CN106562956A - New use of natural product Eupalinolide J - Google Patents
New use of natural product Eupalinolide J Download PDFInfo
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- CN106562956A CN106562956A CN201610975687.XA CN201610975687A CN106562956A CN 106562956 A CN106562956 A CN 106562956A CN 201610975687 A CN201610975687 A CN 201610975687A CN 106562956 A CN106562956 A CN 106562956A
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- eupalinolide
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- breast cancer
- stat3
- negative breast
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- 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
- A61K31/365—Lactones
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Abstract
The invention discloses a new use of a natural product Eupalinolide J; the natural product Eupalinolide J can be used as an STAT3 inhibitor, and furthermore, the natural product Eupalinolide J is used as a raw material for preparing anti-breast cancer drugs. The invention discloses an inhibitory effect of the Eupalinolide J on STAT3 in triple-negative breast cancer cells for the first time; the compound is proved to be an efficient STAT3 inhibitor, and provides a theoretical basis for new triple-negative breast cancer targeting therapy and clinic entering of the Eupalinolide J.
Description
Technical field
The present invention relates to a kind of new application of natural product, more particularly to a kind of natural product Eupalinolide J's is new
Purposes.
Background technology
Breast carcinoma is a kind of global women malignant tumor occurred frequently, and in recent years sickness rate is increased significantly trend.Three is negative
Breast carcinoma (triple-negative breast cancer, TNBC) is a kind of special hypotype of breast carcinoma, refers in particular to estrogen and receives
Body (estrogen receptor, ER), progesterone receptor (progesterone receptor, PR) and hEGF
Receptor 2 (human epidermal growth factor receptor 2, HER2) is the breast carcinoma of feminine gender, accounts for owning
The 12%~17% of breast carcinoma histological type.It is well known that ER, PR, HER2 are the major target class of current clinical treatment breast carcinoma,
But because TNBC patient lacks these target spots, so can not benefit from endocrine therapy and molecular targeted therapy, therefore, chemistry
Treatment is still the main treatment meanss of triple negative breast cancer patient.Due to TNBC patient's poor prognosis, recurrence and metastatic rate height, death
Rate is high, therefore becomes breast cancer research in recent years and treatment focus of attention.
Treatment currently for triple negative breast cancer relies primarily on operation, chemicotherapy, and wherein chemotherapy is triple negative breast cancer
The Main Means of Comprehensive Treatment, generally by the biochemical metabolism process for disturbing or suppressing tumor cell, and then affect tumor thin
The propagation of born of the same parents is reaching anticancer effect, such as anthracycline and Taxane family.Although, current major part triple negative breast cancer patient's
This two classes medicine was all used in adjuvant chemotherapy, but these medicines were late reused in patient, its curative effect was doubtful.For
Triple negative breast cancer late period, using anthracycline and the patient of Taxane family Endodontic failure, can adopt ipsapirone, due to Yi Sha
Grand have different micro-pipe binding sites from Ramulus et folium taxi cuspidatae class, therefore still active to Ramulus et folium taxi cuspidatae class drug resistance person using ipsapirone.But
Because ipsapirone is mainly used in the treatment in breast carcinoma late period, underproduce and expensive, therefore cannot function as Common Chemotherapy
Medicine.In recent years, tumor cells targeted therapy start rise, its mainly for the link that may cause cell carcinogenesis, from molecule
Level so as to suppress growth of tumour cell, or even makes one kind that it disappears completely brand-new reversing this malignant behaviors
Biotherapeutics pattern.Molecular targeted therapy as research in recent years triple negative breast cancer a focus, its research purpose in order to
Research and development obtain the novel drugs for making patient improve life cycle, and the characteristic molecular target of current triple negative breast cancer mainly has poly- adenosine
Diphosphonic acid polymerase, part small heat shock protein, protein kinase, epidermal growth factor etc..At present, in triple negative breast cancer
In molecular targeted therapy, signal transduction and transcriptional activators (signal transducer and activator of
Transcription, STATs) correlational study of albumen gets most of the attention, and STAT3 albumen is a kind of important nuclear factor, ginseng
Growth, differentiation, hypertrophy, vicious transformation and Apoptosis inhibitor with regulating cell, is present in the canceration of many tumor cell lines and people
In tissue.STAT3 albumen can be by numerous Ligand activations, including EGF, PDGF and IL-6 etc., the weight played the part of after STAT3 activation
Role is wanted to be inhibited apoptosis.STAT3 signals are in the normal tissue the extremely low state of activation, in lasting in tumor tissues
The state of activation, and then induce the processive transcription of target gene.There are some researches show, in all types of breast cancer cells, activation
STAT3 the overwhelming majority in TNBC cells express.It is interesting that the STAT3 of 80% TNBC cell expresses activation states.
