CN108992443A - Application of Jolkinol type (II -2a) a thousand pieces of gold alkane type diterpene in reverse multiple drug resistance of tumor - Google Patents
Application of Jolkinol type (II -2a) a thousand pieces of gold alkane type diterpene in reverse multiple drug resistance of tumor Download PDFInfo
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- 229930004069 diterpene Natural products 0.000 title claims abstract description 43
- 150000004141 diterpene derivatives Chemical class 0.000 title claims abstract description 43
- 239000010931 gold Substances 0.000 title claims abstract description 43
- 229910052737 gold Inorganic materials 0.000 title claims abstract description 43
- 229930183887 jolkinol Natural products 0.000 title claims abstract description 43
- -1 gold alkane Chemical class 0.000 title claims abstract description 42
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 31
- 206010048723 Multiple-drug resistance Diseases 0.000 title claims abstract description 18
- 230000002441 reversible effect Effects 0.000 title claims abstract description 18
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin 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(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 abstract description 44
- 229940009456 adriamycin Drugs 0.000 abstract description 22
- 201000007270 liver cancer Diseases 0.000 abstract description 17
- 208000014018 liver neoplasm Diseases 0.000 abstract description 17
- 230000035755 proliferation Effects 0.000 abstract description 7
- 210000004027 cell Anatomy 0.000 description 18
- 201000011510 cancer Diseases 0.000 description 10
- 238000010586 diagram Methods 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 230000003833 cell viability Effects 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
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- 239000007788 liquid Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- 210000000582 semen Anatomy 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 5
- 238000010828 elution Methods 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 229930012538 Paclitaxel Natural products 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 229960001592 paclitaxel Drugs 0.000 description 4
- 239000013641 positive control Substances 0.000 description 4
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- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 229960001866 silicon dioxide Drugs 0.000 description 4
- 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 4
- 206010059866 Drug resistance Diseases 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000000470 constituent Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 238000002791 soaking Methods 0.000 description 3
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 2
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 229930185597 Euphorbia lathyris Natural products 0.000 description 2
- 241001553700 Euphorbia lathyris Species 0.000 description 2
- 230000001464 adherent effect Effects 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 239000000890 drug combination Substances 0.000 description 2
- 239000012259 ether extract Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 210000004185 liver Anatomy 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
- 230000036457 multidrug resistance Effects 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 229960001722 verapamil Drugs 0.000 description 2
- BJWWOUUGCAPHOV-UHFFFAOYSA-N 1,3-dibenzylisoquinoline Chemical class C=1C2=CC=CC=C2C(CC=2C=CC=CC=2)=NC=1CC1=CC=CC=C1 BJWWOUUGCAPHOV-UHFFFAOYSA-N 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
- 206010003445 Ascites Diseases 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000221079 Euphorbia <genus> Species 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
- 206010054949 Metaplasia Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 235000010627 Phaseolus vulgaris Nutrition 0.000 description 1
- 244000046052 Phaseolus vulgaris Species 0.000 description 1
- 235000016408 Podocarpus macrophyllus Nutrition 0.000 description 1
- 229920005654 Sephadex Polymers 0.000 description 1
- 239000012507 Sephadex™ Substances 0.000 description 1
- 208000004078 Snake Bites Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 244000162450 Taxus cuspidata Species 0.000 description 1
- 235000009065 Taxus cuspidata Nutrition 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000007541 cellular toxicity Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000009513 drug distribution Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 201000004409 schistosomiasis Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 241000894007 species Species 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
- 239000003826 tablet Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 231100000611 venom Toxicity 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 230000002087 whitening effect Effects 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/336—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having three-membered rings, e.g. oxirane, fumagillin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
- C07D301/32—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/32—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by aldehydo- or ketonic radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract
The present invention discloses application of Jolkinol type (II -2a) a thousand pieces of gold alkane type diterpene in reverse multiple drug resistance of tumor, belong to plants ' medicinal component and reverse multiple drug resistance of tumor technical field, Jolkinol type (II -2a) a thousand pieces of gold alkane type diterpene can significantly inhibit the proliferation of human liver cancer Adriamycin resistant cell, in view of its highly-safe, easily separated acquisition, Jolkinol type (II -2a) a thousand pieces of gold alkane type diterpene can be used as the regulator of reverse multiple drug resistance of tumor, be suitble to promote and apply.
