CN107550900A - Application of the Oridonin in terms of protein kinase B inhibitor is prepared - Google Patents
Application of the Oridonin in terms of protein kinase B inhibitor is prepared Download PDFInfo
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- CN107550900A CN107550900A CN201710872587.9A CN201710872587A CN107550900A CN 107550900 A CN107550900 A CN 107550900A CN 201710872587 A CN201710872587 A CN 201710872587A CN 107550900 A CN107550900 A CN 107550900A
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- oridonin
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Abstract
The invention belongs to field of medicaments, and in particular to application of the Oridonin in terms of protein kinase B specific inhibitor is prepared.Oridonin（Oridonin）, molecular formula：C20H28O6, molecular weight：364.44.The present invention has found through experiment：Oridonin passes through to protein kinase B（AKT）Inhibitory action and suppress the growth of tumour.The present invention, which demonstrates Oridonin, can suppress protein kinase B kinase activity, the propagation for suppressing esophageal squamous cell carcinoma cell KYSE70, KYSE450 and suppress cancer of the esophagus humanization Transplanted tumor model（PDX）The growth of tumour, so as to show that Oridonin has significant inhibition to tumour.Oridonin can be used in kinds of tumors as protein kinase B inhibitor（The cancer of the esophagus, lung cancer, stomach cancer, colon cancer, liver cancer, breast cancer etc.）Prevention and treatment.
Description
Technical field
The invention belongs to field of medicaments, and in particular to application of the Oridonin in terms of protein kinase B inhibitor is prepared,
It is sent out by suppressing protein kinase B kinase activity the growth that prevents and suppress tumour, especially protein kinase B in esophageal squamous cell carcinoma
Raw developing functional study.
Background technology
Oridonin（Oridonin）It is from labiate Rabdosia rubescens Rabdosia rubescens（Hemsl.）
The tetracyclic diterpene effective constituents separated in Hara, be mainly used in clearing heat and detoxicating antibacterial, desinsection, anti-inflammatory analgetic, stomach invigorating promoting blood circulation and
Deng effect.AKT is also referred to as protein kinase B（PKB）, it is related to more signal paths, by the work for influenceing a variety of factors in downstream
Change state, play the key effect for suppressing apoptosis, promoting propagation.Protein kinase B kinases is in itself and its upstream regulation molecule exists
There is abnormal change in human tumor more than 50%.Suppress protein kinase B for prevention and treatment tumour to play an important roll.
The present invention it has been investigated that：Protein kinase B altimeter in esophageal squamous cell carcinoma reaches and played an important roll, and Oridonin is to tumour
Inhibitory action mechanism suppress that protein kinase B kinase activity is related, and this discovery will be to protein kinase B unconventionality expression to it
Tumour patient treatment it is significant.
The content of the invention
Present invention aims at provide a kind of native compound Oridonin in terms of protein kinase B inhibitor is prepared
Using, and illustrate protein kinase B（AKT）Important function in esophageal squamous cell carcinoma occurrence and development.
To achieve the above object, the present invention adopts the following technical scheme that：
Oridonin（Oridonin）, alias：Rubescensin, molecular formula：C20H28O6, molecular weight：364.44 it is a kind of light
Yellow needles, dissolve in the organic solvents such as methanol, ethanol, DMSO.
The invention provides application of the Oridonin in terms of protein kinase B inhibitor is prepared.I.e. present invention finds
Oridonin is to the inhibitory action of protein kinase B kinases, thus Oridonin can be used as preparing protein kinase B inhibitor.
Present invention discover that：Oridonin prevents and suppressed tumour growth, winter by suppressing protein kinase B kinase activity
It is 5-10 μM to the concentration range of protein kinase B generation inhibitory action to insult careless A prime.
Further, the application present invention also offers Oridonin in terms of antineoplastic is prepared.Such as, it is of the invention
Provide application of the Oridonin in terms of preparing prevention and suppressing esophageal squamous cell carcinoma medicine.The present invention has found through experiment：Albumen
Kinase b（AKT）The high expression in esophageal squamous cell carcinoma tissue, Oridonin by suppressing protein kinase B kinase activity preventing and
Suppress tumour growth.Therefore, Oridonin can be used for preparing prevention and suppress esophageal squamous cell carcinoma medicine.Oridonin is in concentration
Scope can suppress esophageal squamous cell carcinoma cell when being 2.5-20 μM（KYSE70, KYSE450）Propagation.