This feature of STAT3 signal transduction paths is not affect the therapeutic strategy of normal cell to carry for triple negative breast cancer cell
A reliable point of penetration is supplied.At present, the molecular therapy for STAT3 approach is studied achieved with very big progress, targeting suppression
The activity of STAT3 albumen processed will suppress triple negative breast cancer cell propagation and apoptosis-induced, suppression tumor-blood-vessel growth, so as to
Reach the purpose for improving treatment triple negative breast cancer.
The content of the invention
It is an object of the invention to provide a kind of new application of natural product Eupalinolide J, first natural product
Eupalinolide J can be used as STAT3 inhibitor, and further natural product Eupalinolide J are used as preparing anti-mammary gland
The raw material of cancer drug.
The technical solution adopted for the present invention to solve the technical problems is:
A kind of new application of natural product Eupalinolide J, natural product Eupalinolide J press down as STAT3
The purposes of preparation.
A kind of new application of natural product Eupalinolide J, natural product Eupalinolide J are used as preparing anti-breast
The application of adenocarcinoma medicine.
The main molecular targeted therapy for passing through operation, chemicotherapy and newly rising in recent years of the current treatment to cancer.But
Operation and radiotherapy means can cause quality of life to decline cancer patient, hypoimmunity, and centering patients with advanced malignant tumor
Often because local not thoroughly, the recurrence of residual and far-end transfer and it is dead.Prolonged chemotherapy can produce drug resistance, make medicine
The treatment power of thing declines.Molecular targeted therapy designs medicine mainly for clear and definite oncogenic molecules, makes tumor thin
Born of the same parents' specificity is dead, without the normal tissue cell being related to around tumor.Therefore, find anti-with specific treatment target spot
Breast cancer medicines are still the task of top priority.The natural product Eupalinolide J of the present invention derive from Eupatorium Lindleyanum DC, medium-height grass
Medicine can suppress tumour growth as China's traditional medicine rarity, in terms for the treatment of cancer;Mitigate the toxic and side effects of Radiotherapy chemotherapy;It is anti-
Relapse and metastasis;Improve the life quality of patient with breast cancer;Adjust immunologic function etc. to achieve noticeable achievement.
Applicant Jing numerous studies find that Eupalinolide J can significantly inhibit in vitro triple negative breast cancer cell strain
Propagation, induce triple negative breast cancer apoptosis, arresting cell cycle, and can substantially suppress the expression of STAT3.
The concrete result of study of the present invention is described below:First, using pSTAT3-TA-Luc plasmids, transient transfection
HEK293T cells, establish STAT3 luciferase reporter genes, and whether detection Eupalinolide J can suppress STAT3 to transcribe
Activity;And detect that can it suppress the expression of STAT3 albumen in triple negative breast cancer MDA-MB-468 cell.Research shows
Eupalinolide J can significantly inhibit STAT3 transcriptional activities, and suppression ratio is 53.9 ± 7.2%, and can lower the egg of STAT3
White expression, suppresses its phosphorylation, and with time, dose dependent.
Secondly, by Eupalinolide J to MDA-MB-231, MDA-MB-468 triple negative breast cancer cell strain growth
The research of inhibitory action.It was found that Eupalinolide J are deposited to triple negative breast cancer MDA-MB-231, MDA-MB-468 cell
In obvious growth inhibition effect.