Description
Technical field
The invention belongs to plants ' medicinal components and reverse multiple drug resistance of tumor technical field, in particular to Jolkinol type
Application of (II -2a) a thousand pieces of gold alkane type diterpene in reverse multiple drug resistance of tumor.
Background technique
According to " report of 2017 Cancer in China " display of National Cancer Center publication, there are about 10,000 people to make a definite diagnosis cancer daily in China,
And cancer total number of persons nearly accounts for the 40% of global cancer patient's sum, and chemotherapy is still main effectively treatment malignant tumour at present
Method, if having the tumor stem cell of remaining in patient's body, drug resistance easy to form is frequently resulted in adriamycin, Japanese yew
The sensibility of the drugs such as alcohol reduces, and causes the recurrence and transfer of tumour.Estimate according to American Cancer Society, 90% or more cancer
Disease patient dies of different degrees of drug resistance.Although domestic and international relevant researcher have found in succession a variety of calcium ion antagonists,
Derivative of bisbenzylisoquinoline alkaloid and cyclosporin A etc. can be capable of reverse multiple drug resistance of tumor (MDR) in vitro
Activity still since toxicity of these drugs to internal organs is excessive, influences drug distribution in vivo and metabolism etc., therefore mostly
Number not can enter clinical research, eventually become therapeutic agent.And China's species are abundant, Chinese medicine is even more to have long history,
Therefore, be conducive to the compound that reverse multiple drug resistance of tumor is obtained from Chinese tradition Chinese medicine using extraction and separation technology.
Semen euphorbiae, euphorbia plant also known as thousand liang of gold, Bodhisattva beans, Euphorbia lathyris etc. have treatment first recorded in " another name for Sichuan Province book on Chinese herbal medicine "
The effect of oedema, venomous snake bite, snail fever ascites.Modern pharmacology experiment shows the isolated singulation from semen euphorbiae
Leukaemia can be treated, for whitening, hair tonic etc. by closing object, isolated Jolkinol type (II -2a) a thousand pieces of gold alkane from semen euphorbiae
Type diterpene not yet finds the report about reverse multiple drug resistance of tumor at present.
Summary of the invention
The purpose of the present invention is to provide the new medical usages of Jolkinol type (II -2a) a thousand pieces of gold alkane type diterpene, i.e., inverse
Turn the application in tumor multi-medicine drug-resistant.
The application is cooperated by active constituent and other active constituents of Jolkinol type (II -2a) a thousand pieces of gold alkane type diterpene
Using the pharmacological action for playing reverse multiple drug resistance of tumor, more particularly for the purpose of by reverse multiple drug resistance of tumor phenomenon
The application of regulator, using chemotherapeutics as main component, treating cancer supplemented by regulator.
The application is with Jolkinol type (II -2a) a thousand pieces of gold alkane type diterpene and anti-tumor drug such as adriamycin, taxol
Deng with the use of the pharmacological action for playing reverse multiple drug resistance of tumor.
The application is that the lubricants, carboxylic such as magnesium stearate are added based on Jolkinol type (II -2a) a thousand pieces of gold alkane type diterpene
The fillers such as the disintegrating agents such as methyl starch sodium, lactose and other auxiliary materials, it is more can be made capsule, dripping pill, tablet, injection etc.
Kind form.
Jolkinol type (II -2a) a thousand pieces of gold alkane type diterpene is the separation from semen euphorbiae (Euphorbia lathyris)
Obtained active constituent, has the following structure:
Jolkinol type (II -2a) a thousand pieces of gold alkane type diterpene is that extraction separation method mainly uses second from semen euphorbiae
The raw material cheap and easy to get such as alcohol, petroleum ether, silica gel extracts separation, and simple process is easy to operate, can be used for industrial metaplasia
It produces.
