CN109771430A - Glycocholic acid application in preparation of anti-tumor drugs - Google Patents
Glycocholic acid application in preparation of anti-tumor drugs Download PDFInfo
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- CN109771430A CN109771430A CN201910197871.XA CN201910197871A CN109771430A CN 109771430 A CN109771430 A CN 109771430A CN 201910197871 A CN201910197871 A CN 201910197871A CN 109771430 A CN109771430 A CN 109771430A
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Abstract
The purposes that the present invention relates to chemicals in field of medicaments, specifically glycocholic acid application in preparation of anti-tumor drugs.The present invention provides the new application fields of glycocholic acid, glycocholic acid, which can be applicable to, to be prepared in anti-tumor drug, mainly applicable tumour has breast cancer, oophoroma, carcinoma of endometrium or their combination, effective active composition of the glycocholic acid as anti-tumor drug, the present invention help to develop novel anti-tumor drug.
Description
Technical field
The purposes that the present invention relates to chemicals in field of medicaments, specifically glycocholic acid answering in anti-tumor drug
With.
Background technique
Malignant tumour is to seriously endanger one of the major disease of human health, according to the World Health Organization (WHO) report 2010
Year whole world shares 8,400,000 people and dies of malignant tumour, it is contemplated that may increase to 10,000,000 to the year two thousand twenty.China's malignant tumour is new every year
Number of the infected about 1,800,000, there are about 1,300,000 people to die of malignant tumour, and malignant tumour has become the primary factor of China human mortality death.
The drug therapy of tumour is very short in the history that modern age Internal Medicine-Oncology is treated, so far less than 70 years, but less than one generation
The drug therapy of discipline has obtained many great achievements, so that drug therapy has become indispensable portion in combined therapy of tumour
Point.And that body is killed while killing tumor cell is normally thin for most of anti-tumor drugs for clinically using at present
Born of the same parents embody most obvious in immune system and hemopoietic system.The drug for eventually leading to patient medium-long term is not tolerated answers with tumour
The drug resistance of hair transfer and tumour.Therefore, people have been devoted to exploitation new type antineoplastic medicine in recent years, wherein most of medicines
Object target spot is clear and injures few even fanout free region for immune and hemopoietic system.
Glycocholic acid is a kind of conjucated bile acids, is that metabolite cholic acid of the cholesterol in liver generates in conjunction with glycine
's.Its physiological action is mainly to promote the digestion and absorption of fat in enteron aisle, but as drug, especially apply in antineoplastic
There is not been reported in object.
Summary of the invention
In view of the defects existing in the prior art, the active constituent of glycocholic acid is made full use of, it is an object of the invention to mention
For glycocholic acid application in preparation of anti-tumor drugs.
In order to achieve the above-mentioned object of the invention, the application that the present invention provides glycocholic acid in anti-tumor drug, wherein institute
State the molecular structural formula of glycocholic acid are as follows:
For glycocholic acid in the application for preparing anti-tumor drug, anti-tumor drug is used in anti-tumor drug behaviour.
For glycocholic acid in the application for preparing anti-tumor drug, anti-tumor drug is animal anti-tumor drug.
For glycocholic acid in the application for preparing anti-tumor drug, the animal of the anti-tumor drug application is primate
And rodent.
For glycocholic acid in the application for preparing anti-tumor drug, related tumour is breast cancer, oophoroma, endometrium
The malignant tumours such as cancer.
For glycocholic acid in the application for preparing anti-tumor drug, the application of anti-tumor drug is included in growth of tumour cell suppression
Application in preparation.
The present invention also provides a kind of anti-tumor drug containing glycocholic acid and its derivative.
The above-mentioned anti-tumor drug containing glycocholic acid and its derivative, the anti-tumor drug include the sweet of effective therapeutic dose
The pharmaceutically acceptable carrier of ammonia cholic acid and surplus.
The above-mentioned anti-tumor drug containing glycocholic acid and its derivative, effective therapeutic dose are that (mouse breast cancer is thin by 4T1
Born of the same parents) 0.4~1.6nmol/L, MCF-7 (human breast cancer cell) is 0.16~1.28 μm of ol/L, and (human breast carcinoma is thin by MDA-MB-468
Born of the same parents) it is 0.08~1.32 μm of ol/L.
The above-mentioned anti-tumor drug containing glycocholic acid and its derivative, the drug be oral preparation, suppository, injection or
Transdermal agent.
