WO2022186608A1 - Utilisation anticancéreuse d'extrait de gonades de stichopus japonicus ou de composés dérivés de celles-ci - Google Patents
Utilisation anticancéreuse d'extrait de gonades de stichopus japonicus ou de composés dérivés de celles-ci Download PDFInfo
- Publication number
- WO2022186608A1 WO2022186608A1 PCT/KR2022/002958 KR2022002958W WO2022186608A1 WO 2022186608 A1 WO2022186608 A1 WO 2022186608A1 KR 2022002958 W KR2022002958 W KR 2022002958W WO 2022186608 A1 WO2022186608 A1 WO 2022186608A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cancer
- extract
- sea cucumber
- composition
- present
- Prior art date
Links
- 239000000284 extract Substances 0.000 title claims abstract description 70
- 150000001875 compounds Chemical class 0.000 title claims abstract description 40
- 210000002149 gonad Anatomy 0.000 title claims abstract description 22
- 230000001093 anti-cancer Effects 0.000 title abstract description 21
- 241000965254 Apostichopus japonicus Species 0.000 title abstract description 5
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 84
- 201000011510 cancer Diseases 0.000 claims abstract description 74
- 210000001672 ovary Anatomy 0.000 claims abstract description 34
- 238000000034 method Methods 0.000 claims abstract description 30
- 241000251511 Holothuroidea Species 0.000 claims description 71
- 239000000203 mixture Substances 0.000 claims description 35
- 206010009944 Colon cancer Diseases 0.000 claims description 30
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 29
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 29
- 201000002528 pancreatic cancer Diseases 0.000 claims description 29
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 29
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 24
- 206010006187 Breast cancer Diseases 0.000 claims description 23
- 208000026310 Breast neoplasm Diseases 0.000 claims description 23
- 206010033128 Ovarian cancer Diseases 0.000 claims description 17
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 17
- 230000002710 gonadal effect Effects 0.000 claims description 14
- 230000002265 prevention Effects 0.000 claims description 12
- 201000009036 biliary tract cancer Diseases 0.000 claims description 11
- 208000020790 biliary tract neoplasm Diseases 0.000 claims description 11
- 230000006872 improvement Effects 0.000 claims description 11
- 230000002611 ovarian Effects 0.000 claims description 11
- 208000021010 pancreatic neuroendocrine tumor Diseases 0.000 claims description 10
- 208000033383 Neuroendocrine tumor of pancreas Diseases 0.000 claims description 9
- 206010067517 Pancreatic neuroendocrine tumour Diseases 0.000 claims description 9
- -1 saponin compounds Chemical class 0.000 claims description 7
- 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 claims description 6
- 239000001397 quillaja saponaria molina bark Substances 0.000 claims description 6
- 229930182490 saponin Natural products 0.000 claims description 6
- 208000022679 triple-negative breast carcinoma Diseases 0.000 claims description 6
- 239000000469 ethanolic extract Substances 0.000 claims description 4
- 230000001225 therapeutic effect Effects 0.000 claims description 3
- 230000008569 process Effects 0.000 abstract description 4
- 210000004027 cell Anatomy 0.000 description 70
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 35
- 238000011282 treatment Methods 0.000 description 25
- 239000008194 pharmaceutical composition Substances 0.000 description 18
- 230000000694 effects Effects 0.000 description 15
- 230000006907 apoptotic process Effects 0.000 description 13
- 201000010099 disease Diseases 0.000 description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 13
- 230000002147 killing effect Effects 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 238000000605 extraction Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 208000024891 symptom Diseases 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- 208000029742 colonic neoplasm Diseases 0.000 description 6
- 238000012790 confirmation Methods 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 235000013305 food Nutrition 0.000 description 6
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 5
- 239000003242 anti bacterial agent Substances 0.000 description 5
- 229940088710 antibiotic agent Drugs 0.000 description 5
- 239000002246 antineoplastic agent Substances 0.000 description 5
- 238000011161 development Methods 0.000 description 5
- 230000018109 developmental process Effects 0.000 description 5
- 239000012091 fetal bovine serum Substances 0.000 description 5
- 239000000796 flavoring agent Substances 0.000 description 5
- 235000013355 food flavoring agent Nutrition 0.000 description 5
- 201000009030 Carcinoma Diseases 0.000 description 4
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 238000005194 fractionation Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 230000035945 sensitivity Effects 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 231100000002 MTT assay Toxicity 0.000 description 3
- 238000000134 MTT assay Methods 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 230000001640 apoptogenic effect Effects 0.000 description 3
- 230000005880 cancer cell killing Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000002651 drug therapy Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 210000000936 intestine Anatomy 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 108010092160 Dactinomycin Proteins 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 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 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 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
- 229930006000 Sucrose Natural products 0.000 description 2
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 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 2
- 230000004611 cancer cell death Effects 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 230000022534 cell killing Effects 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 229960000640 dactinomycin Drugs 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 238000009169 immunotherapy Methods 0.000 description 2
- 239000004615 ingredient 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