The present invention utilizes external reverse multiple drug resistance of tumor model, assesses Jolkinol type (II -2a) thousand by MTT experiment
The influence that golden alkane type diterpene is proliferated cell strain, Jolkinol type (II -2a) a thousand pieces of gold alkane type diterpene do not have cell to normal cell
Toxicity is applied to liver cancer HepG2/Adr cell results and shows that Jolkinol type (II -2a) a thousand pieces of gold alkane type diterpene is in independent role
When HepG2/Adr cell strain, be proliferated no inhibiting effect to it, and when Jolkinol type (II -2a) a thousand pieces of gold alkane type diterpene with
When adriamycin or taxol are combined, HepG2/Adr cell viability is decreased obviously, and illustrates Jolkinol type (II -2a) a thousand pieces of gold alkane type
Diterpene has the pharmacological activity of reverse multiple drug resistance of tumor, has potential application.
Jolkinol type (II -2a) a thousand pieces of gold alkane type diterpene of the present invention can significantly inhibit human liver cancer anti-tumor drug such as Ah mould
The proliferation of the mdr cells such as element, taxol, it is contemplated that its highly-safe, easily separated acquisition, Jolkinol type (II -2a) a thousand pieces of gold alkane
Type diterpene can be used as the regulator of a kind of reverse multiple drug resistance of tumor, be suitble to promote and apply.
Detailed description of the invention
Fig. 1 is that Jolkinol type (II -2a) a thousand pieces of gold alkane type diterpene is living to the cell of HepG2/Adr cell strain in embodiment 2
Degree influences result schematic diagram；
Fig. 2 is Jolkinol type (II -2a) a thousand pieces of gold alkane type diterpene (20 μm of ol/L) and adriamycin (20 μm of ol/ in embodiment 3
Result schematic diagram is influenced on the cell viability of liver cancer persister HepG2/Adr when L) being combined；
Fig. 3 is Jolkinol type (II -2a) a thousand pieces of gold alkane type diterpene (0.8 μm of ol/L) and various concentration Ah mould in embodiment 3
Result schematic diagram is influenced on the cell viability of liver cancer persister HepG2/Adr when element combination；
Fig. 4 is Jolkinol type (II -2a) a thousand pieces of gold alkane type diterpene (4 μm of ol/L) and various concentration adriamycin in embodiment 3
Result schematic diagram is influenced on the cell viability of liver cancer persister HepG2/Adr when combination；
Fig. 5 is Jolkinol type (II -2a) a thousand pieces of gold alkane type diterpene (20 μm of ol/L) and various concentration adriamycin in embodiment 3
Result schematic diagram is influenced on the cell viability of liver cancer persister HepG2/Adr when combination.
Specific embodiment
Below by drawings and examples, invention is further described in detail, but the scope of the present invention is not limited to
The content, reagent is conventional commercial reagent or the reagent for preparing according to a conventional method unless otherwise specified in the present embodiment.
Embodiment 1
The extraction of Jolkinol type (II -2a) a thousand pieces of gold alkane type diterpene, the specific steps are as follows:
(1) dry semen euphorbiae seed is taken, with 95% ethanol solution soaking at room temperature of volume fraction 3 times, soaking time for the first time
For 48h, second, third time soaking time be for 24 hours, after merging extracting solution three times, ethyl alcohol to be recovered under reduced pressure, successively uses petroleum later
Ether, ethyl acetate, extracting n-butyl alcohol respectively obtain petroleum ether extract, acetic acid ethyl ester extract, n-butyl alcohol extract；
(2) by silicagel column on petroleum ether extract, pure acetone, the sample that methanol elutes and weighing are first collected, later
It mixes silica gel upper prop again again, and successively carries out gradient elution with petroleum ether/acetone that volume ratio is 50:1 to 0:1, collect elution
Liquid finally obtains 7 and is partially separated liquid, and number is Fr1~Fr7, later, the separating liquid for numbering as Fr3 is partly prepared HPLC,
Jolkinol type (II -2a) a thousand pieces of gold alkane type diterpene is finally obtained, structure is as follows.