Finally, Eupalinolide J are studied on the apoptotic impact of triple negative breast cancer.Jing flow cytometer showeds, find
Eupalinolide J can substantially induce triple negative breast cancer apoptosis.
Preferably, the chemical structural formula of the natural product Eupalinolide J is:
Preferably, the breast carcinoma is triple negative breast cancer.
Preferably, natural product Eupalinolide J significantly inhibit in vitro the increasing of triple negative breast cancer cell strain
Grow, induce triple negative breast cancer apoptosis, arresting cell cycle, and can substantially suppress the expression of STAT3 albumen.
Preferably, the triple negative breast cancer cell strain is MDA-MB-231, MDA-MB-468.
The invention has the beneficial effects as follows:Present invention firstly discloses Eupalinolide J are in triple negative breast cancer cell
Inhibitory action to STAT3, it was demonstrated that the compound is efficient STAT3 inhibitor, is to find new triple negative breast cancer targeting
Treatment and Eupalinolide J enter clinical there is provided theoretical foundation.
Description of the drawings
Fig. 1:Act on for luciferase reporter gene detection Eupalinolide J and transfect pSTAT3-TA-Luc plasmids
HEK293T cells after, the relative expression quantity of STAT3.
Fig. 2:Detect Eupalinolide J to STAT3 and p- in MDA-MB-468 cells for Western Bolt methods
The impact of STAT3 protein expression situations.
Fig. 3:Growth inhibited of the Eupalinolide J to MDA-MB-231, MDA-MB-468 cell strain is detected for mtt assay
Effect.
Fig. 4:MDA- is induced with flow cytomery Eupalinolide J using Annexin V-FITC/7AAD methods
The situation of MB-231, MDA-MB-468 cell strain apoptosis.
Specific embodiment
Below by specific embodiment, technical scheme is described in further detail.
In the present invention, if not refering in particular to, the raw material for being adopted and equipment etc. are commercially available or commonly used in the art.
Method in following embodiments, if no special instructions, is the conventional method of this area.
Embodiment:
1st, natural product Eupalinolide J preparation methoies
Natural product Eupalinolide J (abbreviation EJ) preparation method:Herba Eupatorii Lindleyani (Eupatorium lindleyanum
DC. dry aerial parts (7kg)) are ground into coarse powder, and with 95% ethanol 24h is soaked, and are then existed with 20 times of 95% ethanol
Extraction is impregnated with room temperature, is concentrated under vacuum and is obtained crude extract.After reduction vaporization, take ethyl acetate extract (194g) and enter
Row silica gel column chromatography is separated, with polyethylene-ethyl acetate (20:1-0:1, v/v) gradient elution, obtains 12 fraction (Frs.A-
L).The Fr.K of 3g is taken, methanol/water is adopted and is separated for flowing (difference 50%, 70%, 100%, flow velocity 50ml/min), one
Divide and be prepared high performance liquid chromatography (55% methanol/water, flow velocity 15ml/min) with 70%MeOH (139.2mg), obtain
92.4mg colorless gum material.Scan it1H-NMR、13C-NMR, HRMS, identified compound Eupalinolide J (references
Document:Shuang-Qing Wu,Nai-Yu Xu,Qun Sun,Hai-Yan Han,and Jian Zhang*,Six New
Sesquiterpenes from Eupatorium lindleyanum.HelveticaChimicaActa,2012.95(9):
1637-1644.)。
2nd, Eupalinolide J suppress the expression of STAT3
HEK293T cells are inoculated in 24 orifice plates (1.5 × 105/ hole) culture 24h, build luciferase reporter gene.Utilize
The reagents of Lipofectamine 2000 are by purpose plasmid pSTAT3-TK-Luc and control plasmid pRL-TK cotransfections in HEK293T
In cell.After transfection 24h, 10 μM of Sesquiterpene lactones compound Eupalinolide J (EJ) are added.Medicine acts on 24h
Afterwards, using Dual-Luciferase Reagent cell lysis, are placed on shaking table and shake 10~20min, Aspirate supernatant
In being placed in 96 hole blanks, using multi-function microplate reader its fluorescence intensity 1 is detected;Isopyknic Stop reagents are added, is placed on and is shaken
10~20min is shaken on bed, then detects its fluorescence intensity 2.Using formula:The fluorescence intensity 2 of relative intensity of fluorescence=fluorescence intensity 1/,
The transcriptional activity of STAT3 after different compound effects is calculated, all tests are in triplicate.Research shows Eupalinolide J poles
Significantly suppress STAT3 transcriptional activities, suppression ratio is:53.9 ± 7.2%, as shown in Figure 1.Therefore it is following to surround
Eupalinolide J expand series of studies.
