CN111166756B - 20(S)-人参皂苷-Rg3在逆转胶质瘤细胞对化疗药物的耐药性中的用途 - Google Patents
20(S)-人参皂苷-Rg3在逆转胶质瘤细胞对化疗药物的耐药性中的用途 Download PDFInfo
- Publication number
- CN111166756B CN111166756B CN201811340240.0A CN201811340240A CN111166756B CN 111166756 B CN111166756 B CN 111166756B CN 201811340240 A CN201811340240 A CN 201811340240A CN 111166756 B CN111166756 B CN 111166756B
- Authority
- CN
- China
- Prior art keywords
- ginsenoside
- glioma
- tmz
- mgmt
- cells
- 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
- 206010018338 Glioma Diseases 0.000 title abstract description 101
- 208000032612 Glial tumor Diseases 0.000 title abstract description 92
- 239000002246 antineoplastic agent Substances 0.000 title abstract description 23
- 229940044683 chemotherapy drug Drugs 0.000 title abstract description 17
- 206010059866 Drug resistance Diseases 0.000 title abstract description 11
- 230000014509 gene expression Effects 0.000 claims abstract description 41
- 108091046869 Telomeric non-coding RNA Proteins 0.000 claims abstract 2
- 150000003839 salts Chemical class 0.000 claims description 33
- 239000003112 inhibitor Substances 0.000 claims description 17
- 238000002360 preparation method Methods 0.000 claims description 16
- 230000005764 inhibitory process Effects 0.000 claims description 5
- 230000001225 therapeutic effect Effects 0.000 claims description 3
- RWXIFXNRCLMQCD-JBVRGBGGSA-N (20S)-ginsenoside Rg3 Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@H]1CC[C@]2(C)[C@H]3C[C@@H](O)[C@H]4[C@@]([C@@]3(CC[C@H]2C1(C)C)C)(C)CC[C@@H]4[C@@](C)(O)CCC=C(C)C)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O RWXIFXNRCLMQCD-JBVRGBGGSA-N 0.000 abstract description 89
- CKUVNOCSBYYHIS-UHFFFAOYSA-N (20R)-ginsenoside Rg3 Natural products CC(C)=CCCC(C)(O)C1CCC(C2(CCC3C4(C)C)C)(C)C1C(O)CC2C3(C)CCC4OC1OC(CO)C(O)C(O)C1O CKUVNOCSBYYHIS-UHFFFAOYSA-N 0.000 abstract description 85
- 210000004027 cell Anatomy 0.000 abstract description 64
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 abstract description 59
- 229960004964 temozolomide Drugs 0.000 abstract description 58
- 102100025825 Methylated-DNA-protein-cysteine methyltransferase Human genes 0.000 abstract description 33
- 102000015735 Beta-catenin Human genes 0.000 abstract description 14
- 108060000903 Beta-catenin Proteins 0.000 abstract description 14
- 230000006907 apoptotic process Effects 0.000 abstract description 13
- 101150042248 Mgmt gene Proteins 0.000 abstract description 8
- 230000002401 inhibitory effect Effects 0.000 abstract description 8
- 210000004881 tumor cell Anatomy 0.000 abstract description 7
- 230000019491 signal transduction Effects 0.000 abstract description 5
- 230000001404 mediated effect Effects 0.000 abstract description 3
- 238000011160 research Methods 0.000 abstract description 2
- 108040008770 methylated-DNA-[protein]-cysteine S-methyltransferase activity proteins Proteins 0.000 abstract 1
- 230000008092 positive effect Effects 0.000 abstract 1
- 101000796998 Bacillus subtilis (strain 168) Methylated-DNA-protein-cysteine methyltransferase, inducible Proteins 0.000 description 32
- 206010028980 Neoplasm Diseases 0.000 description 15
- 208000005017 glioblastoma Diseases 0.000 description 12
- 102000013814 Wnt Human genes 0.000 description 11
- 108050003627 Wnt Proteins 0.000 description 11
- 102200082402 rs751610198 Human genes 0.000 description 11
