemical class 0.000 abstract description 5
- 230000000903 blocking effect Effects 0.000 abstract description 3
- 230000001404 mediated effect Effects 0.000 abstract description 3
- 210000001772 blood platelet Anatomy 0.000 description 67
- 150000001875 compounds Chemical class 0.000 description 14
- 230000005764 inhibitory process Effects 0.000 description 14
- 241000699670 Mus sp. Species 0.000 description 10
- 238000000684 flow cytometry Methods 0.000 description 9
- 238000001514 detection method Methods 0.000 description 8
- 238000003032 molecular docking Methods 0.000 description 8
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 8
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 230000004913 activation Effects 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 238000012216 screening Methods 0.000 description 6
- 108090000190 Thrombin Proteins 0.000 description 5
- 239000007850 fluorescent dye Substances 0.000 description 5
- 229960004072 thrombin Drugs 0.000 description 5
- 108010067225 Cell Adhesion Molecules Proteins 0.000 description 4
- 102000016289 Cell Adhesion Molecules Human genes 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 210000004072 lung Anatomy 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 210000000822 natural killer cell Anatomy 0.000 description 4
- 230000001737 promoting effect Effects 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 101000622137 Homo sapiens P-selectin Proteins 0.000 description 3
- 102100023472 P-selectin Human genes 0.000 description 3
- 210000001744 T-lymphocyte Anatomy 0.000 description 3
- 230000002776 aggregation Effects 0.000 description 3
- 238000004220 aggregation Methods 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 230000035790 physiological processes and functions Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 238000003041 virtual screening Methods 0.000 description 3
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- 241000123346 Chrysosporium Species 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 230000004075 alteration Effects 0.000 description 2
- 230000033115 angiogenesis Effects 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 239000012154 double-distilled water Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229930182470 glycoside Natural products 0.000 description 2
- 150000002338 glycosides Chemical class 0.000 description 2
- 230000023597 hemostasis Effects 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 201000008968 osteosarcoma Diseases 0.000 description 2
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 2