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- MWWSFMDVAYGXBV-MYPASOLCSA-N (7r,9s)-7-[(2r,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical compound Cl.O([C@@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-MYPASOLCSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- UZOVYGYOLBIAJR-UHFFFAOYSA-N 4-isocyanato-4'-methyldiphenylmethane Chemical compound C1=CC(C)=CC=C1CC1=CC=C(N=C=O)C=C1 UZOVYGYOLBIAJR-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
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- 241000251468 Actinopterygii Species 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
- 241000271566 Aves Species 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 101150115876 Ccdc51 gene Proteins 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 206010011732 Cyst Diseases 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
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 239000004278 EU approved seasoning Substances 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 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
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 108091092878 Microsatellite Proteins 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 208000008846 Neurocytoma Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 208000012868 Overgrowth Diseases 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 244000228451 Stevia rebaudiana Species 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000032683 aging Effects 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
- 229930013930 alkaloid Natural products 0.000 description 1
- JAZBEHYOTPTENJ-JLNKQSITSA-N all-cis-5,8,11,14,17-icosapentaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O JAZBEHYOTPTENJ-JLNKQSITSA-N 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 238000001815 biotherapy Methods 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 238000010322 bone marrow transplantation Methods 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 229960001714 calcium phosphate Drugs 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- 229960003340 calcium silicate Drugs 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- 230000009702 cancer cell proliferation Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 208000031513 cyst Diseases 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000000235 effect on cancer Effects 0.000 description 1
- JAZBEHYOTPTENJ-UHFFFAOYSA-N eicosapentaenoic acid Natural products CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O JAZBEHYOTPTENJ-UHFFFAOYSA-N 0.000 description 1
- 229960005135 eicosapentaenoic acid Drugs 0.000 description 1
- 235000020673 eicosapentaenoic acid Nutrition 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- 229940009714 erythritol Drugs 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 235000013376 functional food Nutrition 0.000 description 1
- 201000008361 ganglioneuroma Diseases 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
- 239000008103 glucose Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000001794 hormone therapy Methods 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 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
- 239000000463 material Substances 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 201000007439 ovarian mucinous cystadenocarcinoma Diseases 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- HELXLJCILKEWJH-NCGAPWICSA-N rebaudioside A Chemical compound O([C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HELXLJCILKEWJH-NCGAPWICSA-N 0.000 description 1
- 238000009256 replacement therapy Methods 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 235000014102 seafood Nutrition 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 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
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/56—Materials from animals other than mammals
- A61K35/616—Echinodermata, e.g. starfish, sea cucumbers or sea urchins
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention relates to the anticancer use of a sea cucumber gonad extract, or the anticancer use of a saponin compound isolated from a sea cucumber gonad extract.
- Sea cucumber ( Stichopus japonicus ) is a traditional seafood used as an important ingredient in Asian countries, especially China, Japan and Korea. There are many bioactive substances isolated from sea cucumber. In particular, collagen peptides and polysaccharides are well known to exhibit various biological activities. The ovaries of sea cucumbers are called sea cucumbers and are famous for their delicacies.
- Cancer is a disease in which the mortality rate continues to increase every year due to changes in the environment, an aging population, and changes in lifestyle. It is one of the five leading causes of death worldwide and is the leading cause of death in Korea. Cancer treatment is performed through surgery, radiation therapy, and drug therapy. In the case of drug therapy, starting with the first-generation chemotherapy, the second-generation targeted drug therapy has been developed and used the most, but it faces a major problem of anticancer drug resistance.
- the inventors of the present invention have completed the present invention as a result of conducting a study on anticancer activity through natural sea cucumber.
- the problem to be solved by the present invention is to provide an anticancer use of a sea cucumber extract, preferably a gonadal extract of sea cucumber.
- a sea cucumber extract preferably a gonadal extract of sea cucumber.
- saponin compound isolated from the sea cucumber extract preferably a gonadal extract of sea cucumber. It also provides a method of treating or preventing cancer in an individual in need thereof by treating the sea cucumber extract.
- the present invention is to provide an anticancer use of a sea cucumber extract, preferably a gonad extract of a sea cucumber, and more preferably an ovarian extract of a sea cucumber.
- An object of the present invention is to provide an anticancer composition comprising a gonad extract of sea cucumber.
- the present invention provides a composition for the treatment, improvement, or prevention of cancer or tumor comprising a gonadal extract of sea cucumber.
- the present invention provides a composition for killing cancer cells or tumor cells comprising the gonadal extract of sea cucumber.