- 239000003814 drug Substances 0.000 description 10
- 230000004083 survival effect Effects 0.000 description 9
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 8
- 238000001262 western blot Methods 0.000 description 8
- 230000000973 chemotherapeutic effect Effects 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 230000003833 cell viability Effects 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 5
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 238000002512 chemotherapy Methods 0.000 description 5
- 229940127089 cytotoxic agent Drugs 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 229940126585 therapeutic drug Drugs 0.000 description 5
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 4
- 108020004414 DNA Proteins 0.000 description 4
- 241000699660 Mus musculus Species 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 238000010609 cell counting kit-8 assay Methods 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 230000002596 correlated effect Effects 0.000 description 4
- 231100000135 cytotoxicity Toxicity 0.000 description 4
- 230000003013 cytotoxicity Effects 0.000 description 4
- 238000000684 flow cytometry Methods 0.000 description 4
- 238000003119 immunoblot Methods 0.000 description 4
- 230000001965 increasing effect Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000011580 nude mouse model Methods 0.000 description 4
- 125000004430 oxygen atom Chemical group O* 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- 230000002441 reversible effect Effects 0.000 description 4
- 230000035945 sensitivity Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 102000053602 DNA Human genes 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 241000288906 Primates Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 102100030627 Transcription factor 7 Human genes 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000000411 inducer Substances 0.000 description 3
- 230000036210 malignancy Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 108020004999 messenger RNA Proteins 0.000 description 3
- 230000011987 methylation Effects 0.000 description 3
- 238000007069 methylation reaction Methods 0.000 description 3
- 238000003757 reverse transcription PCR Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 230000002195 synergetic effect Effects 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- 102100027308 Apoptosis regulator BAX Human genes 0.000 description 2
- 108050006685 Apoptosis regulator BAX Proteins 0.000 description 2
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 241000283707 Capra Species 0.000 description 2
- 102000003952 Caspase 3 Human genes 0.000 description 2
- 108090000397 Caspase 3 Proteins 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 2
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 2
- 101000972291 Homo sapiens Lymphoid enhancer-binding factor 1 Proteins 0.000 description 2
- 101000653540 Homo sapiens Transcription factor 7 Proteins 0.000 description 2
- 101000911513 Homo sapiens Uncharacterized protein FAM215A Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 102100022699 Lymphoid enhancer-binding factor 1 Human genes 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 101710179684 Poly [ADP-ribose] polymerase Proteins 0.000 description 2
- 102100023712 Poly [ADP-ribose] polymerase 1 Human genes 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 102100026728 Uncharacterized protein FAM215A Human genes 0.000 description 2