- 210000004623 platelet-rich plasma Anatomy 0.000 description 2
- 239000002599 prostaglandin synthase inhibitor Substances 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 230000008439 repair process Effects 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- -1 small molecule compounds Chemical class 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 230000005748 tumor development Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- QMMRCKSBBNJCMR-KMZPNFOHSA-N Angiotensin III Chemical group C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CCCN=C(N)N)C(C)C)C1=CC=C(O)C=C1 QMMRCKSBBNJCMR-KMZPNFOHSA-N 0.000 description 1
- 101800000738 Angiotensin-3 Proteins 0.000 description 1
- 102400000348 Angiotensin-3 Human genes 0.000 description 1
- SMDOOINVMJSDPS-UHFFFAOYSA-N Astragaloside Natural products C1=C(O)C(OC)=CC(C2=C(C(=O)C3=C(O)C=C(O)C=C3O2)OC2C(C(OC3C(C(O)C(O)C(CO)O3)O)C(O)C(CO)O2)O)=C1 SMDOOINVMJSDPS-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 101100016363 Caenorhabditis elegans his-67 gene Proteins 0.000 description 1
- 229940122204 Cyclooxygenase inhibitor Drugs 0.000 description 1
- OCZZCFAOOWZSRX-LRHLXKJSSA-N Epimedin B Chemical compound C1=CC(OC)=CC=C1C1=C(O[C@H]2[C@@H]([C@H](O)[C@@H](O)[C@H](C)O2)O[C@H]2[C@@H]([C@@H](O)[C@H](O)CO2)O)C(=O)C2=C(O)C=C(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O)C(CC=C(C)C)=C2O1 OCZZCFAOOWZSRX-LRHLXKJSSA-N 0.000 description 1
- LKNITMBRWDCKMG-UHFFFAOYSA-N Epimedin B Natural products COc1ccc(cc1)C2=C(OC3OC(C)C(O)C(O)C3OC4OC(CO)C(O)C4O)C(=O)c5c(O)cc(OC6OC(CO)C(O)C(O)C6O)c(CC=C(C)C)c5O2 LKNITMBRWDCKMG-UHFFFAOYSA-N 0.000 description 1
- 206010015866 Extravasation Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 101001078143 Homo sapiens Integrin alpha-IIb Proteins 0.000 description 1
- 102100025306 Integrin alpha-IIb Human genes 0.000 description 1
- 206010027458 Metastases to lung Diseases 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 206010061309 Neoplasm progression Diseases 0.000 description 1
- 108010035766 P-Selectin Proteins 0.000 description 1
- 102000008212 P-Selectin Human genes 0.000 description 1
- 108010070519 PAR-1 Receptor Proteins 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 102100037136 Proteinase-activated receptor 1 Human genes 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 230000025164 anoikis Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- QMNWISYXSJWHRY-XWJCTJPOSA-N astragaloside Chemical compound O1[C@H](C(C)(O)C)CC[C@]1(C)[C@@H]1[C@@]2(C)CC[C@]34C[C@]4(CC[C@H](O[C@H]4[C@@H]([C@@H](O)[C@H](O)CO4)O)C4(C)C)C4[C@@H](O[C@H]4[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O4)O)CC3[C@]2(C)C[C@@H]1O