- An object of the present invention is to provide a method for treating or preventing cancer in an individual in need thereof by treating a sea cucumber extract, preferably a sea cucumber gonad extract, more preferably a sea cucumber ovary extract.
- the present invention is intended to provide a method for killing cancer cells or tumor cells of an individual in need by treating the gonadal extract of sea cucumber.
- Cancer as referred to herein may be understood in a broad sense including tumors.
- a tumor refers to a cell mass that has grown abnormally by the autonomous overgrowth of body tissues, and can be divided into benign tumors and malignant tumors. While benign tumors have a relatively slow growth rate and do not metastasize, malignant tumors infiltrate into surrounding tissues, grow rapidly, and spread or metastasize to various parts of the body, endangering life. Therefore, diseases induced by tumors are collectively defined as cancer, and malignant tumors and cancer are used without special distinction.
- anticancer may mean inhibiting the proliferation of cancer cells or killing cancer cells.
- the composition may inhibit cancer proliferation and induce apoptosis, but is not limited thereto.
- treatment refers to alleviating, attenuating, or ameliorating one or more signs of a disease or condition, preventing additional signs, inhibiting the disease or symptom, e.g., treatment of a disease or condition. preventing the occurrence, alleviating the disease or symptom, causing regression of the disease or symptom, alleviating the symptoms caused by the disease or symptom, or prophylactically and/or therapeutically of the disease or symptom It can be used in a broad sense including stopping a symptom.
- Prevention means any action that inhibits or delays the onset of a disease by administration of the composition according to the present invention.
- the ovary extract of sea cucumber means that the ovary, which is the reproductive organ of sea cucumber, is extracted with a solvent.
- a solvent As the gonads of sea cucumbers mature, it is known that the testes turn milky white and the ovaries turn red.
- the solvent may be water, a C1 to C4 lower alcohol, or a mixed solvent thereof, preferably ethanol or an aqueous ethanol solution.
- the extract of the present invention may be prepared according to a method for preparing an extract for an extraction target of a conventional animal, and specifically may be a cold extraction method, a hot extraction method, or a heat extraction method, and a conventional extraction device, ultrasonic grinding extractor or fractionation. gear is available.
- the sea cucumber gonad extract preferably the ovary extract
- the sea cucumber ovary extract can be extracted with a 45 to 85% (V/V) aqueous ethanol solution as a solvent, and more preferably, the sea cucumber ovary with a 48 to 55% (V/V) aqueous ethanol solution as a solvent.
- V/V aqueous ethanol solution
- 75 to 83% (V/V) aqueous ethanol solution may be extracted as a solvent.
- the sea cucumber gonad may undergo a process of fractionating the extract, and the sea cucumber ovary fraction obtained therefrom may also be included in the scope of the present invention.
- the extract obtained by extracting sea cucumber ovaries with an aqueous ethanol solution may be fractionated, and preferably, the aqueous ethanol solution may be 45 to 85% (V/V) aqueous ethanol solution.
- the fraction may preferably be fractionated by using the sea cucumber ovary extract as a solvent butanol.
- the fraction can be obtained by suspending the sea cucumber ovary extract in distilled water, etc. and then using a separatory funnel, etc.
- the sea cucumber ovary extract can be fractionated with butanol.
- the fractionation may be carried out by a fractionation method commonly used in the art.
- the prepared extract or the fraction obtained by performing the fractionation process may then be filtered or concentrated or dried to remove the solvent, and both filtration, concentration and drying may be performed.
- the filtration may be performed using filter paper or a reduced pressure filter, and the concentration may be concentrated under reduced pressure using a reduced pressure concentrator, for example, a rotary evaporator, and the drying may be performed by, for example, a freeze-drying method.
- the extract or fraction is excellent in inhibiting cancer cells, killing, or inhibiting the generation of cancer cells, and preferably, the cancer cells may include pancreatic cancer and colorectal cancer.
- the extract or fraction may inhibit cancer cell proliferation in a cancer cell line, and the cancer cell line may include a pancreatic cancer cell line or a colon cancer cell line.
- the extract or fraction of the present invention provides a use for treating, preventing and/or improving pancreatic cancer or colorectal cancer.
- the extract or fraction of the present invention may provide a use for apoptosis of pancreatic neuroendocrine tumor, treatment, prevention and/or improvement of pancreatic neuroendocrine tumor.
- the sea cucumber gonadal, preferably ovarian extract is an anticancer composition comprising any one or more compounds selected from the group consisting of the following formulas S2, S3, S4, S5, S6, S8 and S9, preferably anticancer A pharmaceutical composition is provided.
- One embodiment of the present invention provides a composition for the treatment, improvement, or prevention of cancer or tumor comprising the gonad extract of sea cucumber.
- the use of the compound for anticancer, treatment, improvement, or prevention of cancer or tumor there is provided the use of the compound for anticancer, treatment, improvement, or prevention of cancer or tumor.