The separating liquid for numbering as Fr4 is crossed into Sephadex LX-20 chromatographic column, with volume ratio be 1:1 chloroform/methanol into
Row elution, collects eluent, and number (Fr4.1~Fr4.3)；Then by Fr4.3 separating liquid ODS gradient elution, eluant, eluent
For 50%, 75%, 85%, 90% methanol-water, eluent is collected, number is Fr4.3.1~Fr4.3.6, finally by Fr4.3.5
Separating liquid silica gel column separating purification after the elution of petroleum ether/acetone (30:1) system, carries out half to the part Fr4.3.5.2 and prepares
HPLC obtains Jolkinol type (II -2a) a thousand pieces of gold alkane type diterpene, and structure is as follows, and the separating liquid for being Fr3 with number is extracted
It is identical.
Embodiment 2
Jolkinol type (II -2a) a thousand pieces of gold alkane type diterpene in vitro toxicity assessment experiment (thiazole blue laws), using implementation
Jolkinol type (II -2a) a thousand pieces of gold alkane type diterpene that example 1 is extracted, the specific steps are as follows:
(1) the HepG2/Adr cell for taking logarithmic phase to grow, 100 μ L are added in every hole in 96 orifice plates after cell count dilution
Cell suspension (1 × 104A/hole), after cell is adherent, cell is divided into three groups, i.e. blank control group, positive controls, reality
Test group:
1. complete medium is added in blank control group；
2. positive controls are that 20 μm of ol/L adriamycins and 20 μm of ol/L Verapamils are combined；
3. 20 μm of ol/L compound, that is, Jolkinol type (II -2a) a thousand pieces of gold alkane type diterpene are added in experimental group, similarly hereinafter；
3 multiple holes of every group of setting continue to cultivate 48h after dosing, 5mg/mL thiazolyl blue (MTT) are added later, places back in
After incubator is incubated for 4h, the dimethyl sulfoxide (DMSO) that then 120 μ L are added in every hole dissolves first a ceremonial jade-ladle, used in libation, is finally existed with microplate reader
The light absorption value in every hole is detected at 490nm wavelength；And cell viability is calculated separately by SPSS software.
Fig. 1 is influence result schematic diagram of Jolkinol type (II -2a) a thousand pieces of gold alkane type diterpene to HepG2/Adr cell strain,
It can be seen that Jolkinol type (II -2a) a thousand pieces of gold alkane type diterpene of 20 μm of ol/L is to the proliferation of HepG2/Adr cell without obvious
It influences, 20 μm of ol/L adriamycins and 20 μm of ol/L Verapamil combinations but can obviously inhibit liver cancer persister HepG2/Adr cell
Proliferation.
Embodiment 3
The external reverse multiple drug resistance of tumor experiment of Jolkinol type (II -2a) a thousand pieces of gold alkane type diterpene, using embodiment 1
Jolkinol type (II -2a) a thousand pieces of gold alkane type diterpene of extraction, the specific steps are as follows:
(1) the HepG2/Adr cell of logarithmic growth phase, is inoculated in 96 orifice plates, inoculum density, condition of culture, etc.
