CN105640940B - Application of the Ligustilide in preventing breast cancer - Google Patents
Application of the Ligustilide in preventing breast cancer Download PDFInfo
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- CN105640940B CN105640940B CN201610177667.8A CN201610177667A CN105640940B CN 105640940 B CN105640940 B CN 105640940B CN 201610177667 A CN201610177667 A CN 201610177667A CN 105640940 B CN105640940 B CN 105640940B
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- breast cancer
- ligustilide
- tamoxifen
- estrogen receptor
- receptor alpha
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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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- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
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Abstract
It is of the invention research shows that Ligustilide is negative to estrogen receptor alpha (ER α) and positive breast cancer cells all have certain inhibiting effect the invention discloses application of the Ligustilide in preventing breast cancer.In addition, existing listing anti-breast cancer medicines tamoxifen etc. mainly works to estrogen receptor alpha positive breast cancer cells, it produces little effect for the effect of estrogen receptor alpha negative breast cancer cells, and the present invention research shows that, Ligustilide can be such that the ER α protein expressions of breast cancer cell raise, and then cooperateed with tamoxifen and play the role of preventing breast cancer.
Description
Technical field
The present invention relates to the new applications of Ligustilide, and in particular to purposes of the Ligustilide in preventing breast cancer.
Background technology
Breast cancer also known as " mammary calculus ", " breast cancer " etc. are most multiple one of the malignant tumours of women.2016《Cancer
Statistics》Data show that there are 1,685,210 new cancer cases in the U.S. in 2015, and 595,690 patients can be because of cancer
And die, breast cancer is come out top with 29% ratio in female cancer incidence, and the death rate is only second to lung cancer and occupies second.And
It is also pessimistic in the incidence of China, breast cancer, disclose China women breast early in China's tumour registration annual report data in 2013
The average age of gland cancer morbidity is 48.7 years old, has done sth. in advance 10 years than western countries, in women cancer occurred frequently, breast cancer has surpassed
More lung cancer becomes first.2016《Cancer Statistics in China, 2015》Statistical result show 2009-
2011 China Nian Jian female cancer incidence dramatically increase, and wherein breast cancer ranks first place position, and in increasing situation year by year.Cause
This, breast cancer is a kind of disease seriously affecting the physically and mentally healthy even crisis life of women.
Estrogen plays an important roll in many physiological functions of women, includes the sexual organ of development women, for pregnancy
The preparation of breast and uterus is provided and human milk feeding etc. is provided after fertility.Estrogen receptor (estrogen receptor
Alpha, ER) during the occurrence and development of breast cancer play key player, in vivo by and the combination of estrogen activate
Gene containing estrogen response element and the expression containing other transcription factor binding member genes, and then lead to the hair of breast cancer
It is raw.ER expresses in about 2/3 its breast cancer tissue of patient with breast cancer, and the general good differentiation of these tumour cells, growth transfer is slow, right
Anti- endocrine therapy is sensitive, has estrogen-dependent.But the breast cancer tissue of about 1/3 patient expresses without ER, these tumours point
It is poor to change, and growth fraction is high, and clinical prognosis is bad, and confrontation endocrine therapy is also insensitive.Therefore, so that ER is expressed again and restore interior
The sensibility of secretion treatment is just particularly important.
Rhizoma Chuanxiong is the dry rhizome of samphire Rhizoma Chuanxiong Ligusticum chuanxiong Hort., first recorded in《The legendary god of farming
Book on Chinese herbal medicine warp》, warm-natured, acrid flavour, slight bitter have effects that blood-activating and qi-promoting, wind-expelling pain-stopping.Rhizoma Chuanxiong cures mainly menstruation caused by stagnation of QI and blood
It is uncomfortable, dysmenorrhoea Amenorrhea, stagnation of QI due to depression of the liver and the pain in chest and hypochondrium for causing hematogenous blockage, headache, wind-cold-dampness arthralgia, the diseases such as treating swelling and pain by traumatic injury.Face
Bed be mainly used for treat cardiovascular and cerebrovascular, breathing, urinary system and gynecology disease.
Radix Angelicae Sinensis (Angelica sinensis (Oliv.) Diels) is that a kind of perennial herb of Umbelliferae angelica is planted
Object.Its storage root dried is China's common Chinese medicine simply, and medicinal history is long, and history tree is on the books, enrich blood,
It is the effect of with blood, regulating menstruation, hemostasis, ease constipation laxation, common for doctor, it is known as the title of " ten side's rules for doing division with a one-digit divisor on the abacus ".