- 239000002250 absorbent Substances 0.000 description 2
- 230000002745 absorbent Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 238000003766 bioinformatics method Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- -1 e.g. Substances 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000003365 immunocytochemistry Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000007619 statistical method Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 108050008874 Annexin Proteins 0.000 description 1
- 102000000412 Annexin Human genes 0.000 description 1
- 102100035683 Axin-2 Human genes 0.000 description 1
- 101700047552 Axin-2 Proteins 0.000 description 1
- 238000009020 BCA Protein Assay Kit Methods 0.000 description 1
- 102100021663 Baculoviral IAP repeat-containing protein 5 Human genes 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 230000033616 DNA repair Effects 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 108010040476 FITC-annexin A5 Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 241000206672 Gelidium Species 0.000 description 1
- XIRZPICFRDZXPF-UHFFFAOYSA-N Ginsenoside Rg3 Natural products CC(C)=CCCC(C)(O)C1CCC(C2(CC(O)C3C4(C)C)C)(C)C1C(O)CC2C3(C)CCC4OC1OC(CO)C(O)C(O)C1OC1OC(CO)C(O)C(O)C1O XIRZPICFRDZXPF-UHFFFAOYSA-N 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
- 101710088172 HTH-type transcriptional regulator RipA Proteins 0.000 description 1
- 101000868273 Homo sapiens CD44 antigen Proteins 0.000 description 1
- 101001045751 Homo sapiens Hepatocyte nuclear factor 1-alpha Proteins 0.000 description 1
- 101000990912 Homo sapiens Matrilysin Proteins 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000283953 Lagomorpha Species 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 102100030417 Matrilysin Human genes 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
- 239000002033 PVDF binder Substances 0.000 description 1
- 244000131316 Panax pseudoginseng Species 0.000 description 1
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 1
- 235000003140 Panax quinquefolius Nutrition 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 241000283089 Perissodactyla Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 241001493546 Suina Species 0.000 description 1
- 108010002687 Survivin Proteins 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 230000004156 Wnt signaling pathway Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 238000011226 adjuvant chemotherapy Methods 0.000 description 1
- 238000011353 adjuvant radiotherapy Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 230000025084 cell cycle arrest Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000010219 correlation analysis Methods 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000010201 enrichment analysis Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229940014259 gelatin Drugs 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000008434 ginseng Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000029824 high grade glioma Diseases 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 238000010166 immunofluorescence Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 208000030173 low grade glioma Diseases 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 201000011614 malignant glioma Diseases 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 230000001035 methylating effect Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000019735 mitochondria-nucleus signaling pathway Effects 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 239000001397 quillaja saponaria molina bark Substances 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000010814 radioimmunoprecipitation assay Methods 0.000 description 1