QMNWISYXSJWHRY-XWJCTJPOSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 108010044022 bradykinin (2-9) Proteins 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000018732 detection of tumor cell Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- FSBUXLDOLNLABB-ISAKITKMSA-N echinacoside Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@H]1[C@H](OC(=O)\C=C\C=2C=C(O)C(O)=CC=2)[C@@H](CO[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)O[C@@H](OCCC=2C=C(O)C(O)=CC=2)[C@@H]1O FSBUXLDOLNLABB-ISAKITKMSA-N 0.000 description 1
- NJYVDFDTLLZVMG-UHFFFAOYSA-N echinacoside Natural products CC1OC(OC2C(O)C(OCCc3ccc(O)c(O)c3)OC(COC4OC(CO)C(O)C(O)C4O)C2OC(=O)C=Cc5cc(O)cc(O)c5)C(O)C(O)C1O NJYVDFDTLLZVMG-UHFFFAOYSA-N 0.000 description 1
- 230000007705 epithelial mesenchymal transition Effects 0.000 description 1
- 230000036251 extravasation Effects 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 1
- 238000013537 high throughput screening Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000000126 in silico method Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 150000002605 large molecules Chemical class 0.000 description 1
- URLZCHNOLZSCCA-UHFFFAOYSA-N leu-enkephalin Chemical compound C=1C=C(O)C=CC=1CC(N)C(=O)NCC(=O)NCC(=O)NC(C(=O)NC(CC(C)C)C(O)=O)CC1=CC=CC=C1 URLZCHNOLZSCCA-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 208000037841 lung tumor Diseases 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000010197 meta-analysis Methods 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- GUMSHIGGVOJLBP-SLRPQMTOSA-N methyl hesperidin Chemical compound C1=C(OC)C(OC)=CC=C1[C@H]1OC2=CC(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO[C@H]4[C@@H]([C@H](O)[C@@H](O)[C@H](C)O4)O)O3)O)=CC(O)=C2C(=O)C1 GUMSHIGGVOJLBP-SLRPQMTOSA-N 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- ARGKVCXINMKCAZ-UZRWAPQLSA-N neohesperidin Chemical compound C1=C(O)C(OC)=CC=C1[C@H]1OC2=CC(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O[C@H]3[C@@H]([C@H](O)[C@@H](O)[C@H](C)O3)O)=CC(O)=C2C(=O)C1 ARGKVCXINMKCAZ-UZRWAPQLSA-N 0.000 description 1
- ARGKVCXINMKCAZ-UHFFFAOYSA-N neohesperidine Natural products C1=C(O)C(OC)=CC=C1C1OC2=CC(OC3C(C(O)C(O)C(CO)O3)OC3C(C(O)C(O)C(C)O3)O)=CC(O)=C2C(=O)C1 ARGKVCXINMKCAZ-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- DSNBHJFQCNUKMA-SCKDECHMSA-N thromboxane A2 Chemical compound OC(=O)CCC\C=C/C[C@@H]1[C@@H](/C=C/[C@@H](O)CCCCC)O[C@@H]2O[C@H]1C2 DSNBHJFQCNUKMA-SCKDECHMSA-N 0.000 description 1