Take the logarithm the breast cancer cell MDA-MB-468 of trophophase, adds the hyclone DMEM/F12 containing volume fraction 10%
Culture medium culturing, in being inoculated in 6cm wares, 8 × 10 is added per hole5Individual cell, cumulative volume is 3ml, with 0,5,10,15 μM
Eupalinolide J act on 24h or 5 μM be respectively acting on 0,0.5,1,2,3,4h process.After 24h, cell is collected, used
Ice PBS is washed 2 times, and with RIPA lysates 30min is cracked, and then 15min is centrifuged with 4 DEG C of centrifuge 12000rpm, is centrifuged twice,
Supernatant carries out degenerative treatments (100 DEG C, 10min).Pvdf membrane is separated and be transferred to by SDS-PAGE, uses 5% skim milk
1h is closed at room temperature, adds an anti-STAT3 and p-STAT3,4 DEG C of overnight incubations.By the film tween of Tris- buffer saline -5%
20 (TBST) are washed three times, each 5min.Add two to resist, be incubated at room temperature 1~2h, wash three times on shaking table with TBST, every time
5min.Chemiluminescence detection albumen situation of change is carried out using ECL working solutions, all tests are in triplicate.As a result show
Eupalinolide J can be in the protein expression that time-dose dependency ground suppresses STAT3 and p-STAT3.
Luciferase reporter gene detection is shown in that the protein expression situation of Fig. 1, STAT3 and p-STAT3 is shown in Fig. 2.
3rd, Eupalinolide J suppress breast carcinoma cell strain propagation
It is to grind from breast carcinoma cell strain MDA-MB-231, MDA-MB-468 (coming from Chinese Academy of Sciences's Shanghai cell bank)
Study carefully object.Trophophase cell MDA-MB-231, MDA-MB-468 PBS that take the logarithm are washed 2 times, plus containing the tire cattle of volume fraction 10%
Serum DMEM/F-12 culture medium, is inoculated in 96 orifice plates, adjusts cell concentration, and 4 × 10 are added per hole3Individual cell, cumulative volume is
100 μ l, respectively with 0,1,5,10,20 μM of Eupalinolide J process.After effect 48h, 20 μ l 5mg/ are added per hole
The MTT working solutions of ml, mix rearmounted 37 DEG C, 5%CO24h is cultivated in saturated humidity incubator.Add the liquid (10% of 100 μ l tri-
Isobutanol -0.012M the hydrochloric acid of sodium lauryl sulphate -5%), it is completely dissolved hyacinthine formazan precipitation.In being placed in microplate reader, use
Microplate reader (570nm) detects absorbance, and all tests are in triplicate.Suppressed with the computed in software halves of GraphPad Prism 5
Rate (IC50) be respectively:MDA-MB-231(3.06±0.56μM),MDA-MB-468(2.13±0.27μM).As a result Fig. 3, shows
Eupalinolide J can substantially suppress breast cancer cell growth, with dose dependent.
Fig. 3 is shown in mtt assay detection.