- an anti-cancer method a method for treating, improving or preventing cancer or tumor using the compound.
- the present invention provides a composition for killing cancer cells or tumor cells comprising a gonadal extract of sea cucumber, or the following compounds isolated from the extract.
- the compound may be derived from nature or may be synthesized by a chemical synthesis method, and the process for obtaining the compound is not particularly limited.
- the compound may be extracted or isolated from the gonads of sea cucumbers, preferably extracted or isolated from the ovaries of sea cucumbers.
- the cancer may preferably be a solid cancer, and the solid cancer may include pancreatic cancer, colorectal cancer, biliary tract cancer, ovarian cancer, breast cancer, and the like.
- One embodiment of the present invention provides a composition for treating, improving, or preventing pancreatic cancer.
- the composition may include any one or more of the compounds S2, S3, S4, S5, S6, S8, and S9.
- One embodiment of the present invention provides a composition for treating, improving, or preventing breast cancer.
- the composition may include any one or more of the compounds S3, S4, S5, S6, S8, and S9.
- One embodiment of the present invention provides a composition for treating, improving, or preventing colon cancer.
- the composition comprises the compound It may include any one or more of S3, S4, S5, S6, S8, and S9.
- One embodiment of the present invention provides a composition for treating, improving, or preventing biliary tract cancer and/or ovarian cancer, comprising any one or more of compounds S2, S3 and S9.
- the ovarian cancer may include ovarian mucinous cystic cancer
- the breast cancer may include triple negative breast cancer.
- Ovarian mucinous cystic cancer is classified as a rare cancer among ovarian cancer, and is known to have different histological characteristics from epithelial cell carcinoma, which accounts for the majority of ovarian cancer.
- Triple-negative breast cancer is the most aggressive carcinoma among breast cancers with the characteristics of highly differentiated, rapid progression, frequent recurrence, and low response rate to treatment, but it has been developed because there is no known target for treatment (e.g., HER2). It is classified as a representative intractable cancer for which there is no targeted anticancer agent.
- One embodiment of the present invention provides a compound having excellent anticancer effect on colorectal cancer, pancreatic cancer, and the like among solid cancers.
- the composition according to an embodiment of the present invention is a saponin compound derived from sea cucumber gonadal, preferably ovarian extract, or sea cucumber gonadal, preferably ovary of the present invention for the treatment, prevention, and/or improvement of cancer or tumor. It can be used without limitation as long as it is a field to which the novel use can be applied, and it may be preferably provided in the form of a pharmaceutical composition or a food composition. Preferably, the food composition may be provided as a health functional food composition.
- the composition according to an embodiment of the present invention may be provided in the form of a pharmaceutical composition for cancer treatment or a food composition.
- One embodiment of the present invention may be provided as a pharmaceutical composition for killing cancer cells comprising the sea cucumber gonad extract of the present invention, or a compound derived therefrom.
- the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier.
- Pharmaceutically acceptable carriers included in the pharmaceutical composition of the present invention are commonly used in formulation, and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, methyl cellulose, methylhydroxybenzoate, talc, magnesium stearate, and mineral oil.
- the pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, and the like, in addition to the above components.
- the pharmaceutical carrier is a non-limiting example and is not limited to the above type.
- the pharmaceutical composition of the present invention may further include a known anticancer agent as an active ingredient, and may be used in combination with other known treatments for the treatment of a desired cancer.
- Other treatments include, but are not limited to, chemotherapy, radiation therapy, hormone therapy, bone marrow transplantation, stem-cell replacement therapy, other biological therapies, immunotherapy, and the like.
- anticancer agents examples include anticancer antibiotics such as dactinomycin (actinomycin D), doxorubicin (adriamycin), daunorubicin, idarubicin, mitok mitoxantrone, plicamycin, mitomycin C and bleomycin; and plant alkaloids vincristine, vinblastine, paclitaxel, docetaxel, etoposide, teniposide, topotecan and iridotecan, but is not limited thereto.
- anticancer antibiotics such as dactinomycin (actinomycin D), doxorubicin (adriamycin), daunorubicin, idarubicin, mitok mitoxantrone, plicamycin, mitomycin C and bleomycin
- the pharmaceutical composition of the present invention may be administered orally or parenterally, and is preferably applied by oral administration.
- a suitable dosage of the pharmaceutical composition of the present invention is variously prescribed depending on factors such as formulation method, administration method, age, weight, sex, pathological condition, food, administration time, administration route, excretion rate and reaction sensitivity of the patient.