- OEKWJQXRCDYSHL-FNOIDJSQSA-N ticagrelor Chemical compound C1([C@@H]2C[C@H]2NC=2N=C(N=C3N([C@H]4[C@@H]([C@H](O)[C@@H](OCCO)C4)O)N=NC3=2)SCCC)=CC=C(F)C(F)=C1 OEKWJQXRCDYSHL-FNOIDJSQSA-N 0.000 description 1
- 229960002528 ticagrelor Drugs 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/043—Kallidins; Bradykinins; Related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
- A61K38/085—Angiotensins
-
- 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)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Molecular Biology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Oncology (AREA)
- Vascular Medicine (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Abstract
本发明属于生物技术领域,具体涉及一种靶向CD226分子的抑制剂在抗肿瘤转移中的应用。本发明针对血小板介导肿瘤转移的重要作用,靶向CD226分子这一重要靶点开发具有阻断作用的小分子抑制剂,能够破坏血小板与肿瘤细胞的相互作用,抑制肿瘤细胞的转移,对于研发控制肿瘤转移的新方法具有重要的价值。
Description
技术领域
本发明属于生物技术领域,具体涉及一种靶向CD226分子的抑制剂在抗肿瘤转移中的应用。
背景技术
血小板具有明确的促进肿瘤细胞转移的作用,主要的机制包括:肿瘤细胞促使血小板激活聚集,激活后的血小板互相交联,保护肿瘤细胞免受循环剪切力的伤害以及NK细胞的杀伤;血小板通过直接接触或者释放可溶性因子促进肿瘤失巢凋亡抵抗、EMT、血管生成以及外渗;血小板募集多种免疫细胞发挥免疫调节作用、协助肿瘤转移。这一过程中,细胞黏附分子起着重要作用,介导血小板与血小板、血小板与肿瘤细胞的交联,还可以通过各种信号通路启动血小板和肿瘤细胞的各种病理生理功能。
细胞黏附分子(Cell Adhesion Molecules,CAM)介导细胞与细胞以及细胞与细胞外基质(ECM)之间的黏附与沟通。血小板上的细胞黏附分子在促进肿瘤转移的过程中发挥其黏附与信号分子的作用。
肿瘤细胞转移是大部分恶性肿瘤患者面临的严峻问题,90%与肿瘤相关的死亡都是由于肿瘤细胞转移而非原发肿瘤引起的。即使经历了手术、化疗、靶向治疗以及免疫治疗,也依然存在着肿瘤细胞转移的巨大风险,转移始终是危及患者生命的危险。目前,临床治疗和肿瘤基础研究的重要方向之一,就是如何减少肿瘤细胞的转移路径。
肿瘤病人的高血小板状态,促进了肿瘤生长、血管生成、转移和肿瘤相关血栓形成而参与肿瘤发展的每个过程,为一个独立的不良预后因素。根据血小板参与肿瘤进展和众多实验模型以及用抗血小板药物预防肿瘤的流行病学研究的结果,可以把血小板作为一个潜在靶点,干预血小板有助于降低肿瘤转移和死亡率。因此,血小板对肿瘤的进展机制研究和抗肿瘤治疗措施的开发都具有深远意义和使用价值,也需要越来越多的实验去证实其联合其他抗肿瘤药物的临床效果。
现有的技术解决该技术问题所采用的方案主要是血小板抑制剂,在肿瘤治疗中已有研究的主要包括:1.环氧合酶抑制剂:例如阿司匹林,可以阻断花生四烯酸转化为TXA2,抑制血小板的聚集。一项大型的荟萃分析显示阿司匹林不仅能降低远处转移的风险,而且降低了肿瘤的死亡风险。2.ADP P2Y12受体拮抗剂:例如替格瑞洛在小鼠黑色素瘤及乳腺癌模型中显示具有抑制肿瘤黏附和转移的能力。3.血小板蛋白酶激活受体-1抑制剂:能阻断凝血酶介导的血小板活化聚集,敲除血小板蛋白酶激活受体-1降低了黑色素瘤细胞的侵袭能力。
但上述技术存在的问题是环氧合酶抑制剂、ADP P2Y12受体拮抗剂和血小板蛋白酶激活受体-1抑制剂等的副作用较大,因为这些分子都是血小板正常的止血、修复血管内皮细胞等生理功能所必须,这些药物在抑制肿瘤转移的同时,也在一定程度上破坏了血小板的正常生理功能,带来明显的副作用。因此,需要开发一种副作用较小的抗肿瘤转移的位点。
发明内容
为了解决上述技术问题,本发明提供了一种靶向CD226分子的抑制剂在抗肿瘤转移中的应用。
本发明的目的是提供一种靶向CD226分子的抑制剂在抗肿瘤转移中的应用。
优选的,上述靶向CD226分子的抑制剂在抗肿瘤转移中的应用,所述CD226分子位于血小板上。
优选的,上述靶向CD226分子的抑制剂在抗肿瘤转移中的应用,干预血小板上的CD226分子能减少血小板活化、抑制肿瘤转移。
优选的,上述靶向CD226分子的抑制剂在抗肿瘤转移中的应用,CD226分子是调控血小板和肿瘤细胞作用的位点,据此制备抑制肿瘤转移的抑制剂。
优选的,上述靶向CD226分子的抑制剂在抗肿瘤转移中的应用,所述抑制剂为小分子抑制剂或者大分子抑制剂。
优选的,上述靶向CD226分子的抑制剂在抗肿瘤转移中的应用,所述小分子抑制剂为血管紧张素III、新橙皮苷、[Leu5]-脑啡肽、朝藿定B、甲基橙皮苷、丹酚酸B、缓激肽(2-9)、松果菊苷、黄芪皂苷或金石蚕苷。
优选的,上述靶向CD226分子的抑制剂在抗肿瘤转移中的应用,所述肿瘤为小鼠骨肉瘤细胞系K7M2或小鼠黑素瘤细胞系B16F10。
优选的,上述靶向CD226分子的抑制剂在抗肿瘤转移中的应用,CD226分子是调控血小板和肿瘤细胞作用的位点,据此制备肿瘤检测试剂盒。
与现有技术相比,本发明具有以下有益效果:
已有研究发现,CD226对血小板的正常生理功能影响较低,实验发现靶向抑制剂对止血等功能影响轻微,副作用小,但对肿瘤转移有很好的抑制效果,因而是良好的抗肿瘤转移的治疗靶点。