Ligustilide is a kind of phthalide analog compound being widely present in the various plants such as Radix Angelicae Sinensis, Rhizoma Chuanxiong, with volatile oil
Form exists, and has stronger pharmacological action, is the compound of a great Development volue, and evaluates Radix Angelicae Sinensis, Rhizoma Chuanxiong at present
One of the important evidence of equal medicinal materials and the quality of the pharmaceutical preparations.Ligustilide nineteen sixty is planted from Umbelliferae Ligusticum for the first time by Mitsuhashi
It is separated in object Ligusticum acutilobum, and is named as ligustilide, be the faint yellow oil with fragrance of tool
Shape liquid, boiling point are 168-169 DEG C, dissolve in the organic solvents such as ethyl alcohol, methanol, ether, ethyl acetate, petroleum ether, molecular formula
For C12H14O2, relative molecular mass 190.24.There is exocyclic double bond in Ligustilide structure, can be divided into along anti-two kinds of isomeries
Body, i.e. (Z)-ligustilide and (E)-ligustilide, it is more more stable than E type since Z-type structure is space advantage conformation,
Thus 10 times or so that Z-type Ligustilide content in Chinese medicine is E types.Now studies have reported that showing Ligustilide to heart and brain blood
Pipe, the circulatory system and immune function etc. have stronger pharmacological action, but these researchs generally use Angelica oil or cnidium oil etc.
Mixture containing Ligustilide, and it is not deep enough and careful to the pharmacological research of Ligustilide, and Ligustilide is in breast cancer
The pharmacology activity research of aspect is less.
Invention content
In view of this, the application the purpose of the present invention is to provide Ligustilide in preventing breast cancer, of the invention grinds
Study carefully and show that Ligustilide directly can not only play inhibiting effect to breast cancer cell, additionally it is possible to assist existing ripe anti-breast cancer
Drug plays more preferable curative effect.
The technical solution adopted by the present invention is as follows：
1, Ligustilide is preparing the purposes in preventing or treating breast cancer medicines.
2, purposes of the Ligustilide as the accelerating agent for having listed prevention breast cancer medicines.
Preferably, the Ligustilide is cis form ligustilide.
Preferably, Ligustilide works as the expression accelerating agent of estrogen receptor alpha albumen.
Preferably, the ripe breast cancer medicines are tamoxifen.
3, purposes of the Ligustilide in preparing the reagent or drug that improve estrogen receptor alpha protein expression.
4, Ligustilide prepare improve estrogen receptor alpha do not express or express in lower breast cancer cell estrogen by
The reagent of body α protein expressions or the purposes in drug.
Preferably, the breast cancer cell is MDA-MB-231 cells.
5, Ligustilide analogue is preparing the purposes in preventing or treating breast cancer medicines.
Preferably, the Ligustilide analogue be Senkyunolide A, it is Senkynolide H, senkyunolide I, new
One kind in cnidiumlactone, n-butylbenzene peptide, butylidene phthalide, Levistilide A.
The beneficial effects of the present invention are：Ligustilide is negative to estrogen receptor alpha and positive breast cancer cells all have
Certain inhibiting effect.In addition, existing listing anti-breast cancer medicines tamoxifen etc. is mainly to estrogen receptor alpha positive breast cancer
Cell works, and produces little effect for the effect of estrogen receptor alpha negative breast cancer cells, and the present invention studies have shown that ligusticumic
This lactone can be such that the ER α protein expressions of breast cancer cell raise, and then the work for playing prevention breast cancer is cooperateed with tamoxifen
With.The mechanism of Primary Study Ligustilide up-regulation ER alpha expressions is the epigenetic that Ligustilide can change ER α promoters
On the one hand modification reduces MTA1, HDAC family correlative protein expression, on the other hand check MTA1 and recruit HDAC family proteins institute group
At combination of the compound in ER α promoters, its transcriptional activity is finally improved.