The present invention provides the new application field of glycocholic acid, glycocholic acid, which can be applicable to, to be prepared in anti-tumor drug,
Mainly applicable tumour has breast cancer (such as 4T1, MCF-7, MDA-MB-468), oophoroma (such as NIH:OVCAR-3), endometrium
Cancer (such as RL95-2) or their combination, effective active composition of the glycocholic acid as anti-tumor drug, effective therapeutic dose are
4T10.4~1.6nmol/L, MCF-7 are 0.16~1.28 μm of ol/L, and MDA-MB-468 is 0.08~1.32 μm of ol/L；The present invention
Help to develop novel anti-tumor drug.
Detailed description of the invention
Fig. 1: 4T1 mouse mastopathy cell glycocholic acid 0.8nmol/L group, the inhibiting rate of each period is (with negative control
Group is compared,*P < 0.05).
Fig. 2: 4T1 mouse mastopathy cell each group 12 hours inhibiting rate (be compared with negative control group,*P <
0.05)。
Fig. 3: MCF-7 1.28 μm of human breast cancer cell ol/L group, the inhibiting rate of each period (are compared with negative control group
Compared with,*P < 0.05).
Fig. 4: MCF-7 human breast cancer cell each group 36 hours inhibiting rate (be compared with negative control group,*P <
0.05)。
Fig. 5: MDA-MB-468 1.32 μm of human breast cancer cell ol/L group, the inhibiting rate of each period is (with negative control group
It is compared,*P < 0.05).
Fig. 6: MDA-MB-468 human breast cancer cell each group 36 hours inhibiting rate (be compared with negative control group,*
P < 0.05).
Fig. 7: NIH:OVCAR-3 1.28 μm of Proliferation of Human Ovarian Cell ol/L group, the inhibiting rate of each period is (with negative control group
It is compared,*P < 0.05).
Fig. 8: NIH:OVCAR-3 Proliferation of Human Ovarian Cell each group (is compared in 48 hours inhibiting rates with negative control group
Compared with,*P < 0.05).
Fig. 9: RL95-2 1.28 μm of people's endometrial carcinoma cell ol/L group, the inhibiting rate of each period is (with negative control group
It is compared,*P < 0.05).
Figure 10: RL95-2 people's endometrial carcinoma cell each group (compares in 36 hours inhibiting rates with negative control group
Compared with,*P < 0.05).
Figure 11: 4T1 mouse mastopathy cell NaGC 0.7nmol/L group, the inhibiting rate of each period are (right with feminine gender
It is compared according to group,*P < 0.05).
Figure 12: 4T1 mouse mastopathy cell each group 12 hours inhibiting rate (be compared with negative control group,*P <
0.05)。
Figure 13: 4T1 mouse mastopathy cell 0.8nmol/L group FXR gene expression amount curve in 12h
Figure 14: 4T1 mouse mastopathy cell 0.8nmol/L group FXR gene expression amount histogram in 12h is (right with feminine gender
It is compared according to group,*P < 0.05).
Figure 15: 4T1 mouse mastopathy cell 0.8nmol/L group FXR expressing quantity trace band in 12h
Figure 16: 4T1 mouse mastopathy cell 0.8nmol/L group FXR expressing quantity histogram in 12h is (right with feminine gender
It is compared according to group,*P < 0.05).
Specific embodiment
Below in conjunction with specific embodiment, the present invention will be further described.
Glycocholic acid used is purchased from Aladdin reagent, product number G131002 in embodiment.
The anticancer experiment in vitro of 1 glycocholic acid of embodiment
1. cell strain: 4T1 (mouse mastopathy cell), MCF-7 (human breast cancer cell), MDA-MB-468 (human breast carcinoma
Cell), NIH:OVCAR-3 (Proliferation of Human Ovarian Cell), RL95-2 (people's endometrial carcinoma cell) (be purchased from Chinese Academy of Sciences Shanghai above
Cell bank)
2. culture medium: RPMI-1640 (Gibco article No. 31800022)；DMEM in high glucose culture medium (Gibco article No.
11965092)
3. method
3.1 collect logarithmic growth phase cells, respectively with 1640 culture mediums and DMEM culture medium adjustment cell concentration for 5 ×
104The cell suspension of 100 μ l is added in a/ml in 96 orifice plates.