Present invention also offers Oridonin to prepare suppression cancer of the esophagus humanization Transplanted tumor model tumour growth medicine
In application, i.e., its can suppress cancer of the esophagus humanization Transplanted tumor model（PDX）The growth of tumour.
Further, Oridonin suppresses protein kinase B kinase activity to the inhibitory action of PDX Model Tumors with it has
Close, Oridonin can suppress the life of cancer of the esophagus humanization Transplanted tumor model tumour in the mg/kg of dosage 40,160 mg/kg
It is long.PDX model tumor-bearing mices with Oridonin after being treated, tumor sample p-AKT, p-GSK3 β expression quantity conspicuousness drop
It is low.
Compared to the prior art, beneficial effects of the present invention：
1）The present invention has found through experiment：Oridonin suppresses protein kinase B kinases with it to the inhibitory action mechanism of tumour and lived
Property it is related, this discovery is significant by the treatment to the tumour patient with protein kinase B unconventionality expression；
2）The present invention has found through experiment：Protein kinase B high expression in esophageal squamous cell carcinoma tissue, and its expression in cancer beside organism
Also significantly greater than normal structure, illustrate that protein kinase B plays an important roll in the occurrence and development of esophageal squamous cell carcinoma；
3）By taking the present invention as an example, the prevention and treatment of tumour can be applied to using Oridonin as protein kinase B inhibitor
In.Protein kinase B and cell survival, Apoptosis are closely related, suppress protein kinase B kinases activity can play prevention and
Treat the effect of tumour.Oridonin can suppress protein kinase B kinase activity in the present invention, and it is thin to suppress the cancer of the esophagus
Born of the same parents' propagation, suppress cancer of the esophagus humanization Transplanted tumor model（PDX）The growth of tumour.Therefore Oridonin can be applied to a variety of swollen
Knurl（The cancer of the esophagus, lung cancer, stomach cancer, colon cancer, liver cancer, breast cancer etc.）Prevention and treatment, may also can be by protein kinase B
The suppression of kinase activity and suppress the growth of tumour.In addition, the Oridonin of the present invention can also be with other chemotherapeutics or kinases
Inhibitor is used together, prevention and treatment for tumour.
Brief description of the drawings
Fig. 1 is protein kinase B（Total protein and phosphorylated protein）Immunohistochemical staining on esophageal squamous cell carcinoma tissue chip
As a result.Expression of the protein kinase B in cancerous tissue is significantly higher than normal structure and cancer beside organism；
Fig. 2 is inhibitory action of the Oridonin to protein kinase B, wherein, Oridonin produces to protein kinase B to be suppressed to make
Concentration range is:5-10 μM；
Fig. 3 be Oridonin in the inhibitory action to esophageal squamous cell carcinoma cell, wherein, Oridonin is in concentration range:
Esophageal squamous cell carcinoma cell KYSE70, KYSE450 propagation can be suppressed at 2.5-20 μM.This figure by control group as 100%, its
He calculates cytoactive at dosing various concentrations group compared with it.*p<0.05, **p<0.01, ***p<0.001；
Fig. 4 is Oridonin to cancer of the esophagus humanization Transplanted tumor model（PDX）EG9 prevention and inhibitory action result.Winter insults
Careless A prime can significantly inhibit the growth of tumour when dosage is 40 mg/kg and 160 mg/kg.*p<0.05, **p<0.01；
Fig. 5 is the ImmunohistochemistryResults Results of PDX model E G9 tumor samples.By being used for PDX model E G9 tumours to Oridonin
Prevention and therapeutic action in obtained tumor sample carry out immunohistochemical staining, find tumor sample p-AKT, p-GSK3 β's
Expression quantity conspicuousness reduces.*p<0.05, **p<0.01, ***p<0.001；
Fig. 6 is Oridonin to cancer of the esophagus humanization Transplanted tumor model（PDX）HEG18 prevention and inhibitory action result.Winter
The growth of tumour can be significantly inhibited when dosage is 40 mg/kg and 160 mg/kg by insulting careless A prime.*p<0.05, **p<0.01；
Fig. 7 is the ImmunohistochemistryResults Results of PDX model HEG18 tumor samples.By being used for PDX models HEG18 to Oridonin
The tumor sample obtained in the prevention and therapeutic action of tumour carries out immunohistochemical staining, finds tumor sample p-AKT, p-
GSK3 β expression quantity conspicuousness reduces.*p<0.05, **p<0.01, ***p<0.001.