针对血小板介导肿瘤转移的重要作用,靶向CD226分子这一重要靶点开发具有阻断作用的小分子抑制剂,期望能够破坏血小板与肿瘤细胞的相互作用,抑制肿瘤细胞的转移,对于研发控制肿瘤转移的新方法具有重要的价值。
需要说明的是,血小板CD226与其他细胞表达的CD226的抗肿瘤机制不一样;T细胞、NK细胞表达CD226分子,主要是作为活化型受体,激活T细胞、NK细胞直接杀伤肿瘤细胞;而本发明中,CD226在血小板上的作用不同,这种差异是由于血小板和T细胞/NK细胞的生理功能不同造成的,本发明的主要发现是,阻断血小板上CD226的功能,可以阻断血小板促进肿瘤转移的作用。
本发明首次发现并验证了10种小分子化合物阻断CD226的作用。
附图说明
图1为本发明的技术路线。
图2为血小板聚集实验结果;
从左至右依次为使用凝血酶诱导WT血小板、肿瘤细胞诱导WT血小板和肿瘤细胞诱导CD226KO(以下简称KO)血小板。
图3为荧光探针检测肿瘤细胞诱导血小板黏附结果;
A为荧光显微镜下肿瘤细胞分别诱导WT和KO结果,B为酶标仪检测荧光强度统计结果(n=4),标尺长度为275μm。
图4为流式细胞术检测肿瘤细胞诱导血小板活化结果;
A为肿瘤细胞分别诱导WT和KO血小板活化密度图,B为血小板活化标志物CD62P占比统计结果(n=3)。
图5为肿瘤转移体内实验转移灶大体结果;
A为CD226fl/fl小鼠和CD226fl/flPF4-Cre小鼠右肺下叶转移灶大体结果,B为全肺转移灶计数统计结果(n=4),标尺长度为75μm。
图6为肿瘤转移体内实验转移灶镜下HE染色结果;
A为CD226fl/fl小鼠和CD226fl/flPF4-Cre小鼠转移灶镜下HE染色结果,B为镜下转移灶计数统计结果(n=4)。
图7为10种候选抑制剂计算机分子对接评分结果。
图8为10种候选抑制剂化合物中文名称。
图9为金石蚕苷3D(A)和2D(B)对接互作示意图。
图10为荧光探针检测候选抑制剂抑制效率结果;
A为10种候选抑制剂抑制效率统计结果,B为荧光显微镜下丹酚酸B(Sal B)抑制效果图(n=4);标尺长度为275μm。
图11为流式细胞术检测候选抑制剂抑制效率统计结果(n=3)。
图12为流式细胞术检测候选抑制剂抑制效率密度图结果。
具体实施方式
为了使本领域技术人员更好地理解本发明的技术方案能予以实施,下面结合具体实施例和附图对本发明作进一步说明。
在本发明的描述中,如未特殊说明,所用试剂均为市售,所用方法均为本领域常规技术。
本发明的技术路线参见图1。
1.肿瘤诱导血小板聚集与活化(TCIPA)检测
培养CD155阳性的肿瘤细胞系,包括鼠源性细胞系小鼠骨肉瘤细胞系K7M2(BALB/c来源)和小鼠黑素瘤细胞系B16F10(C57BL/6J来源)。
制备小鼠血小板:抗凝后的小鼠全血1:1(体积比)与Tyrode's缓冲液(137mMNaCl,2mM KCl,12mM NaHCO3,0.3mM NaH2PO4,5.5mM葡萄糖,5mM HEPES,pH 7.3,0.35%BSA,溶剂为超纯水)混匀,室温下180×g离心10min,上清即为富血小板血浆(platelet richplasma,PRP);PRP转移到新的离心管中室温下2000rpm离心10min,沉淀即为血小板,加入适当体积Tyrode's缓冲液重悬后立即使用。
血小板聚集实验:血小板聚集仪(LBY-NJ4)测试杯中加入250μl血小板(1.5×108个/ml),实验组中30sec后加入4μl肿瘤细胞(4×105个/ml)悬液诱导聚集。采用凝血酶(1U/ml)作为阳性对照。检测结果参见图2,从左至右依次为使用凝血酶诱导WT(野生型)血小板、肿瘤细胞诱导WT(野生型)血小板和肿瘤细胞诱导CD226KO(CD226敲除)血小板。结果显示,肿瘤细胞诱导WT血小板聚集的能力接近凝血酶,而血小板敲除CD226分子后,肿瘤细胞几乎无法诱其聚集,说明CD226分子参与肿瘤细胞诱导的血小板聚集。
荧光探针检测肿瘤细胞诱导血小板黏附:将肿瘤细胞消化后以每孔100μl种于96孔板(5×105/ml),37℃孵箱隔夜培养。取洗涤后的血小板(1.5×108个/ml)加入DIL荧光探针37℃水浴避光染色5min,洗掉多余探针,将血小板以每孔100μl加入96孔板,37℃孵箱共培养30min,洗去未黏附血小板,4%多聚甲醛避光固定10min,放入酶标仪(540nm-570nm)检测荧光强度,在荧光显微镜RFP通道下进行拍照。检测结果参见图3,A为荧光显微镜下肿瘤细胞分别诱导WT和KO黏附的结果,B为酶标仪检测荧光强度统计结果(n=4)。结果显示,血小板敲除CD226分子后黏附在肿瘤细胞表面的能力显著下降。
流式细胞术检测肿瘤细胞诱导血小板活化:首先制备小鼠血小板悬液(1.5×108个/ml),胰酶消化肿瘤细胞后使用含体积分数10%胎牛血清的培养基重悬(5×105个/ml)。将300μl的血小板悬液与100μl的肿瘤细胞重悬液混匀,37℃细孵箱共培养30min,流式细胞术检测P-选择素(CD62P;克隆号:Psel.KO2.3)和αIIbβ3(CD41;克隆号:JON/A)等血小板表面活化标志物的水平。检测结果参见图4,A为肿瘤细胞分别诱导WT和KO血小板活化密度图,B为血小板活化标志物CD62P占比统计结果(n=3)。结果表明尽管血小板在敲除CD226后CD62P荧光强度最强的部分血小板无差别,但大部分血小板活化能力显著减弱。
综合三部分实验结果显示,血小板敲除CD226分子后,肿瘤诱导血小板聚集与活化的能力均减弱。
2.肿瘤转移体内实验
培养黑素瘤B16F10细胞,经尾静脉注射入小鼠体内(1.0×106个/只)。10天后安乐死小鼠取肺组织,取小鼠右肺下叶进行病理组织的大体观,取左肺下叶进行HE切片镜检,观察计数肿瘤细胞转移灶数量。
体内实验结果见图5和图6。结果显示,在大体上和镜下,血小板特异敲除CD226的小鼠肺部肿瘤转移灶均显著少于对照小鼠(n=4),说明血小板CD226分子可以促进肿瘤肺转移。
3.CD226抑制剂筛选