- 238000003753 real-time PCR Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 239000012313 reversal agent Substances 0.000 description 1
- 229930182490 saponin Natural products 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 230000007781 signaling event Effects 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 150000003521 tetracyclic triterpenoids Chemical class 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 210000001364 upper extremity Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- 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
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供一种20(S)人参皂苷‑Rg3在逆转胶质瘤细胞对化疗药物的耐药性中的用途。研究发现20(S)人参皂苷‑Rg3通过抑制Wnt/β‑catenin信号通路和抑制LncRNA NKILA,从而抑制MGMT基因的表达,显著逆转胶质瘤细胞MGMT介导的对替莫唑胺的耐药性,促进肿瘤细胞的凋亡,为胶质瘤患者的治疗起到了十分积极的作用。
Description
技术领域
本发明涉及一种化学物质的新用途,特别是涉及一种提供20(S)-人参皂苷-Rg3在制备逆转胶质瘤细胞对化疗药物的耐药性的药物中的用途。
背景技术
20(S)-人参皂苷-Rg3(Ginsenoside Rg3),分子式C42H72O13,分子量785.01g/mol,CAS号:14197-60-5,从人参中分离出来的四环三萜皂苷单体。
胶质瘤是成人最常见的中枢神经系统原发性恶性脑肿瘤。目前,手术配合术后辅助放疗化疗是胶质瘤患者的首选方案。替莫唑胺(TMZ)是胶质瘤患者的一线化疗药物。尽管如此,胶质瘤的预后仍很差,高级别胶质瘤中位生存期仅为14.6个。替莫唑胺通过对DNA分子上鸟嘌呤第6位氧原子上的甲基化,诱导细胞周期停滞和细胞凋亡。然而,DNA修复蛋白MGMT(O6-甲基鸟嘌呤-DNA-甲基转移酶)通过去除甲基加合物来逆转TMZ的作用。因此,MGMT介导胶质瘤细胞对替莫唑胺的耐药性。再者,临床研究证明,MGMT低表达的患者对TMZ化疗较为敏感,这证明了MGMT的表达仍然是胶质瘤化疗耐药的主要原因。因此,胶质瘤细胞中MGMT表达的降低可能有助于克服对替莫唑胺的耐药性。.胶质瘤的快速复发和TMZ耐药是治疗的主要难点。因此,迫切需要寻找胶质瘤治疗的新疗法。
Wnt/β-catenin信号通路在包括胶质瘤在内的多种类型恶性肿瘤的发生、发展中起着举足轻重的作用。抑制β-catenin表达水平和转录因子TCF/LEF1表达水平对于Wnt/β-catenin信号传导,导致Wnt/β-catenin信号传导活性的下调。靶向Wnt/β-catenin通路是胶质瘤的一种新的治疗策略。现有技术中尚未出现关于20(S)-人参皂苷-Rg3与Wnt/β-cateni信号通路之间的关系的报道。
NKILA是近年发现的一种非编码长链RNA(LncRNA),具有调控基因表达的作用,但是NKILA在胶质瘤中的作用尚无文献报道,更没有NKILA和MGMT所介导的胶质瘤耐药性的研究报道。
发明内容
鉴于以上所述现有技术的缺点,本发明的目的在于提供20-(S)人参皂苷-Rg3在逆转胶质瘤细胞对化疗药物的耐药性中的用途,用于解决现有技术中胶质瘤对替莫唑胺的耐药性的问题。
基于实验发明人发现了20(S)人参皂苷-Rg3抑制Wnt/β-catenin/MGMT途径,抑制NKILA,从而抑制MGMT基因表达,并在体外和体内增强胶质瘤细胞对TMZ的化疗敏感性。
所述20(S)-人参皂苷-Rg3为现有物质,可以市购。
为实现上述目的及其他相关目的,本发明提供20(S)-人参皂苷-Rg3或其药学上可接受的盐在制备逆转胶质瘤细胞对化疗药物的耐药性的逆转剂中的用途。
所述制备逆转胶质瘤细胞对化疗药物的耐药性包括:提高肿瘤细胞对化疗药物的敏感性;和/或降低肿瘤细胞对化疗药物的耐药性。
本发明的另一方面提供了20(S)-人参皂苷-Rg3或其药学上可接受的盐在制备诱导胶质瘤细胞在化疗药物的作用下周期阻滞或凋亡的诱导剂中的用途。
本发明的另一方面提供了20(S)-人参皂苷-Rg3或其药学上可接受的盐在制备提高胶质瘤对化疗药物敏感性的促进剂中的用途。
所述提高是指与未施用20(S)-人参皂苷-Rg3抑制剂或其药学上可接受的盐、而只施用胶质瘤化疗药物相比。
进一步地,所述逆转剂、诱导剂以及促进剂并非20(S)-人参皂苷-Rg3抑制剂或其药学上可接受的盐单独作用于肿瘤细胞实现其作用,而是在肿瘤细胞在化疗药物的作用下实现。
进一步地,上述化疗药物是指选自替莫唑胺(temozolomide,TMZ);或者其他化疗药物。
本发明的另一方面提供了20(S)-人参皂苷-Rg3或其药学上可接受的盐在制备阻滞Wnt/β-catenin信号通路的阻滞剂中的用途。
本发明的另一方面提供了20(S)-人参皂苷-Rg3或其药学上可接受的盐在制备抑制MGMT基因表达的抑制剂中的用途。
本发明的另一方面提供了20(S)-人参皂苷-Rg3或其药学上可接受的盐在制备抑制LncRNA NKILA表达的抑制剂中的用途。
抑制MGMT基因表达包括但不限于:抑制MGMT基因活性,或者抑制MGMT基因转录或表达、抑制MGMT蛋白水平。
本发明的另一方面提供了20(S)-人参皂苷-Rg3或其药学上可接受的盐在制备抑制MGMT合成的抑制剂中的用途。
本发明的另一方面提供了20(S)-人参皂苷-Rg3或其药学上可接受的盐在制备促进DNA分子上鸟嘌呤第6位氧原子上的甲基化的促进剂中的用途。
所述DNA分子上鸟嘌呤第6位氧原子上的甲基化是在DNA分子在化疗药物的作用下实现的;而非单独施加20(S)-人参皂苷-Rg3或其药学上可接受的盐就可以实现的过程。
本发明的另一方面提供了20(S)-人参皂苷-Rg3或其药学上可接受的盐在制备具有以下任意一项或者多项作用的药物中的用途:提高胶质瘤细胞凋亡率、降低胶质瘤细胞存活力、和/或降低胶质瘤细胞存活率。
所述提高是指与未施用20(S)-人参皂苷-Rg3抑制剂或其药学上可接受的盐、而只施用胶质瘤化疗药物相比。
所述降低是指与未施用20(S)-人参皂苷-Rg3抑制剂或其药学上可接受的盐、而只施用胶质瘤化疗药物相比。