4th, Eupalinolide J inducing mammaries cancer cell-apoptosis
After the double dyes of AnnexinV-FITC/7AAD, flow cytomery apoptosis:Take the logarithm the breast of trophophase
Adenocarcinoma cell MDA-MB-231, MDA-MB-468, are washed 2 times with PBS, plus containing the hyclone DMEM/F-12 of volume fraction 10%
Culture medium, adjusts cell concentration, and 3 × 10 are added per hole5Individual cell, cumulative volume is 2ml, is inoculated in 6 orifice plates, respectively with 0,7.5,
15 μM of Eupalinolide J process.After 24h, cell is collected, washed with ice PBS 2 times, disappeared with the pancreatin without EDTA
Change and collect cell, washed with PBS 3 times, collect 1 × 105Individual cell, adds 1 × Binding Buffer of 500 μ l resuspended thin
Born of the same parents, the AnnexinV-FITC for adding 5 μ l is dyeed 5 minutes at lucifuge, subsequently dyes 10min with 5 μ l 7AAD lucifuges, last light
Lightly mixed cell suspension, using Millipore Guava flow cytometry analysis apoptosis, in the 1h on machine testing, weight
It is multiple three times.As a result see Fig. 4, show that Eupalinolide J can dramatically increase the ratio of Apoptosis of Breast Cancer, show
Eupalinolide J energy significantly inducing mammary cancer cell-apoptosis, in dose dependent.
Fig. 4 is shown in apoptosis detection.
Embodiment described above is one kind preferably scheme of the present invention, not makees any pro forma to the present invention
Limit, also have other variants and remodeling on the premise of without departing from the technical scheme described in claim.
Claims (6)
1. a kind of new application of natural product Eupalinolide J, it is characterised in that natural product Eupalinolide J make
For the purposes of STAT3 inhibitor.
2. a kind of new application of natural product Eupalinolide J, it is characterised in that natural product Eupalinolide J make
To prepare the application of anti-breast cancer medicines.
3. a kind of new application of natural product Eupalinolide J according to claim 1 and 2, it is characterised in that institute
The chemical structural formula for stating natural product Eupalinolide J is:
4. a kind of new application of natural product Eupalinolide J according to claim 2, it is characterised in that the breast
Adenocarcinoma is triple negative breast cancer.
5. a kind of new application of natural product Eupalinolide J according to claim 2, it is characterised in that natural product
Thing Eupalinolide J significantly inhibit in vitro the propagation of triple negative breast cancer cell strain, and induction triple negative breast cancer cell withers
Die, arresting cell cycle, and can substantially suppress the expression of STAT3 albumen.
6. the new application of a kind of natural product Eupalinolide J according to claim 5, it is characterised in that described three
Negative breast cancer cells strain is MDA-MB-231, MDA-MB-468.
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN107243005A (en) * | 2017-05-04 | 2017-10-13 | 浙江中医药大学 | A kind of anti-cancer composition extracted from eupatorium lindleynun var. trifoliolatum and its preparation method and application |
CN110393712A (en) * | 2019-03-05 | 2019-11-01 | 浙江中医药大学 | Anti-tumor effective component extracted from agrimony and its preparation method and application |
Citations (1)
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CN105294623A (en) * | 2015-11-18 | 2016-02-03 | 浙江中医药大学 | Sesquiterpene lactone compound, preparation method and application thereof |
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2016
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CN105294623A (en) * | 2015-11-18 | 2016-02-03 | 浙江中医药大学 | Sesquiterpene lactone compound, preparation method and application thereof |
Non-Patent Citations (3)
Title |
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N.-Y. YANG等: "Cytotoxic sesquiterpene lactones from Eupatorium lindleyanum", 《JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH》 * |
SHUANG-QING WU等: "Six new sesquiterpenes from Eupatorium lindleyanum", 《HELVETICA CHIMICA ACTA》 * |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107243005A (en) * | 2017-05-04 | 2017-10-13 | 浙江中医药大学 | A kind of anti-cancer composition extracted from eupatorium lindleynun var. trifoliolatum and its preparation method and application |
CN110393712A (en) * | 2019-03-05 | 2019-11-01 | 浙江中医药大学 | Anti-tumor effective component extracted from agrimony and its preparation method and application |
CN110393712B (en) * | 2019-03-05 | 2023-04-21 | 浙江中医药大学 | Anti-tumor effective part extracted from cannabis sativa leaf herba lycopi and preparation method and application thereof |
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