计算机分子对接模拟:针对CD226-CD55的结合口袋进行计算机虚拟筛选,期望获得与靶蛋白CD226结合力强的小分子化合物。从RCSB PDB数据库上下载CD226的晶体结构(PDB ID:6O3O)。使用 Maestro 11.4软件的Protein Preparation Wizard模块对CD226蛋白进行优化加氢,删除水分子,修补缺失残基、侧链等。随后进行能量优化(OPLS2005力场,RMSD为/>)。将处理好的蛋白用Receptor Grid Generation模块制作格点文件,以CD226结合口袋(界面关键氨基酸残基为THR46/GLN47/GLU49/SER64/HIS67/VAL70/AGR72/TYR113/PRO114/GLY116/THR117)生成格点文件。将Life Chemicals50KDiversity Library(含50.2K个化合物)、MCE Bioactive Compound Library Plus(含12.6K个化合物)的2D格式通过/>软件Lig Prep Module模块输出3D结构,以Virtual Screening Workflow模块进行虚拟筛选。利用Glide模块进行分子对接,首先采用高通量筛选(HTVS)模式筛选小分子化合物,挑选打分值前10%的化合物采用标准(SP)模式进行第二轮筛选;随后挑选打分值前10%采用高精度(XP)模式进行第三轮筛选,获得小分子化合物的排名。人工复核靶点与化合物结合力、化合物结构等,从排名前200的化合物中最终筛选10种经济易得、已知副作用轻微的化合物作为候选抑制剂。使用MOE软件Compute模块的Dock选项计算10种候选抑制剂的对接评分(Docking score),每种候选抑制剂输出排名前五的评分以及2D互作示意图。使用Pymol绘制3D互作示意图。筛选结果参见图7、图8和图9。图7为10种候选抑制剂计算机分子对接评分结果;图8为化合物中文名称,10种化合物对接评分均在-5分以下,说明它们在空间结构上均能很好地与CD226分子的结合口袋对接。图9为金石蚕苷3D(A)和2D(B)对接互作示意图,它与CD226分子形成多个氢键,并且能够很好地贴合结合口袋。
荧光探针检测候选抑制剂抑制效率:血小板染完色后加入候选抑制剂(25μg/ml),对照组依照药物储存液溶剂的不同加入等体积DMSO或双蒸水,其余步骤同第一部分荧光探针检测肿瘤细胞诱导血小板黏附。采用差异倍数(fold change,FC)表示抑制效率,即所有样本减去本底荧光强度后实验组与相应对照组荧光强度的比值。筛选结果参见图10,A为10种候选抑制剂抑制效率统计结果,B为荧光显微镜下丹酚酸B(Sal B)抑制效果图。结果表明10种候选抑制剂均可显著抑制肿瘤细胞与血小板之间的黏附。
流式细胞术检测候选抑制剂抑制效率:血小板在与肿瘤细胞悬液混匀前加入候选抑制剂(25μg/ml)或DMSO、双蒸水,其余步骤同第一部分流式细胞术检测肿瘤细胞诱导血小板活化。采用差异倍数表示抑制效率,即在肿瘤细胞大小的事件中实验组与对相应照组CD41阳性事件占比的比值。筛选结果参见图11和图12。图11为流式细胞术检测候选抑制剂抑制效率统计结果。图12为流式细胞术检测候选抑制剂抑制效率密度图结果。
综上所述,本发明的研究结果显示,1.血小板在促进肿瘤细胞转移中具有重要作用;2.CD226在血小板上高水平表达;3.干预血小板上的CD226分子可以有效减少血小板活化、抑制肿瘤转移。所以,CD226分子是调控血小板和肿瘤细胞作用的位点,并挑选出能够有效抑制肿瘤转移的小分子抑制剂,为开发预防和治疗肿瘤转移的药物提供了实验证据。
需要说明的是,本发明中涉及数值范围时,应理解为每个数值范围的两个端点以及两个端点之间任何一个数值均可选用,由于采用的步骤方法与实施例相同,为了防止赘述,本发明描述了优选的实施例。尽管已描述了本发明的优选实施例,但本领域内的技术人员一旦得知了基本创造性概念,则可对这些实施例做出另外的变更和修改。所以,所附权利要求意欲解释为包括优选实施例以及落入本发明范围的所有变更和修改。
显然,本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样,倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内,则本发明也意图包含这些改动和变型在内。
Claims (5)
1.靶向CD226分子的抑制剂在制备抗肿瘤转移药物中的应用,其特征在于,所述抑制剂是以丹酚酸B为唯一活性成分,所述肿瘤是指黑色素瘤。
2.根据权利要求1所述的靶向CD226分子的抑制剂在制备抗肿瘤转移药物中的应用,其特征在于,所述CD226分子位于血小板上。
3.根据权利要求2所述的靶向CD226分子的抑制剂在制备抗肿瘤转移药物中的应用,其特征在于,干预血小板上的CD226分子能减少血小板活化、抑制肿瘤转移。
4.根据权利要求2所述的靶向CD226分子的抑制剂在制备抗肿瘤转移药物中的应用,其特征在于,CD226分子是调控血小板和肿瘤细胞作用的位点,据此制备抑制肿瘤转移的抑制剂。
5.根据权利要求1-4任一项所述的靶向CD226分子的抑制剂在制备抗肿瘤转移药物中的应用,其特征在于,所述肿瘤为小鼠黑素瘤细胞系B16F10。
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202211066187.6A CN115624627B (zh) | 2022-09-01 | 2022-09-01 | 靶向cd226分子的抑制剂在抗肿瘤转移中的应用 |
US18/554,465 US20240189383A1 (en) | 2022-09-01 | 2023-04-26 | Application of Inhibitors Targeting CD226 Molecules in Anti-Tumor Metastasis |