- a preferred dosage of the pharmaceutical composition of the present invention may be in the range of 0.001-100 mg/kg, 0.005-90 mg/kg, 0.01-80 mg/kg based on an adult, and the dosage is conventional, such as administration method, administration purpose, etc. It can be controlled by factors considered as
- the pharmaceutical composition of the present invention is prepared in unit dosage form by formulating using a pharmaceutically acceptable carrier and/or excipient according to a method that can be easily carried out by a person of ordinary skill in the art to which the present invention pertains. or may be prepared by incorporation into a multi-dose container.
- the formulation may be in the form of a solution, suspension, syrup, or emulsion in oil or aqueous medium, or may be in the form of an extract, powder, powder, granule, tablet or capsule, and may additionally include a dispersant or stabilizer.
- the composition of the present invention when prepared as a food composition, it includes ingredients commonly added during food production, for example, proteins, carbohydrates, fats, nutrients, seasonings and flavoring agents.
- the above-mentioned carbohydrates include monosaccharides such as glucose, fructose and the like; disaccharides such as maltose, sucrose, oligosaccharides and the like; and polysaccharides, for example, conventional sugars such as dextrin, cyclodextrin, and the like, and sugar alcohols such as xylitol, sorbitol, and erythritol.
- a natural flavoring agent such as stevia extract or a synthetic flavoring agent such as saccharin may be used.
- An embodiment of the present invention provides a method of improving the cancer prevention, improvement or therapeutic effect of a sea cucumber gonadal extract by increasing any one or more saponin compounds selected from the group consisting of Formulas S2, S3, S4, S5, S6, S8 and S9. to provide.
- the sea cucumber gonad extract may include a sea cucumber ovary extract.
- One embodiment of the present invention provides a method for cancer prevention, improvement or treatment of a gonadal extract of sea cucumber, or a method for treating cancer in an individual in need thereof by treating the gonadal extract of sea cucumber, or a method for killing cancer cells.
- Another embodiment of the present invention provides a pharmaceutical for the treatment of cancer or a method for preparing the same, wherein the pharmaceutical includes a gonadal extract of sea cucumber.
- the cancer may include any one or more selected from the group consisting of pancreatic cancer, colorectal cancer, biliary tract cancer, ovarian cancer, breast cancer, pancreatic neuroendocrine tumor and colorectal cancer, preferably consisting of pancreatic cancer, pancreatic neuroendocrine tumor and colorectal cancer It may include any one or more cancers selected from the group.
- the gonad extract may include an ethanol extract of sea cucumber ovary, and preferably, the gonad extract may include 45 to 85% ethanol extract of sea cucumber ovary.
- One embodiment of the present invention is for cancer prevention, improvement or treatment use of any one or more compounds selected from the group consisting of the following formulas S2, S3, S4, S5, S6, S8 and S9, or treating the compound and requiring it
- a method for treating cancer in a subject, or a method for killing cancer cells is provided.
- Another embodiment of the present invention provides a pharmaceutical for the treatment of cancer or a method for preparing the same, wherein the pharmaceutical comprises any one or more compounds selected from the group consisting of Formulas S2, S3, S4, S5, S6, S8 and S9 mentioned herein.
- the cancer may include any one or more selected from the group consisting of pancreatic cancer, colorectal cancer, biliary tract cancer, ovarian cancer, breast cancer, pancreatic neuroendocrine tumor and colorectal cancer, preferably pancreatic cancer, colorectal cancer, biliary tract cancer, It may include any one or more selected from the group consisting of ovarian cancer, and breast cancer.
- the "subject" of the present invention means any animal, including humans, that has or can develop a target disease, and by administering the pharmaceutical composition of the present invention to an individual having or suspected of having a cancer-related disease, the individual is efficiently treated Or it can be prevented.
- the pharmaceutical composition of the present invention is not particularly limited as long as it is an individual for the purpose of cancer treatment or cancer cell death prevention or treatment, and can be applied to any individual.
- any animal such as monkey, dog, cat, rabbit, guinea pig, rat, mouse, cow, sheep, pig, goat, birds and fish may be used.
- administering means introducing a predetermined substance into a patient by any suitable method, and the administration route may be administered through any general route as long as it can reach a target tissue.
- Intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, intrapulmonary administration, rectal administration, etc. may be, but are not limited thereto.
- the anticancer pharmaceutical composition comprising the sea cucumber gonadal extract or a saponin compound derived therefrom according to the present invention has excellent apoptosis effect on cancer cells, so that it can treat pancreatic cancer, pancreatic neuroendocrine tumor, colorectal cancer, biliary tract cancer, ovarian cancer, breast cancer, etc. It can be usefully used for the treatment, prevention, or improvement of solid cancer.
- 1 is a result showing the results of confirming the apoptosis effect in pancreatic cancer and pancreatic neurocytoma with extracts obtained using different parts of sea cucumber.
- Figure 2 is the result of confirming the effect of colon cancer apoptosis with extracts obtained using different parts of sea cucumber.