It is same as Example 2, after cell is adherent, cell is divided into blank control group, positive controls, negative control group and experiment
Group；
1. complete medium is added in blank control group；
2. positive controls select Verapamil and adriamycin to be combined, final concentration is 20 μm of ol/L；
3. negative control group is compound (final concentration is respectively 0.8 μm of ol/L, 4 μm of ol/L, 20 μm of ol/L)；
4. group I concentration is that (final concentration is respectively 40 μm of ol/ for the adriamycin of 0.8 μm of ol/L compound and various concentration
L, 20 μm of ol/L, 5 μm of ol/L, 1.25 μm of ol/L, 0.3125 μm of ol/L) combination；
II concentration of experimental group be 4 μm of ol/L compounds and various concentration adriamycin (final concentration is respectively 40 μm of ol/L, 20
μm ol/L, 5 μm of ol/L, 1.25 μm of ol/L, 0.3125 μm of ol/L) combination；
III concentration of experimental group be 20 μm of ol/L compounds and various concentration adriamycin (final concentration is respectively 40 μm of ol/L,
20 μm of ol/L, 5 μm of ol/L, 1.25 μm of ol/L, 0.3125 μm of ol/L) combination；
(2) each grouping is continued to detect after cultivating 48h, testing conditions and data processing method and embodiment 2 one
It causes；Wherein reversal index (RF)=compound and IC associated with adriamycin50/ only plus adriamycin IC50。
When Fig. 2 is Jolkinol type (II -2a) a thousand pieces of gold alkane type diterpene (20 μm of ol/L) and adriamycin (20 μm of ol/L) combination
To the influence result schematic diagram of liver cancer persister HepG2/Adr, it can be seen that experimental result is shown, when 20 μm of ol/L's
When the adriamycin of Jolkinol type (II -2a) a thousand pieces of gold alkane type diterpene and 20 μm of ol/L act on, human liver cancer Adriamycin resistant strain
Cell viability be decreased obviously, more can obviously inhibit liver cancer drug resistance than 20 μm of ol/L adriamycins and the combination of 20 μm of ol/L Verapamils
The proliferation of strain HepG2/Adr cell.
Fig. 3 is Jolkinol type (II -2a) a thousand pieces of gold alkane type diterpene (0.8 μm of ol/L) and when the combination of various concentration adriamycin pairs
The influence result schematic diagram of liver cancer persister HepG2/Adr, it can be seen that experimental result is shown, Jolkinol type (II -2a)
A thousand pieces of gold alkane type diterpene can inhibit the proliferation of liver cancer persister HepG2/Adr in 0.8 μm of ol/L to a certain extent, pass through software
Its IC can be obtained by handling resulting numerical value50For 159 μm of ol/L, can obtain RF according to above-mentioned reversal index calculation formula is 4.5.
To liver when Fig. 4 is Jolkinol type (II -2a) a thousand pieces of gold alkane type diterpene (4 μm of ol/L) and the combination of various concentration adriamycin
The influence result schematic diagram of cancer persister HepG2/Adr can reduce liver it can be seen that experimental result is shown after drug combination
The cell viability of cancer persister HepG2/Adr, its IC can be obtained by handling resulting numerical value by software50For 26.03 μm of ol/L, root
It is 28 that RF, which can be obtained, according to above-mentioned reversal index calculation formula.
Fig. 5 is Jolkinol type (II -2a) a thousand pieces of gold alkane type diterpene (20 μm of ol/L) and when the combination of various concentration adriamycin pairs
The influence result schematic diagram of liver cancer persister HepG2/Adr, it can be seen that experimental result is shown, it can be obvious after drug combination
Inhibit the proliferation of liver cancer persister HepG2/Adr cell, its IC can be obtained by crossing the resulting numerical value of software processing50For 14.32 μm of ol/
L, can obtain RF according to above-mentioned reversal index calculation formula is 50.
The above experimental result shows, 0.8 μm of ol/L, 4 μm of ol/L, Jolkinol type (II -2a) a thousand pieces of gold alkane of 20 μm of ol/L
When the adriamycin of type diterpene and various concentration is combined, the proliferation of liver cancer persister HepG2/Adr can be inhibited to varying degrees；Its
In when concentration is 0.8 μm of ol/L, can reversing tumor to a certain extent multidrug resistance, and be 20 μ in compound concentration
When mol/L, it can obviously inhibit the multidrug resistance of liver cancer Adriamycin resistant strain, i.e. presentation concentration dependent.
When adriamycin is replaced with the drugs such as taxol, also it is available with use the same effect of adriamycin.
Claims (1)
- Application of 1.Jolkinol type (II -2a) a thousand pieces of gold alkane type diterpene in reverse multiple drug resistance of tumor.
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