PCT/CN2023/090750 WO2023179802A1 (zh) | 2022-09-01 | 2023-04-26 | 靶向cd226分子的抑制剂在抗肿瘤转移中的应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202211066187.6A CN115624627B (zh) | 2022-09-01 | 2022-09-01 | 靶向cd226分子的抑制剂在抗肿瘤转移中的应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN115624627A CN115624627A (zh) | 2023-01-20 |
CN115624627B true CN115624627B (zh) | 2024-04-12 |
Family
ID=84903101
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202211066187.6A Active CN115624627B (zh) | 2022-09-01 | 2022-09-01 | 靶向cd226分子的抑制剂在抗肿瘤转移中的应用 |
Country Status (3)
Country | Link |
---|---|
US (1) | US20240189383A1 (zh) |
CN (1) | CN115624627B (zh) |
WO (1) | WO2023179802A1 (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115624627B (zh) * | 2022-09-01 | 2024-04-12 | 中国人民解放军空军军医大学 | 靶向cd226分子的抑制剂在抗肿瘤转移中的应用 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104586831A (zh) * | 2013-10-30 | 2015-05-06 | 江苏丹晟生物科技有限公司 | 一种高含量丹酚酸b在制备抗宫颈癌药物中的应用及其制备方法 |
CN111297943A (zh) * | 2019-12-26 | 2020-06-19 | 闽江学院 | 超临界co2流体萃取丹参提取物的应用 |
CN114886908A (zh) * | 2022-06-27 | 2022-08-12 | 上海中医药大学 | 松果菊苷的医药用途 |
CN114939122A (zh) * | 2022-06-10 | 2022-08-26 | 南京中医药大学 | 天然植物来源的联合抗肿瘤药物组合物 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3293271A1 (en) * | 2016-09-12 | 2018-03-14 | The Provost, Fellows, Foundation Scholars, & the other members of Board, of the College of the Holy & Undiv. Trinity of Queen Elizabeth near Dublin | Marker and target as a diagnostic variable and target for therapy of metastatic cancer |
CN115624627B (zh) * | 2022-09-01 | 2024-04-12 | 中国人民解放军空军军医大学 | 靶向cd226分子的抑制剂在抗肿瘤转移中的应用 |
-
2022
- 2022-09-01 CN CN202211066187.6A patent/CN115624627B/zh active Active
-
2023
- 2023-04-26 US US18/554,465 patent/US20240189383A1/en active Pending
- 2023-04-26 WO PCT/CN2023/090750 patent/WO2023179802A1/zh unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104586831A (zh) * | 2013-10-30 | 2015-05-06 | 江苏丹晟生物科技有限公司 | 一种高含量丹酚酸b在制备抗宫颈癌药物中的应用及其制备方法 |
CN111297943A (zh) * | 2019-12-26 | 2020-06-19 | 闽江学院 | 超临界co2流体萃取丹参提取物的应用 |
CN114939122A (zh) * | 2022-06-10 | 2022-08-26 | 南京中医药大学 | 天然植物来源的联合抗肿瘤药物组合物 |
CN114886908A (zh) * | 2022-06-27 | 2022-08-12 | 上海中医药大学 | 松果菊苷的医药用途 |
Non-Patent Citations (3)
Title |
---|
ZHAOYANG ZENG等.Salvianolic acid B suppresses cell proliferationand induces apoptosis in osteosarcoma throughp38 mediated reactive oxygen species generation.ONCOLOGY LETTERS.第15卷第2679-2685页. * |
丹酚酸B对人喉癌Hep-2细胞增殖、凋亡及侵袭转移能力的影响及机制研究;郭俊宇等;医学研究杂志(第12期);第112页摘要 * |
血小板活化介导的肿瘤转移及丹参治疗的前景展望;钱文慧等;中草药;第41段(第2期);第311-314页 * |
Also Published As
Publication number | Publication date |
---|---|
US20240189383A1 (en) | 2024-06-13 |
WO2023179802A1 (zh) | 2023-09-28 |