20(S)-人参皂苷-Rg3或其药学上可接受的盐可以是上述逆转剂、诱导剂、促进剂、阻滞剂、MGMT基因表达的抑制剂、MGMT合成的抑制剂或其他制剂中的唯一有效成分或者有效成分之一。
本发明的另一方面提供了20(S)-人参皂苷-Rg3或其药学上可接受的盐与胶质瘤化疗药物联合用于制备胶质瘤化疗药物中的用途。
本发明的另一方面提供了一种胶质瘤治疗药物组合物,包括治疗有效量的20(S)-人参皂苷-Rg3或其药学上可接受的盐,以及至少一种其他胶质瘤化疗药物。
进一步地,上述胶质瘤化疗药物是指选自替莫唑胺(temozolomide,TMZ)。
联合治疗的药物可以是以下形式中的任意一种:
一)将20(S)-人参皂苷-Rg3抑制剂或其药学上可接受的盐,与其他胶质瘤治疗药物分别制成独立的制剂,制剂的剂型可相同或不同,给药途径亦可相同或不同。
当其他胶质瘤治疗药物为化学药物时,给药形式可以比较丰富,可以是胃肠道给药亦可以是非胃肠道给药。一般推荐针对各化学药物的已知给药途径给药。所述胶质瘤化疗药可以是替莫唑胺(temozolomide,TMZ)。
进一步地,所述20(S)-人参皂苷-Rg3抑制剂或其药学上可接受的盐用于提高胶质瘤细胞对胶质瘤化疗药物的敏感性。
所述提高是指与未施用20(S)-人参皂苷-Rg3抑制剂或其药学上可接受的盐、而只施用胶质瘤化疗药物相比。
进一步地,所述20(S)-人参皂苷-Rg3抑制剂或其药学上可接受的盐用于降低胶质瘤细胞或肿瘤对胶质瘤化疗药物的耐药性。
所述降低是指与未施用20(S)-人参皂苷-Rg3抑制剂或其药学上可接受的盐、而只施用胶质瘤化疗药物相比。
二)将20(S)-人参皂苷-Rg3抑制剂或其药学上可接受的盐,和其他胶质瘤治疗药物配置成复方制剂,在将20(S)-人参皂苷-Rg3抑制剂或其药学上可接受的盐和其他胶质瘤治疗药物采用相同给药途径给药并同时施加时,可采用将两者配置成复方制剂的形式。
本发明的另一方面提供了一种非治疗性的抑制胶质瘤细胞的生长方法,包括:在20(S)-人参皂苷-Rg3或其药学上可接受的盐以及化疗药物的存在下,体外培养胶质瘤细胞,达到抑制胶质瘤细胞生长的目的。
本发明的另一方面提供了一种胶质瘤的治疗方法,为向对象施用20(S)-人参皂苷-Rg3或其药学上可接受的盐以及至少一种具有胶质瘤治疗药物。
药物可以在接受胶质瘤治疗前、中、后向对象施用。
上述药物、各种制剂或者方法主要针对的对象为哺乳动物,如啮齿类动物、灵长类动物等。所述哺乳动物优选为啮齿目动物、偶蹄目动物、奇蹄目动物、兔形目动物、灵长目动物等。所述灵长目动物优选为猴、猿或人。所述对象也可以是罹患胶质瘤的患者或者期待治疗的胶质瘤的个体。或者所述对象为胶质瘤患者或者期待治疗胶质瘤的个体的胶质瘤细胞。
上述胶质瘤细胞可以为离体胶质瘤细胞或者体内胶质瘤细胞。
上述“药学可接受的盐”是指20(S)-人参皂苷-Rg3与酸或者见形成的适合用于药物的盐,包括有机盐和无机盐。优选的盐是指与20(S)-人参皂苷-Rg3与酸形成的盐。酸或者件具体可列举如下:盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸,甲酸、乙酸、丙酸、草酸、丙二酸、琥铂酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、乙磺酸等有机酸,钠、钾等无机碱等。
上述20(S)-人参皂苷-Rg3或其药学上可接受的盐、或者其他药物、药物组合物的施用方式没有特别限制,代表性的施用方式包括:口服、瘤内、直肠、胃肠外(静脉内、肌肉、或皮下)和局部给药。
用于口服给药的固定剂型包括胶囊剂、片剂、丸剂、散剂、颗粒剂。在这些固体剂型中,活性化合物与至少一种常规赋形剂或载体混合,如柠檬酸钠、磷酸二钙、或与下述成分混合:(a)填料或者增容剂:例如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂:例如羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡络烷酮、蔗糖或者阿拉伯胶;(c)保湿剂:例如:甘油;(d)崩解剂:例如琼脂、碳酸钙、淀粉、硅酸盐、或碳酸钠;(e)缓溶剂:例如石蜡;(f)吸收促进剂,例如季铵化合物;(g)润湿剂,例如单硬脂酸甘油酯;(h)吸收剂,例如高龄土;(i)润滑剂:滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备。可以采用本领域的公知材料制备。
用于口服给药的液体剂型可包括药学上可接受的乳液、溶液、混悬液、糖浆、酊剂。除了活性化合物意外,液体剂型可包含本领域中常规的惰性吸收剂,如水或者其他溶剂、增溶剂、乳化剂,例如乙醇、异丙醇,丙二醇、碳酸乙酯、乙酸乙酯、二甲基甲酰胺,特别是棉籽油,花生油,橄榄油、芝麻油等或者这些物质的混合。
如上所述,本发明的20-(S)人参皂苷-Rg3在逆转胶质瘤细胞对抗肿瘤药物的耐药性中的用途,具有以下有益效果:
能够抑制MGMT基因的表达,抑制Wnt/β-catenin信号通路,抑制LncRNA NKILA,通过抑制MGMT修复TMZ对DNA分子上鸟嘌呤第6位氧原子上的甲基化,显著逆转胶质瘤细胞对TMZ的耐药性,促进肿瘤细胞的凋亡。
附图说明
图1a显示为本发明实施例1的3种胶质瘤细胞系加入20(S)-人参皂苷-Rg3后的存活率
图1b显示为本发明实施例1的3种胶质瘤细胞系加入TMZ后的存活率
图1c显示为本发明实施例2的3种胶质瘤细胞系的实验组和对照组的MGMT mRNA水平
图1d显示为本发明实施例2的3种胶质瘤细胞系的实验组和对照组的MGMT蛋白水平
图1e显示为本发明实施例2的3种胶质瘤细胞系的实验组和对照组免疫印迹分析结果图
图1f显示为本发明实施例2的3种胶质瘤细胞系的实验组免疫细胞化学实验结果图
图2显示为本发明实施例3蛋白印迹分析Wnt/β-catenin信号通路中相关蛋白的表达结果图
图3a显示为本发明实施例4中T98细胞系在24h\48h\72h在对照组、添加20(S)-人参皂苷-Rg3、TMZ以及20(S)-人参皂苷-Rg3+TMZ时的细胞存活率
图3b显示为本发明实施例4中U118细胞系在24h\48h\72h在对照组、添加20(S)-人参皂苷-Rg3、TMZ以及20(S)-人参皂苷-Rg3+TMZ时的细胞存活率
图3c显示为本发明实施例4中GBM-XX细胞系在24h\48h\72h在对照组、添加20(S)-人参皂苷-Rg3、TMZ以及20(S)-人参皂苷-Rg3+TMZ时的细胞存活率
图3d显示为本发明实施例4中3种细胞系在对照组、添加20(S)-人参皂苷-Rg3、TMZ以及20(S)-人参皂苷-Rg3+TMZ时流式细胞分析结果图
图3e显示为本发明实施例4的3种细胞系在对照组、添加20(S)-人参皂苷-Rg3、TMZ以及20(S)-人参皂苷-Rg3+TMZ时流式细胞分析统计结果(细胞凋亡率)图
图3f显示为本发明实施例4中T98细胞系在对照组、添加20(S)-人参皂苷-Rg3、TMZ以及20(S)-人参皂苷-Rg3+TMZ中细胞凋亡相关蛋白的蛋白印迹分析结果图
图4a显示为本发明实施例5中小鼠单独使用TMZ以及同时使用20(S)-人参皂苷-Rg3+TMZ4周内的肿瘤体积大小
图4b显示为本发明实施例5中小鼠单独使用TMZ以及同时使用20(S)-人参皂苷-Rg3+TMZ4周内的肿瘤重量
图4c显示为本发明实施例5中小鼠单独使用TMZ以及同时使用20(S)-人参皂苷-Rg3+TMZ4周肿瘤细胞中MGMT蛋白的蛋白印迹实验结果图
图5a显示为本发明实施例6中NKILA与胶质瘤患者的性别的相关结果图
图5b显示为本发明实施例6中NKILA与胶质瘤患者的年龄的相关结果图
图5c显示为本发明实施例6中NKILA与胶质瘤病理级别的相关结果图
图5d显示为本发明实施例6中NKILA与胶质瘤患者的复发相关结果图
图5e显示为本发明实施例6中NKILA与胶质瘤患者总生存期相关结果图