- 3A to 3I are results confirming the apoptosis effect of compounds isolated from sea cucumber ovary extracts on pancreatic cancer and breast cancer cell lines.
- Figure 4a is the result of confirming the apoptosis effect of each compound on the MSS type colorectal cancer cell line
- Figure 4b is the result of confirming the apoptosis effect of each compound on the MSI-h type colorectal cancer cell line.
- sample number extraction part extraction solvent stock conc. (mg/ml) One Body 100% DW 25 2 Body 80% EtOH 25 3 Intestine 80% EtOH 25 4 Intestine 50% EtOH 25 5 Ovary 80% EtOH 25 6 Ovary 50% EtOH 25
- Samples 1-6 were obtained by extracting the body, intestine, and ovary of sea cucumber with solvents of the indicated concentrations, respectively.
- pancreatic cancer cell lines Two types of pancreatic cancer cell lines (CFPAC-1 and HPAC) and a pancreatic neuroendocrine tumor BON-1 cell line were tested for cytotoxicity of the sample.
- CFPAC-1 and HPAC Two types of pancreatic cancer cell lines
- a pancreatic neuroendocrine tumor BON-1 cell line were tested for cytotoxicity of the sample.
- 3 ⁇ 6 x 10 3 cells/well of each cell was seeded in a 96-well plate and cultured overnight at 37°C, 5% CO 2 in an incubator.
- each sample was dilution in each culture medium to 100ug/ml, and the cells were treated and cultured for 3 days. After 3 days, the survival rate of each cell was calculated by MTT assay.
- the experiment was repeated twice as a triplication.
- the ovarian extract of sea cucumber has a particularly superior cancer cell killing effect on pancreatic cancer cell lines, two types (CFPAC-1 and HPAC) and pancreatic neuroendocrine tumors compared to other sites.
- cytotoxicity tests were performed by seeding cells 1X10 3 cells/well into 96-well plates, and the following experimental protocols were all the same as for pancreatic cancer cell lines.
- Eicosapentaenoic acid and 8 types of compounds were prepared as follows.
- pancreatic cancer cell lines (CFPAC-1, HPAC, PANC-1 and BxPC-3), 1 pancreatic neuroendocrine tumor cell line (BON-1), 2 biliary tract cancer cell lines (Huct-1 and SNU1196), 2 ovarian cancer cell lines
- the species (Sk-OV3, and YDOV-151) and the breast cancer cell line MCF-7 were purchased from the laboratory of Professor Si-Young Song at Yonsei Medical Center, and the breast cancer cell lines MDA-MB-231 and BT-474 and the MSS colorectal cancer cell line SW620 and MSI-H
- the colorectal cancer cell line, HCT116 was purchased from a Korean cell line bank.
- CFPAC-1 is IMDM (containing 10% (v/v) fetal bovine serum (FBS) and 1% (v/v) antibiotics)
- HPAC and BON-1 are DMEM/F12 (containing 10% (v/v) FBS) and 1% (v/v) antibiotics)
- PANC-1 YDOV-151, SW620 and HCT116 in DMEM (containing 10% (v/v) FBS and 1% (v/v) antibiotics)
- RPMI1640 It was cultured in a culture medium containing 10% (v/v) FBS and 1% (v/v) antibiotics).
- each cell was seeded in a 96-well plate at 1 ⁇ 2 x 10 3 cells/well, and the remaining cells were seeded in a 96-well plate at 3 ⁇ 7 x 10 3 cells/well the day before the experiment. Then, it was cultured in an incubator at 37° C. 5% CO 2 overnight. On the day of the experiment, each sample was treated and cultured in cells for 3 days. After 3 days, the survival rate of each cell was calculated by MTT assay (Sigma Aldrich). The experiment was repeated two or more times as a triplication, and was analyzed with GraphPad Prism 8. The experimental results for colorectal cancer cell lines were statistically analyzed using SPSS statistics version 20.0.
- E1 was generally resistant to pancreatic cancer and breast cancer cell line MCF-7, and the S1 compound showed no apoptotic effect in all cancer cell lines tested.
- the S2 compound showed an apoptotic effect in the pancreatic cancer cell line, but was resistant to the breast cancer cell line MCF-7. Therefore, it was confirmed that the S2 compound was particularly effective in apoptosis of the pancreatic cancer cell line.
- the compounds S3, S4, S5, S6, S8, and S9 had an apoptotic effect on both breast cancer cell lines and pancreatic cancer cell lines.
- MTT assay was performed to obtain cytotoxic IC50 values for three single compounds S2, S3 and S9.
- apoptosis effects were also confirmed in biliary tract cancer, ovarian cancer and breast cancer cell lines.
- Table 3 the results shown in Table 3 below were obtained.