Description of the drawings
In order to keep the purpose of the present invention, technical solution and advantageous effect clearer, the present invention provides following attached drawing：
Fig. 1 Ligustilides and tamoxifen synergistic action effect；
Fig. 2 Senkyunolide As share effect with tamoxifen；
Fig. 3 Ligustilides raise ER α protein expression results；
Fig. 4 Senkyunolide As raise ER α protein expression results；
Fig. 5 transfects the synergy of detection Ligustilide and tamoxifen after siER；
The influence that Fig. 6 Ligustilides act synergistically with tamoxifen to Apoptosis of Breast Cancer, combination group are a concentration of
ZLIG50μM+TAM5μM)。
Specific implementation mode
The preferred embodiment of the present invention is described in detail below.The experiment side of actual conditions is not specified in embodiment
Method, usually according to conventional conditions or according to the manufacturer's recommendations.
Ligustilide used in the present invention is cis-structure, molecular formula C12H14O2, relative molecular mass 190.24, Z-type
Structural formula isIt is purchased from Chengdu Chengdu Pu Si biotechnologies company, product article No. CHB-G-020,
CAS 4431-01-0.
Tamoxifen of the present invention is purchased from Sigma companies, product identification T5648, CAS 10540-29-1.
Tumour cell according to the present invention is primarily referred to as estrogen receptor alpha, and not express or express lower breast cancer thin
Born of the same parents, i.e., signified estrogen receptor alpha negative breast cancer cells in inside and outside experiment of the present invention, such as：MDA-MB-231 cells；It is on the contrary
It is then estrogen receptor alpha positive breast cancer cells.
The synergy of embodiment 1 Ligustilide and tamoxifen
Experiment uses MDA-MB-231 cells, Ligustilide concentration to be set as 0,10,25,50 μm of ol/L, and Ligustilide is pre-
After handling 12h, then it is incubated 72h jointly with 1,2.5,5 μm of ol/L tamoxifen respectively, is obtained with Sulforhodamine B decoration methods (SRB)
Experimental result, the results are shown in Figure 1, individual Ligustilide and tamoxifen almost without effect, but cooperate with after use with
Concentration gradually rises, and inhibiting rate gradually increases.
The synergy of embodiment 2 Senkyunolide A and tamoxifen
Experiment uses MDA-MB-231 cells, by Senkyunolide A concentration successively by it is low it is high to be set as 0,50,100,
150 μm of ol/L are incubated 72h jointly with 1,2.5,5 μm of ol/L tamoxifen respectively after pre-processing 12h, are contaminated with Sulforhodamine B
Color method (SRB) is detected, and the results are shown in Figure 2, and individual Senkyunolide A and tamoxifen are almost without effect, after sharing
With gradually rising for concentration, inhibiting rate gradually increases, similar to Fig. 1 results.
Influence of 3 Ligustilide of embodiment to ER α protein expressions
Experiment uses MDA-MB-231 cells, and the Ligustilide of concentration 0,10,25,50 μm of ol/L is used to be incubated respectively first
48h separates and collects albumen and carries out Western Blot experiments, and experimental result is as shown in figure 3, as concentration increases, ER α albumen tables
It is gradually risen up to amount.
Influence of 4 Senkyunolide A of embodiment to ER α protein expressions
Experiment uses MDA-MB-231 cells, and concentration 0,50,100,150 μM of Senkyunolide A is used to be incubated MDA- respectively
MB-231 cell 48h separate and collect albumen and carry out Western Blot experiments, and experimental result is as shown in figure 4, with concentration liter
Height, ER α expressing quantities gradually rise, similar with Ligustilide experimental result.
Embodiment 5 transfects the synergy of detection Ligustilide and tamoxifen after siER α
Experiment uses MDA-MB-231 cells, uses the cell of medium culture containing nonreactive first, rear transfection carrier and siER α are arrived
In cell, liquid is changed after 6h, after transfecting 48h, is administered processing according to 1 condition of embodiment, is finally carried out survival rate inspection with srb assay
It surveys.As shown in figure 5, Ligustilide shares generation lethal effect with tamoxifen, but after silence ER α, this synergistic action effect
Weaken, this result shows that, the synergistic effect that Ligustilide and tamoxifen generate is related with Ligustilide up-regulation ER alpha expressions.
The influence that 6 Ligustilide of embodiment acts synergistically with tamoxifen to Apoptosis of Breast Cancer
Experiment uses MDA-MB-231 cells, first uses 50 μM of pretreatment 12h of Ligustilide, then be separately added into 5 μ of tamoxifen
M is incubated 48h jointly, handles and collect cell, is dyed with V-FITC/PI of Annex, and flow cytometer is detected, as a result as schemed
Shown in 6, the results showed that Ligustilide is with tamoxifen collective effect group apoptosis rate with control group and compared with being administered alone group
It increased.