Embodiment
Technical scheme is further discussed in detail with reference to embodiments, but protection scope of the present invention
It is not limited thereto.
Embodiment：
Materials and methods.
1st, material.
1.1 reagent
Oridonin is purchased from Xi'an Pu Laite bioengineering Co., Ltd, purity 98%.Protein kinase B kinase reagent box is purchased
From CST companies.MK2206 is purchased from selleckchem companies.Tetrazolium bromide（MTT）Purchased from Ruitaibio companies.
1.2 instruments and equipment：
1.2.1 Haier's Medical low-temperature storage box（Qingdao Haire Special Electrical Appliances Co., Ltd）
1.2.2 electronic balance（Plum Teller-support benefit instrument Shanghai Co., Ltd）
1.2.3 Thermo superclean benches
1.2.4 ELIASA Multiskan GO microplate Spectrophotometer.
1.3 tumor tissues
Present invention uses two Human Esophageal Carcinoma samples.Two kinds of pattern numbers are respectively EG9 and HEG18.EG9 derives from river
Affiliated hospital of Nan Sheng Zhengzhou University first, male, 66 years old.Postoperative pathological section prompts for：The b levels of squamous carcinoma II, senior middle school's differentiation, lymph
Have transfer, pathological staging：T2N1M0.HEG18 derives from Henan Prov. Tumour Hospital, women, 73 years old.Postoperative pathological section prompting
For：The low differentiated squamous-cell carcinomas of oesophagus medullary, lymph have transfer.The EG9 models that the present invention uses were the 8th generation, and HEG18 was the 5th generation.
1.4 experimental animal
SCID immunodeficient mouses are purchased from Beijing Vital River Experimental Animals Technology Co., Ltd. in the present embodiment.Licensing is numbered
For：SCXK (capital) 2012-0001, SPF level, 6-8 week old, body weight 16-18g, female mice.Mouse feed is purchased from abundant biological section of Beijing China
Skill limited company.Experimental animal feeding is in Sino-U.S.（Henan）In the animal facility of He Meier tumor researches institute, in constant temperature
（22-26℃）, constant humidity（45%-50%）, fresh air, dust and bacteria removing without special pathogen（SPF levels）Raised under the conditions of receptacle
Support, animal is first put in organic plastics box（Suzhou City Feng Laboratory Animal Equipment Co., Ltd）, then the raising of IVC systems is placed in,
3-4 animal of raising in each raising box, the feed through aseptic process are freely taken in for animal, every three days of the bedding and padding of high-temperature sterilization
Change once, cage tool and the every three days disinfection by ultraviolet lights of drinking-water once, drink sterile distilled water.Followed strictly when changing raising articles for use
Sterile principle operation.By experimental animal 12:Raised under 12 hours illumination/dark cycles, can be freely close to food and water.
The preparation of 1.5 zoopery medicines
Drug solvent is 5% dimethyl sulfoxide (DMSO)（DMSO）, 40% polyethylene glycol 400（PEG400）, 55% phosphate buffered saline solution
（PBS）.
2 methods.
2.1 immunohistochemical assay
Collect clinical esophageal squamous cell carcinoma patient cancer, cancer takes up normal structure, the FFPE system after the processing of various concentrations dehydration of alcohol
Make organization chip.Using immunohistochemical kit, the step given to specifications is tested, and is developed the color through DAB and through bush
After essence is redyed, mounting.Taken pictures under microscope and statistical analysis different tissues in protein kinase B（Total protein and phosphorylated protein）'s
Positive expression rate.As a result Fig. 1 is seen.
2.2 protein kinase B kinase assays
The experimental program provided according to CST companies kinase reagent box, determine various concentrations Oridonin and positive control drug egg
Inhibitory action of the white kinase b kinase inhibitor MK2206 to protein kinase B kinases.As a result Fig. 2 is seen.