- S2, S3, and S9 all have an apoptosis effect on pancreatic cancer, biliary tract cancer, ovarian cancer and breast cancer at a certain concentration or more, so it is used for treatment, improvement of pancreatic cancer, biliary tract cancer, ovarian cancer or breast cancer it can be seen that
- S2, S3 and S9 all showed relatively high sensitivity to YDOV151, especially among ovarian cancer cell lines.
- the YDOV151 cell line is an ovarian mucinous cystadenocarcinoma cell line constructed in the Obstetrics and Gynecology laboratory of Severance Hospital. It is known to have different histological characteristics.
- the S2, S3 and S9 showed high sensitivity to the ovarian mucinous cyst cancer cell line.
- triple-negative breast cancer type MDA-BM-231 cell line showed high sensitivity to S2, S3 and S9.
- Triple-negative breast cancer is the most aggressive carcinoma among breast cancers with the characteristics of high differentiation, rapid progression, frequent recurrence, and low response rate to treatment. classified as cancer. Therefore, the single extract of sea cucumber ovary shows a specific sensitive effect in ovarian mucinous cystic cancer and triple-negative breast cancer, which are representative intractable cancers among ovarian cancer and breast cancer. It is considered
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Marine Sciences & Fisheries (AREA)
- Zoology (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicines Containing Plant Substances (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
La présente invention concerne une utilisation anticancéreuse d'un extrait de gonades de Stichopus Japonicus, de préférence, un extrait de ses ovaires. La présente invention concerne une utilisation anticancéreuse de composés isolés d'un extrait de gonades de Stichopus Japonicus, de préférence, un extrait de ses ovaires. De plus, l'invention concerne un procédé qui traite un extrait de Stichopus Japonicus pour traiter le cancer ou prévenir le cancer d'un individu nécessitant celui-ci.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR10-2021-0027739 | 2021-03-02 | ||
KR1020210027739A KR102659740B1 (ko) | 2021-03-02 | 2021-03-02 | 해삼 생식선 추출물 또는 이로부터 유래된 화합물의 항암 용도 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2022186608A1 true WO2022186608A1 (fr) | 2022-09-09 |
Family
ID=83155494
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/KR2022/002958 WO2022186608A1 (fr) | 2021-03-02 | 2022-03-02 | Utilisation anticancéreuse d'extrait de gonades de stichopus japonicus ou de composés dérivés de celles-ci |
Country Status (2)
Country | Link |
---|---|
KR (1) | KR102659740B1 (fr) |
WO (1) | WO2022186608A1 (fr) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20240044698A (ko) | 2022-09-29 | 2024-04-05 | 엘지디스플레이 주식회사 | 표시 장치 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20130060475A (ko) * | 2011-11-30 | 2013-06-10 | 유한회사 해원 | 해삼 추출물 또는 이의 분획물을 유효성분으로 함유하는 항암용 약학조성물 |
CN108997473A (zh) * | 2018-08-31 | 2018-12-14 | 山东省科学院生物研究所 | 一种非海参烷型海参皂苷及其制备方法与应用 |
-
2021
- 2021-03-02 KR KR1020210027739A patent/KR102659740B1/ko active IP Right Grant
-
2022
- 2022-03-02 WO PCT/KR2022/002958 patent/WO2022186608A1/fr active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20130060475A (ko) * | 2011-11-30 | 2013-06-10 | 유한회사 해원 | 해삼 추출물 또는 이의 분획물을 유효성분으로 함유하는 항암용 약학조성물 |
CN108997473A (zh) * | 2018-08-31 | 2018-12-14 | 山东省科学院生物研究所 | 一种非海参烷型海参皂苷及其制备方法与应用 |
Non-Patent Citations (4)
Title |
---|
AMININ DMITRY, MENCHINSKAYA EKATERINA, PISLIAGIN EVGENY, SILCHENKO ALEXANDRA, AVILOV SERGEY, KALININ VLADIMIR: "Anticancer Activity of Sea Cucumber Triterpene Glycosides", MARINE DRUGS, vol. 13, no. 3, 6 March 2015 (2015-03-06), pages 1202 - 1223, XP055963840, DOI: 10.3390/md13031202 * |