CN115624627A (zh) | 2023-01-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Aspberg et al. | The C-type lectin domains of lecticans, a family of aggregating chondroitin sulfate proteoglycans, bind tenascin-R by protein–protein interactions independent of carbohydrate moiety | |
Kim et al. | The Hsp27-mediated IkBα-NFκB signaling axis promotes radiation-induced lung fibrosis | |
CN100497385C (zh) | 针对非功能性p2x7受体的抗体及其在癌症和其它病情的诊断和治疗中的用途 | |
CN107530402A (zh) | 抗lilrb抗体及其在检测和治疗癌症中的用途 | |
WO2006015079A2 (en) | Erm family binding agents and their use in diagnosis and treatment of proliferative conditions | |
Melo-Lima et al. | Necroptosis is associated with low procaspase-8 and active RIPK1 and− 3 in human glioma cells | |
CA2001815C (en) | Products and methods for controlling the suppression of the neoplastic phenotype | |
CN108138234A (zh) | 治疗骨髓增生性障碍的方法 | |
CN115624627B (zh) | 靶向cd226分子的抑制剂在抗肿瘤转移中的应用 | |
US20170114124A1 (en) | SLIT-ROBO-Myo9-RHOA PATHWAY AND CANCER | |
JP2010514722A (ja) | インビボでの神経膠芽腫細胞の浸潤を阻害するcd95活性の中和 | |
WO2013019945A2 (en) | Method for selection of chemotherapeutic agents for adenocarcinoma cancer | |
Liang et al. | N-acetyl-glucosamine sensitizes non-small cell lung cancer cells to TRAIL-induced apoptosis by activating death receptor 5 | |
CN104177500B (zh) | 一种肿瘤坏死因子相关凋亡配体融合蛋白及其制法和用途 | |
Campos‐Silva et al. | NKG2D‐ligands: Putting everything under the same umbrella can be misleading | |
Zhang et al. | Factor VII light chain-targeted lidamycin targets tissue factor-overexpressing tumor cells for cancer therapy | |
Lo Buono et al. | CD157 at the intersection between leukocyte trafficking and epithelial ovarian cancer invasion | |
Chang et al. | Esophageal cancer cells convert the death signal from TRAIL into a stimulus for survival during acid/bile exposure | |
CN101553259A (zh) | 显示cd63表面表达的细胞的细胞毒性介导 | |
Fann et al. | Identification and preclinical evaluation of the small molecule, NSC745887, for treating glioblastomas via suppressing DcR3-associated signaling pathways | |
US20100266577A1 (en) | Method of Cancer Treatment with Antagonists of FAS Inhibitors | |
Jacobsen et al. | B‐cell tolerance to the B‐cell receptor variable regions | |
Banerjee | Recent insights into the biology of Hodgkin's Lymphoma | |
EP1503780B1 (en) | Androgen-regulated pmepa1 gene and methods of using the same to inhibit cancer cell growth | |
Wise | The Role of Nucleolin in B-cell Lymphomas and Fas-Mediated Apoptotic Signaling |
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 | ||
GR01 | Patent grant | ||
GR01 | Patent grant |