2.3 cell proliferation experiment
Esophageal squamous cell carcinoma cell KYSE70, KYSE450 are inoculated in 96 orifice plates, per hole 1000-2000 cells, are separately added into after 24 hours
The Oridonin of various concentrations, respectively 0 hour after dosing, 24 hours, 48 hours, 72 hours 20 μ l tetrazolium bromides of addition, with
1 hour of incubation in 37 DEG C of incubators is put into, discards the liquid in 96 orifice plates after taking-up, adds 100 μ l dimethyl sulfoxide (DMSO)s
（DMSO）, cell proliferative conditions are detected in the case where wavelength is 570 nm and 620 nm using ELIASA, determine absorbance OD values.As a result
See Fig. 3.
The foundation of 2.4 cancer of the esophagus humanization Transplanted tumor models
Fresh tumor tissue is rejected into slough, 0.1-0.12 g, 3 mm or so fritter is cut into, transplants in female mice
Under skin of back.Treat that tumour grows to about 15 mm or so, remove tumour and be cut into 0.1-0.12g, 3 mm fritters, transplant in small in addition
Mouse is to pass on.Treat the transplantable tumor appearance of each mice with tumor and tumor size difference is little.It is subcutaneous that immunodeficient mouse is migrated to again
Tested.
2.5 experimental animals are grouped and treatment
After being inoculated with one week, mouse back tumour starts to be grouped when growing to 100 cubic millimeters or so, uniform according to gross tumor volume size
Mouse is distributed to every group, per component 10-15 only.Experiment mice is divided into three groups, is respectively：Solvent control group (A), Oridonin
Low dose group (B), Oridonin high dose group (C).Gastric infusion is carried out daily, is recorded mouse weight twice a week and is swollen
Knurl volume, when solvent control group mouse tumor grows to 1000 cubic millimeters or so（About 50 days）, experiment is terminated, removes tumour simultaneously
Weigh.Immunohistochemical staining, analysis p-AKT, p-GSK3 β expression quantity are done after tumor tissues FFPE.
Solvent control group (A)：Gavage solvent（5%DMSO, 40%PEG400,55%PBS）；
Oridonin low dose group (B)：Daily with 40 mg/kg mouse weight gavage Oridonins；
Oridonin high dose group (C)：Daily with 160 mg/kg mouse weight gavage Oridonins.
Experimental result.
1. protein kinase B（Total protein and phosphorylated protein）Expression in human esophageal carcinoma chip（See Fig. 1）,
Wherein, expression of the protein kinase B total protein in cancer and cancer beside organism is above normal structure, the protein kinase B of phosphorylation
Expression is only significantly increased in cancerous tissue.
2. Oridonin is inhibited to protein kinase B kinase activity（See Fig. 2）, wherein, Oridonin pair
Protein kinase B kinases produce inhibitory action concentration range be:5-10 μM.
3. Oridonin is inhibited to esophageal squamous cell carcinoma cell（See Fig. 3）, wherein Oridonin is in concentration model
Enclose for 2.5-20 μM when can suppress esophageal squamous cell carcinoma cell KYSE70, KYSE450 propagation.
4. Oridonin is to cancer of the esophagus humanization Transplanted tumor model（PDX）EG9 prevention and inhibitory action result are shown in figure
4.Oridonin can significantly inhibit the growth of tumour when dosage is 40 mg/kg and 160 mg/kg.
5. Oridonin is shown in Fig. 5 to the testing result of PDX model E G9 SABCs.PDX moulds are used for Oridonin
The tumor sample obtained in the prevention and therapeutic action of type EG9 tumours carries out immunohistochemical staining, visible by result：With compareing
Group is compared, and experimental group tumor sample p-AKT, p-GSK3 β expression quantity conspicuousness reduce.
6. Oridonin is to cancer of the esophagus humanization Transplanted tumor model（PDX）HEG18 prevention and inhibitory action result are shown in
Fig. 6.Oridonin can significantly inhibit the growth of tumour when dosage is 40 mg/kg and 160 mg/kg.
7. Oridonin is shown in Fig. 7 to the testing result of PDX model HEG18 SABCs.PDX is used for Oridonin
The tumor sample obtained in the prevention and therapeutic action of model HEG18 tumours carries out immunohistochemical staining, visible by result：With
Control group is compared, and experimental group tumor sample p-AKT, p-GSK3 β expression quantity conspicuousness reduce.