7 experiment in vivo of embodiment detects Ligustilide and the synergistic antitumor of tamoxifen acts on
It is before experiment that the nude mice purchased from Shanghai Si Laike zooperies Co., Ltd is 60 total, raising to 5 week old.It will
MDA-MB-231 cells (5 × 104A cell/μ l) it is subcutaneously injected into nude mouse, after raising nude mice for a period of time, grow about
After the tumour of 2mm or so sizes, nude mice is randomly divided into 5 groups (n=6), every group 10, respectively：1 group is blank control group
(physiological saline 150ml/kg), 2 groups are Ligustilide low dose group (50mg/kg), and 3 groups are Ligustilide high dose group
(100mg/kg), 4 groups are tamoxifen group (20mg/kg), and 5 groups low with tamoxifen for Ligustilide low dosage (50mg/kg)
Dosage (70mg/kg) group, 6 groups are Ligustilide high dose (100mg/kg) and tamoxifen high dose (120mg/kg) group, often
It is administered once, and is administered 4 weeks altogether.After treatment end, animal is weighed, compares each group tumour growth situation.
1 Ligustilide of table shares the internal inhibiting rate to tumour cell with tamoxifen
As shown in table 1, the experimental results showed that certain density Ligustilide has certain inhibiting effect to tumour, in addition,
Tamoxifen is used alone to tumour without obvious effect, but there is apparent inhibition in when Ligustilide and tamoxifen are shared to tumour
Effect.
Finally illustrate, preferred embodiment above is merely illustrative of the technical solution of the present invention and unrestricted, although logical
It crosses above preferred embodiment the present invention is described in detail, however, those skilled in the art should understand that, can be
Various changes are made to it in form and in details, without departing from claims of the present invention limited range.
Claims (4)
1. Ligustilide joint has listed prevention breast cancer medicines and has prepared the purposes in preventing or treating breast cancer medicines, special
Sign is：The breast cancer is that lower breast cancer is not expressed or expressed to estrogen receptor alpha；It is described to have listed prevention breast cancer drug
Object is tamoxifen.
2. purposes according to claim 1, it is characterised in that：The Ligustilide is cis form ligustilide.
3. purposes according to claim 1, it is characterised in that：Table of the Ligustilide as estrogen receptor alpha albumen
It works up to accelerating agent.
4. Ligustilide analogue joint has listed prevention breast cancer medicines in preparing prevention or treatment breast cancer medicines
Purposes, it is characterised in that：The breast cancer is that lower breast cancer is not expressed or expressed to estrogen receptor alpha；It is described to have listed
Prevention breast cancer medicines are tamoxifen；The Ligustilide analogue is Senkyunolide A.
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| CN201610177667.8A CN105640940B (en) | 2016-03-25 | 2016-03-25 | Application of the Ligustilide in preventing breast cancer |
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| CN201610177667.8A CN105640940B (en) | 2016-03-25 | 2016-03-25 | Application of the Ligustilide in preventing breast cancer |
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|---|---|---|---|---|
| CN101049329A (en) * | 2006-04-07 | 2007-10-10 | 刘志峰 | Application of angelica oil in raising level of estradiol from internal source for treating estradiol related disease |
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| CN105079059B (en) * | 2015-09-07 | 2020-03-31 | 宜诺(天津)医药工程有限公司 | Angelica sinensis extract and extraction method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101049329A (en) * | 2006-04-07 | 2007-10-10 | 刘志峰 | Application of angelica oil in raising level of estradiol from internal source for treating estradiol related disease |
Non-Patent Citations (3)
| Title |
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| Estrogenic Activity of Standardized Extract of;Clara Circosta等;《PHYTOTHERAPY RESEARCH》;20060512;第20卷;第665-669页 * |
| 当归中苯酞类成分及其药理作用研究进展;张来宾等;《中国中药杂志》;20160131;第41卷(第2期);第167-176页 * |
| 藁本内酯抗人肺癌A549细胞增殖作用研究;王立宏等;《中国中医药信息杂志》;20150731;第22卷(第7期);第55-59页 * |
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