ESO AMIRUDDIN, UINARNI HERLINA, TOMMY THOMAS, KAROBUANA SITEPU RYANTO, KURNIA EFFENDI IWAN, ARIESTIYANTO YUSTINUS CHARLES, HUTASOI: "A Reviews on Use of Sea Cucumber as a Treatment for Oral Cancer", SYSTEMATIC REVIEWS IN PHARMACY, vol. 11, no. 05, 1 June 2020 (2020-06-01), XP055963836, ISSN: 0976-2779, DOI: 10.31838/srp.2020.5.44 * |
MASHJOOR, SAKINEH YOUSEFZADI, MORTEZA PISHEVARZAD, FATEMEH: "Assessment of anticancer potential of selected Holothuria species", INDIAN JOURNAL OF TRADITIONAL KNOWLEDGE, NATIONAL INSTITUTE OF SCIENCE COMMUNICATION AND INFORMATION RESOURCES, NEW DELHI - INDIA, vol. 18, no. 2, 1 April 2019 (2019-04-01), New Delhi - India , pages 272 - 280, XP018030393 * |
SILCHENKO ALEXANDRA S.; KALINOVSKY ANATOLY I.; AVILOV SERGEY A.; ANDRYJASCHENKO PELAGEYA V.; DMITRENOK PAVEL S.; YURCHENKO EKATERI: "Cladolosides C4, D1, D2, M, M1, M2, N and Q, new triterpene glycosides with diverse carbohydrate chains from sea cucumberCladolabes schmeltzii. An uncommon 20,21,22,23,24,25,26,27-okta-nor-lanostane aglycone. The synergism of inhibitory action of non-toxic dose of the glycosides and radioactive irra", CARBOHYDRATE RESEARCH, PERGAMON, GB, vol. 468, 7 August 2018 (2018-08-07), GB , pages 36 - 44, XP085467607, ISSN: 0008-6215, DOI: 10.1016/j.carres.2018.08.003 * |
Also Published As
Publication number | Publication date |
---|---|
KR20220124040A (ko) | 2022-09-13 |
KR102659740B1 (ko) | 2024-04-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5755633B2 (ja) | 新規サルビアノール酸化合物l、その調製方法及び使用 | |
RU2455002C2 (ru) | Композиция, включающая оридонин и предназначенная для лечения резистентных злокачественных опухолей | |
TWI422377B (zh) | 用於促進抗癌治療活性之方法及組成物 | |
WO2005003145A1 (fr) | Extrait de shanzhuyu et utilisations associees | |
WO2022186608A1 (fr) | Utilisation anticancéreuse d'extrait de gonades de stichopus japonicus ou de composés dérivés de celles-ci | |
US20100297760A1 (en) | Pharmaceutical composition and a method for treatment of prostate cancer | |
KR101131224B1 (ko) | 염주괴불주머니 유래 쿠마린계 화합물, 및 이를 함유하는 항암용 조성물 | |
WO2011008052A2 (fr) | Composition pour la prévention ou le traitement de maladies osseuses comprenant du daropate de colforsine | |
CN111743883A (zh) | 二苯甲酮衍生物组合物及其制备方法和用途 | |
Peng et al. | Dehydrocostus lactone inhibits the proliferation of esophageal cancer cells in vivo and in vitro through ROS-mediated apoptosis and autophagy | |
WO2012030150A2 (fr) | Composition contenant un extrait de solvant organique d'ailante glanduleux pour prévenir et traiter le cancer de la prostate | |
CN101977612A (zh) | 苯酚苷衍生物在制备抗细胞增生疾病组合物中的应用 | |
US8227512B2 (en) | Pharmaceutical composition containing daurinol for the prevention and treatment of cancers | |
JP2012520301A (ja) | エストロゲン化合物及びその使用方法 | |
KR101186264B1 (ko) | 산자나무 추출물 또는 이로부터 분리된 화합물을 포함하는 il-6으로 매개되는 질환 또는 라이노바이러스 감염성 질환의 예방 또는 치료용 조성물 | |
US10501472B2 (en) | Method to isolate inoscavin a from Fulviformes fastuosus and medicinal preparation thereof to treat rhabdomyosarcoma cancer conditions | |
WO2012030142A2 (fr) | Composition pour traiter le cancer de la prostate comprenant un extrait de nard | |
KR101201866B1 (ko) | 고미신-a를 유효성분으로 함유하는 암 예방 및 치료를 위한 약학 조성물 | |
KR100361480B1 (ko) | 미크로콕신의 항암제로서의 용도 | |
US20240115537A1 (en) | Composition for preventing or treating breast cancer comprising compound derived from dendropanax morbiferus | |
CN111494397B (zh) | 麦冬皂苷类化合物在制备预防和治疗肿瘤的药物中的用途 | |
KR100471580B1 (ko) | 뱀딸기 추출물 및 영지버섯 추출물 혼합물의 세포사멸증진제로서의 용도 | |
KR20040036092A (ko) | 진세노사이드 Rh2 및 Rg3 항암 조성물 | |
WO2024016142A1 (fr) | Utilisation d'une composition de bergaptène, de quercétine et de flavone dans la préparation d'un médicament pour le traitement du cancer | |
WO2012030148A2 (fr) | Composition contenant un extrait de racine de chardon pour prévenir et traiter le cancer de la prostate |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 22763589 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 22763589 Country of ref document: EP Kind code of ref document: A1 |