图5f显示为本发明实施例6中NKILA与胶质瘤患者MGMT表达的相关结果图
图6a显示为本发明实施例6中T98G细胞系实验组和对照组在20(S)-人参皂苷-Rg3处理后NKILA、MGMT的表达情况结果图
图6b显示为本发明实施例6中U118细胞系实验组和对照组在20(S)-人参皂苷-Rg3处理后NKILA、MGMT的表达情况结果图
图6c显示为本发明实施例6中GBM-XX细胞系实验组和对照组在20(S)-人参皂苷-Rg3处理后NKILA、MGMT的表达情况结果图
具体实施方式
以下通过特定的具体实例说明本发明的实施方式,本领域技术人员可由本说明书所揭露的内容轻易地了解本发明的其他优点与功效。本发明还可以通过另外不同的具体实施方式加以实施或应用,本说明书中的各项细节也可以基于不同观点与应用,在没有背离本发明的精神下进行各种修饰或改变。
在进一步描述本发明具体实施方式之前,应理解,本发明的保护范围不局限于下述特定的具体实施方案;还应当理解,本发明实施例中使用的术语是为了描述特定的具体实施方案,而不是为了限制本发明的保护范围;在本发明说明书和权利要求书中,除非文中另外明确指出,单数形式“一个”、“一”和“这个”包括复数形式。
当实施例给出数值范围时,应理解,除非本发明另有说明,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。除非另外定义,本发明中使用的所有技术和科学术语与本技术领域技术人员通常理解的意义相同。除实施例中使用的具体方法、设备、材料外,根据本技术领域的技术人员对现有技术的掌握及本发明的记载,还可以使用与本发明实施例中所述的方法、设备、材料相似或等同的现有技术的任何方法、设备和材料来实现本发明。
表1试剂和化学品
以下实施例中涉及的基本实验原理如蛋白印迹实验、Western印迹法、PCR、RT-PCR、流式细胞分析实验、免疫荧光实验等利用现有技术中的试剂和原理,在此不再赘述。
实施例1 20(S)-人参皂苷-Rg3和TMZ对胶质瘤的毒性作用
GBM-XX是来源于世界卫生组织IV级胶质瘤患者手术标本的原代细胞株,按照本院伦理委员会批准的方案进行切除,并得到患者事先知情同意。培养基由DMEM(美国加利福尼亚州卡尔斯巴德市的生命技术/Gibco公司)和10%胎牛血清(FBS;生命技术/Gibco,卡尔斯巴德,加利福尼亚州,美国),100u/ml青霉素和100μg/ml链霉素(Gibco,格兰德岛,纽约州)。细胞以1×105细胞/毫升接种。培养条件:温度37℃、5%CO2和100%湿度。
将T98G,U118和GBM-XX细胞以5000个细胞/孔接种在96孔平底板中,在补充有10%FBS的DMEM中培养,然后用递增浓度(0、60、120、240、360和480μM)的20(S)人参皂苷-Rg3、(0、75、150、300、450和600μM)TMZ以及DMSO(对照)处理。72小时后,每孔100μl培养基中加入10μl CCK-8混合试剂,37℃孵育2小时。用分光光度计在450nm处测量光密度(OD)。
MTT法显示20(S)-人参皂苷-Rg3和TMZ对多种胶质瘤细胞系表现出浓度依赖性杀伤作用,IC50(半数抑制浓度)值分别约为200μM和250μM(图1a,1b)。
为了避免单一试剂的明显细胞毒性,因此使用20(S)-人参皂苷-Rg3浓度为100μM和TMZ浓度为100μM进行以下研究。
实施例2 20(S)-人参皂苷-Rg3对MGMT的表达产生影响
用20(S)-人参皂苷-Rg3(100μM)处理T98G,U118和GBM-XX 72小时。
mRNA测定:根据制造商的方案使用TRIzol(TaKaRa,大连,中国)从细胞系中提取总RNA。对于mRNA分析,使用引物-脚本一步法RT-PCR试剂盒(TaKaRa,大连,中国)将RNA逆转录为cDNA。使用SYBR预混剂橡皮擦试剂盒(TaKaRa,大连,中国)通过RT-PCR扩增cDNA模板。GAPDH被用作内部对照。实时PCR一式三份进行。使用的引物序列如下:对于GAPDH引物如下;SEQ ID NO1.:5'-gtcaacggattggtctggtatt-3'(正向)和SEQ ID NO2.:5'-agtctgggggcagtgat-3'(反向);MGMT引物如下:SEQ ID NO3.:5′-gttatgaatgtaggagcccttatg-3′(正向),SEQ ID NO4.:5′-tgacaacgggaatgaagtaatg-3′(反向)。结果如图1c所示,20(S)-人参皂苷-Rg3显著抑制了胶质瘤细胞系的MGMT水平。
蛋白质分析:用免疫印迹法测定MGMT的表达(n=4)。与对照组比较p<0.001。免疫印迹显示T98G,U118和GBM-XX中的所有细胞均为MGMT阳性,而20(S)-人参皂苷-Rg3(100μmol/L作用72小时)处理后,所有胶质瘤细胞系中MGMT表达均受到明显抑制(图1d,1e)。另外,免疫细胞化学的结果与蛋白质印迹的结果相似(图1f)。
实施例3 20(S)-人参皂甙-Rg3通过调节Wnt/β-catenin途径抑制胶质母细胞瘤中MGMT的表达
用20(S)人参皂苷-Rg3(100μM)处理T98G,U118和GBM-XX 72小时,测定Wnt/β-catenin通路相关蛋白。
蛋白质印迹分析细胞用PBS洗涤,然后用RIPA裂解缓冲液(Solarbio,中国)和蛋白酶抑制剂(瑞士罗氏应用科学公司)裂解。使用BCA蛋白质测定试剂盒(BeyotimeBiotechnology,中国)测量蛋白质浓度。将等量的蛋白质进行10%SDS-聚丙烯酰胺凝胶电泳并转移到PVDF膜上。随后用5%脱脂牛奶封闭膜2小时,并在4℃下与一抗一起温育过夜。使用的一抗是抗MGMT(1:500,美国Abcam公司)和抗Survivin(1:1000,美国Abcam公司)抗β-catenin,抗CD44,抗C-Jun,抗C-Myc,抗cyclinD1,抗LEF1,抗TCF1/TCF7,抗MMP7,抗Axin2,抗Met,抗PARP,抗caspase3,抗BAX,抗Bcl2,抗cleaved-caspase3,抗-E-cadherin,抗N--cadherin,抗Vimentin(前述一抗均为:1:1000,Cell Signaling Technology,USA),抗GAPDH和二抗辣根过氧化物酶标记的山羊抗小鼠或山羊抗兔IgG抗体(1:1000,Beyotime,中国)。所有实验一式三份进行。
结果表明:如图2所示,Wnt信号通路的关键下游效应子β-catenin的表达被20(S)-人参皂苷-Rg3明显抑制;相关的核转录因子LEF1和TCF1/TCF7明显减少。此外,靶基因CD44、C-Jun、C-Myc、cyclinD1、Survivin和MMP7也发生了与MGMT相似的改变,但对MET和Axin-2无明显影响。
实施例4 20(S)-人参皂苷-Rg3增强替莫唑胺介导的化疗
将T98G,U118和GBM-XX细胞以5×103/孔的密度接种在96孔板中。细胞贴壁12小时后,用TMZ(100μM)或/和20(S)-人参皂苷-Rg3(100μM)或DMSO作为对照处理它们72小时。
在指定的时间点(24小时,48小时,72小时)使用细胞计数试剂盒-8溶液(CCK-8)测定法(Dojindo,日本)分别评价细胞活力和增殖。按照制造商的说明书将细胞与10μl CCK-8溶液孵育1小时。通过使用酶标仪(BioTek,Winooski,VT,USA)在450nm处测量光密度(OD)来评估数据。
结果表明:20(S)-人参皂苷-Rg3(100μmol/L持续3天本身没有明显的细胞毒性,TMZ(100μmol/L持续3天)单独在细胞系T98G、U118和GBM-XX中不引起明显的细胞毒性,然而,如图3(a、b、c)所示,20(S)-人参皂苷-Rg3在所有三种胶质瘤细胞系中都显著增强TMZ(100μmol/L持续3天)的细胞毒性。