It in summary it can be seen：Protein kinase B occupies important function in the occurrence and development of esophageal squamous cell carcinoma, can be used as clinic
Treat the specific target of esophageal squamous cell carcinoma；Oridonin can suppress protein kinase B as a kind of small molecule native compound
Kinase activity, it is a kind of protein kinase B kinase inhibitor；Esophageal squamous cell carcinoma cell KYSE70, KYSE45 propagation can be suppressed；Energy
Suppress cancer of the esophagus humanization Transplanted tumor model（PDX）The growth of tumour.Oridonin passes through to protein kinase B kinase activity
Suppress the generation so as to pre- preventing tumor and the growth of suppression tumour.
Claims (7)
1. application of the Oridonin in terms of protein kinase B inhibitor is prepared.
2. application as claimed in claim 1, it is characterised in that Oridonin by suppress protein kinase B kinase activity come
Prevention and suppression tumour growth, the concentration range that Oridonin produces inhibitory action to protein kinase B are 5-10 μM.
3. application as claimed in claim 2, it is characterised in that application of the Oridonin in terms of antineoplastic is prepared.
4. application as claimed in claim 3, it is characterised in that Oridonin is preparing prevention and suppressing esophageal squamous cell carcinoma medicine
The application of aspect.
5. application as claimed in claim 4, it is characterised in that Oridonin is in concentration range:2.5-20 μM when energy
Enough suppress the propagation of esophageal squamous cell carcinoma cell.
6. application as claimed in claim 3, it is characterised in that Oridonin is preparing suppression cancer of the esophagus humanization transplantable tumor
Application in Model Tumor growth medicine.
7. application as claimed in claim 6, it is characterised in that Oridonin energy in the mg/kg of dosage 40,160 mg/kg
Suppress the growth of cancer of the esophagus humanization Transplanted tumor model tumour.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111821303A (en) * | 2020-09-04 | 2020-10-27 | 郑州大学 | Application of vortioxetine and salts thereof in preparation of antitumor drugs |
| CN112107574A (en) * | 2020-09-30 | 2020-12-22 | 郑州大学 | Application of pectolinarin in preparation of anti-esophageal cancer drugs |
| CN113230405A (en) * | 2021-05-08 | 2021-08-10 | 中国医学科学院肿瘤医院 | Application of agent for inhibiting activity of protein kinase CLK in preparation of medicine for treating or improving esophageal squamous cell carcinoma |
| CN113768911A (en) * | 2021-10-20 | 2021-12-10 | 郑州大学 | APOBEC3B inhibitor and application thereof |
| CN115212216A (en) * | 2022-05-25 | 2022-10-21 | 郑州大学 | Pharmaceutical composition for resisting esophageal squamous carcinoma |
-
2017
- 2017-09-25 CN CN201710872587.9A patent/CN107550900A/en active Pending
Non-Patent Citations (3)
| Title |
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| HONG-ZHEN HU ET AL: "Oridonin induces apoptosis via PI3K/Akt pathway in cervical carcinoma HeLa cell line", 《ACTA PHARMACOL SIN》 * |
| 刘俊保等: "冬凌草甲素对EC9706 细胞增殖、凋亡的影响", 《郑州大学学报( 医学版)》 * |
| 田甜甜等: "人源化胃镜活检胃癌组织裸鼠移植瘤模型的建立与鉴定", 《第八届中国肿瘤学术大会暨第十三届海峡两岸肿瘤学术会议论文汇编》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111821303A (en) * | 2020-09-04 | 2020-10-27 | 郑州大学 | Application of vortioxetine and salts thereof in preparation of antitumor drugs |
| CN112107574A (en) * | 2020-09-30 | 2020-12-22 | 郑州大学 | Application of pectolinarin in preparation of anti-esophageal cancer drugs |
| CN113230405A (en) * | 2021-05-08 | 2021-08-10 | 中国医学科学院肿瘤医院 | Application of agent for inhibiting activity of protein kinase CLK in preparation of medicine for treating or improving esophageal squamous cell carcinoma |
| CN113768911A (en) * | 2021-10-20 | 2021-12-10 | 郑州大学 | APOBEC3B inhibitor and application thereof |
| CN113768911B (en) * | 2021-10-20 | 2023-10-27 | 郑州大学 | APOBEC3B inhibitor and application thereof |
| CN115212216A (en) * | 2022-05-25 | 2022-10-21 | 郑州大学 | Pharmaceutical composition for resisting esophageal squamous carcinoma |
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