根据制造商的说明书通过膜联蛋白V-FACS凋亡检测试剂盒(Becton Dickinson)测量细胞凋亡。(20(S)-人参皂苷-Rg3单独处理,TMZ单独处理,20(S)-人参皂苷-Rg3与TMZ联合72小时,用磷酸盐缓冲盐水洗涤细胞两次,并在300μl含有5μl Annexin V-FITC的1x结合缓冲液中温育10分钟,然后在25℃在黑暗中用碘化丙啶重悬5分钟。根据制造商的方案在1小时内使用FC 500流式细胞仪(Beckman Coulter,Brea,CA,USA)分析染色的细胞(含有200,000个细胞/样品)。
流式细胞仪分析中显示了类似的结果。从图3(d,e)可以看出,与对照相比,20(S)-人参皂苷-Rg3(100μmol/L,3天)或替莫唑胺(100μmol/L,3天)单独作用于胶质瘤细胞系时,两者均不能明显诱导细胞凋亡的增加,然而,20(S)人参皂苷-Rg3和TMZ联合应用可以显著增加胶质瘤细胞的凋亡效应。对于T98G细胞,对照组的早期和晚期凋亡百分率分别为5.4%和2.2%,20(S)-人参皂苷-Rg3组为5.4%和2.2%,TMZ组为6.7%和3.0%,而20(S)人参皂苷-Rg3+TMZ组的早期凋亡百分率最高为15.6%,晚期凋亡百分率最高为44.8%(P<0。05)。在U118和GBM-XX细胞系中的结果与T98G一致。
实验48h时,采用蛋白质印迹实验来检测T98G细胞中凋亡相关蛋白的表达变化,包括BAX,Bcl-2,caspase3,cleaved-caspase3,PARP,cleaved-PARP,结果如图3f所示,20(S)-人参皂苷-Rg3+TMZ增加胶质瘤细胞系T98G中BAX,cleaved-caspase3,cleaved-PARP的表达,反之降低Bcl-2,caspase3和PARP的表达。说明20(S)人参皂苷-Rg3(100μmol/L连续3d)+TMZ(100μmol/L连续3d)可通过线粒体信号通路诱导胶质瘤细胞凋亡。
实施例5 20(S)-人参皂苷-Rg3与TMZ在裸鼠种植瘤模型中显示协同活性
为了进一步检测20(S)-人参皂苷-Rg3在体内与TMZ协同活性的影响,将U118细胞注射到裸鼠右上肢腋下皮下,7天后,肿瘤达到100毫米左右,小鼠每天用20mg/kg TMZ单独或20mg/kg 20(S)人参皂苷-Rg3+20mg/kg TMZ治疗4周。用游标卡尺每周监测裸鼠肿瘤大小。4周后,处死小鼠,切除肿瘤,称重(n=6)。*免疫印迹法测定肿瘤组织的MGMT表达水平(n=3)。*与对照组比较p<0.05。
结果显示:与单独使用TMZ相比,20(S)-人参皂苷-Rg3加TMZ治疗显示出明显抑制的皮下肿瘤生长(图4a,4b)。皮下肿瘤的蛋白质印迹表明肿瘤组织中的MGMT水平被显著抑制(图4c)。表明20(S)-人参皂苷-Rg3与TMZ表现出优越的协同活性。更重要的是,20(S)-人参皂苷-Rg3和TMZ的组合没有表现出不良后果或明显的毒性,它在裸鼠中耐受性良好。
实施例6肿瘤生物信息学分析
NKILA是近年发现的一种非编码长链RNA(LncRNA),具有调控基因表达的作用。但是在胶质瘤中,NKILA的作用还未有研究。我们通过对TCGA数据库中的696个胶质瘤的基因表达谱芯片数据进行生物信息学分析,以明确在胶质瘤中,NKILA与肿瘤生物学性状的关系;分析方法包括相关性分析、生存分析、GSEA基因富集分析。我们发现,在胶质瘤中,NKILA与MGMT表达呈正相关,并与胶质瘤的恶性程度呈正相关,与患者的总生存时间呈负相关,同时我们发现,20(S)-人参皂苷-Rg3可以显著抑制NKILA。
统计分析
所有统计分析均使用R语言3.51(The R Foundation for StatisticalComputing)进行。数据表示为平均值±标准差。组间差异采用Student's t检验计算。所有p值均为双侧,p<0.05认为有统计学意义。
结果如图5a-5f所示,表明:(1)NKILA与胶质瘤患者的年龄、性别无关;(2)NKILA与胶质瘤恶性程度正相关:低级别胶质瘤NKILA表达低,高级别的胶质母细胞瘤NKILA表达高;(3)NKILA与胶质瘤复发有关:原发胶质瘤的NKILA表达低,复发胶质瘤的NKILA表达高;(4)NKILA和胶质瘤患者的总生存期呈负相关:NKILA高表达组,患者生存较差;NKILA低表达组,患者生存较好;以上四点提示NKILA在胶质瘤中是一个促癌基因和潜在的治疗靶点;(5)NKILA和胶质瘤患者的MGMT表达呈正相关,提示NKILA与胶质瘤的化疗耐药性相关。
在此基础上,我们通过PCR发现,20(S)-人参皂苷-Rg3可以显著抑制三个胶质瘤细胞的NKILA表达,抑制率达到80%左右;同时抑制MGMT的表达,MGMT表达的下降趋势和NKILA下降趋势一致(图6a,b,c)。
以上的实施例是为了说明本发明公开的实施方案,并不能理解为对本发明的限制。此外,本文所列出的各种修改以及发明中方法、组合物的变化,在不脱离本发明的范围和精神的前提下对本领域内的技术人员来说是显而易见的。虽然已结合本发明的多种具体优选实施例对本发明进行了具体的描述,但应当理解,本发明不应仅限于这些具体实施例。事实上,各种如上所述的对本领域内的技术人员来说显而易见的修改来获取发明都应包括在本发明的范围内。
Claims (1)
1.20(S)-人参皂苷-Rg3或其药学上可接受的盐在制备非治疗性抑制LncRNA NKILA表达的抑制剂中的用途。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201811340240.0A CN111166756B (zh) | 2018-11-12 | 2018-11-12 | 20(S)-人参皂苷-Rg3在逆转胶质瘤细胞对化疗药物的耐药性中的用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201811340240.0A CN111166756B (zh) | 2018-11-12 | 2018-11-12 | 20(S)-人参皂苷-Rg3在逆转胶质瘤细胞对化疗药物的耐药性中的用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN111166756A CN111166756A (zh) | 2020-05-19 |
CN111166756B true CN111166756B (zh) | 2024-01-30 |
Family
ID=70624368
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201811340240.0A Active CN111166756B (zh) | 2018-11-12 | 2018-11-12 | 20(S)-人参皂苷-Rg3在逆转胶质瘤细胞对化疗药物的耐药性中的用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN111166756B (zh) |
-
2018
- 2018-11-12 CN CN201811340240.0A patent/CN111166756B/zh active Active
Non-Patent Citations (8)
Title |
---|
20(S)-ginsenoside Rg3 Inhibits Human Glioma Cell Growth Through the Suppression of Voltage-gated K+ Channels;Qin Ru等;《Advanced Materials Research》;20140730;第998-999卷;160-163 * |
Additive antiangiogenesis effect of ginsenoside Rg3 with low-dose metronomic temozolomide on rat glioma cells both in vivo and in vitro;Caixing Sun等;《Journal of Experimental & Clinical Cancer Research》;20160213;第35卷(第32期);1-12 * |
BAI-CHENG HE等.Ginsenoside Rg3 inhibits colorectal tumor growth through the down-regulation of Wnt/β-catenin signaling.《International Journal of Oncology》.2011,第38卷437-445. * |
Effects of ginsenosides Re and Rg3 on intracellular redox state and cell proliferation in C6 glioma cells;Wai Yee Ng等;《Chinese Medicine》;20080711;第3卷(第8期);1-8 * |
Ginsenoside Rg3 inhibits colorectal tumor growth through the down-regulation of Wnt/β-catenin signaling;BAI-CHENG HE等;《International Journal of Oncology》;第38卷;437-445 * |
Qin Ru等.20(S)-ginsenoside Rg3 Inhibits Human Glioma Cell Growth Through the Suppression of Voltage-gated K+ Channels.《Advanced Materials Research》.2014,第998-999卷 * |
Wai Yee Ng等.Effects of ginsenosides Re and Rg3 on intracellular redox state and cell proliferation in C6 glioma cells.《Chinese Medicine》.2008,第3卷(第8期), * |
黄芩素通过调控Wnt/β-catenin信号通路抑制人胶质母细胞瘤细胞MGMT表达;卫翔宇等;《现代生物医学进展》;第18卷(第8期);1414-1418 * |
Also Published As
Publication number | Publication date |
---|---|
CN111166756A (zh) | 2020-05-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11839591B2 (en) | Pharmaceutical combination for the treatment of melanoma | |
KR102431257B1 (ko) | 담즙정체성 및 섬유증 질환의 치료 방법 | |
Zhang et al. | Harmine induces apoptosis and inhibits tumor cell proliferation, migration and invasion through down-regulation of cyclooxygenase-2 expression in gastric cancer | |
US8637493B2 (en) | Methods for treating glioblastoma | |
US10688104B2 (en) | Combination therapy with Notch and PD-1 or PD-L1 inhibitors | |
JP7125353B2 (ja) | Htlv-1関連脊髄症を治療することに用いるための医薬組成物 | |
Ramezani et al. | Rolipram potentiates bevacizumab-induced cell death in human glioblastoma stem-like cells | |
US9427413B2 (en) | Uses of hypoxia-inducible factor inhibitors | |
Wang et al. | Matrine suppresses NLRP3 inflammasome activation via regulating PTPN2/JNK/SREBP2 pathway in sepsis | |
JP2023179550A (ja) | 高サイトカイン血症および重篤なインフルエンザの処置または予防のための方法および化合物 | |
Cai et al. | Patchouli alcohol suppresses castration-resistant prostate cancer progression by inhibiting NF-κB signal pathways | |
Li et al. | Anthraquinone derivative C10 inhibits proliferation and cell cycle progression in colon cancer cells via the Jak2/Stat3 signaling pathway | |
JP7285001B2 (ja) | サフラナール製剤による肝臓癌治療の方法 | |
JP2006502117A (ja) | 抗腫瘍活性を上昇させるための化学療法薬物の組み合わせ | |
CN111166756B (zh) | 20(S)-人参皂苷-Rg3在逆转胶质瘤细胞对化疗药物的耐药性中的用途 | |
JP2019510743A (ja) | 痛風、ざ瘡及び糖尿病の予防又は治療のためのジメチルフマレート(dmf) | |
US20230026808A1 (en) | Compounds, compositions, and methods for treating ischemia-reperfusion injury and/or lung injury | |
US20240226214A1 (en) | Methods for treating inflammatory and fibrotic diseases and disorders | |
US20220339233A1 (en) | Compositions and methods for preventing recurrence of cancer | |
WO2020073642A1 (zh) | 靛玉红类化合物和硼替佐米在制备治疗多发性骨髓瘤的药物中的用途 | |
CN114984007B (zh) | Pradx-ezh2小分子抑制剂及其在制备肿瘤治疗药物中的用途 | |
CN114159427B (zh) | 一种包含安卓幸醇的组合物用于制备抑制肝癌细胞或肝癌干细胞生长的药物的用途 | |
US20230165873A1 (en) | Methods of Use for Single Molecule Compounds Providing Multi-Target Inhibition to Treat Covid 19 | |
KR102582097B1 (ko) | 야누스키나아제 표적 억제제 및 이의 용도 | |
US20120309821A1 (en) | Use of epigallocatechin-3-gallate for immune regulation |
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 |