3.2 5% CO2, after 37 DEG C are cultivated 24 hours, 4T1 mouse mastopathy cell is added concentration gradient and is respectively
(0.1nmol/L, 0.2nmol/L, 0.4nmol/L, 0.8nmol/L, 1.6nmol/L, 3.2nmol/L, 6.4nmol/L), MCF-7
Cell be added concentration gradient be (0.02 μm of ol/L, 0.04 μm of ol/L, 0.08 μm of ol/L, 0.16 μm of ol/L, 0.32 μm of ol/L,
0.64 μm of ol/L, 1.28 μm of ol/L), MDA-MB-468 cell be added concentration gradient be (0.02 μm of ol/L, 0.04 μm of ol/L,
0.08 μm of ol/L, 0.16 μm of ol/L, 0.33 μm of ol/L, 0.66 μm of ol/L, 1.32 μm of ol/L), NIH:OVCAR-3 cell be added it is dense
Spend gradient be (0.02 μm of ol/L, 0.04 μm of ol/L, 0.08 μm of ol/L, 0.16 μm of ol/L, 0.32 μm of ol/L, 0.64 μm of ol/L,
1.28 μm of ol/L), RL95-2 cell be added concentration gradient be (0.02 μm of ol/L, 0.04 μm of ol/L, 0.08 μm of ol/L, 0.16 μ
Mol/L, 0.32 μm of ol/L, 0.64 μm of ol/L, 1.28 μm of ol/L) glycocholic acid, if 5 multiple holes, while be arranged blank group and
Control group.
3.3 respectively in 12h, and for 24 hours, CCK-8 reagent is added in 36h, 48h after 60h hours, continues to be incubated for 3h, after the completion of incubation
Each hole light absorption value is measured at microplate reader OD450nm.
3.4 utilize formula: inhibiting rate=(control wells OD- medicine feeding hole OD)/(control wells OD- blank well OD) × 100% is asked
Inhibiting rate of the glycocholic acid of each concentration for tumour cell out.
4. result: the inhibition highest point that 4T1 mouse mastopathy cell reached at 12 hours is glycocholic acid concentration
0.8nmol/L is shown in Fig. 1, Fig. 2, and for IC50 between 0.01nmol/L-0.1nmol/L, MCF-7 cell reached suppression at 36 hours
The highest point of rate processed is 1.28 μm of ol/L, sees Fig. 3, Fig. 4, and IC50 is respectively between 0.64 μm of ol/L-1.00 μm of ol/L, MDA-
The highest point that MB-468 cell reached inhibiting rate at 36 hours is 1.32 μm of ol/L, sees Fig. 5, Fig. 6, IC50 is respectively in 0.33 μ
Between mol/L-0.66 μm of ol/L, the highest point that NIH:OVCAR-3 cell reached inhibiting rate at 48 hours is 1.28 μm of ol/L, is seen
Fig. 7, Fig. 8, for IC50 respectively between 0.16 μm of ol/L-0.32 μm of ol/L, RL95-2 cell reached inhibiting rate at 36 hours
Highest point is 1.28 μm of ol/L, sees Fig. 9, Figure 10, IC50 is respectively between 0.32 μm of ol/L-0.64 μm of ol/L.
2 NaGC anticancer experiment in vitro of embodiment
1. cell strain: 4T1 (mouse mastopathy cell) (is purchased from Chinese Academy of Sciences's Shanghai cell bank) above
2. culture medium: RPMI-1640 (Gibco article No. 31800022)
3. method
3.1 collect logarithmic growth phase cell, are 5 × 10 with 1640 culture mediums adjustment cell concentration4A/ml, in 96 orifice plates
The interior cell suspension that 100 μ l are added.
3.2 5% CO2, after 37 DEG C are cultivated 24 hours, 4T1 mouse mastopathy cell is added concentration gradient and is respectively
(0.1nmol/L, 0.25nmol/L, 0.35nmol/L, 0.7nmol/L, 1.4nmol/L, 2.8nmol/L, 5.6nmol/L's) is sweet
Ammonia sodium taurocholate, if 5 multiple holes, while blank group and control group are set.
3.3 respectively in 12h, and for 24 hours, CCK-8 reagent is added in 36h, 48h after 60h hours, continues to be incubated for 3h, after the completion of incubation
Each hole light absorption value is measured at microplate reader OD450nm.
3.4 utilize formula: inhibiting rate=(control wells OD- medicine feeding hole OD)/(control wells OD- blank well OD) × 100% is asked
Inhibiting rate of the NaGC of each concentration for tumour cell out.
4. result: the inhibition highest point that 4T1 mouse mastopathy cell reached at 12 hours is glycocholic acid na concn
0.7nmol/L is shown in Figure 11, Figure 12, and IC50 is between 0.01nmol/L-0.1nmol/L.
3 animal model of embodiment measures glycocholic acid tumour inhibiting rate
1. material: female 10 week old of BABL/c mouse 30, being purchased from Dalian Medical Univ SPF Experimental Animal Center.4T1 is swollen
Oncocyte is purchased from Chinese Academy of Sciences Shanghai cell bank.
2. method:
2.1 modelings: collecting logarithmic growth phase 4T1 mouse mastopathy cell, is 2 × 10 with PBS adjustment cell concentration6/ml。
0.1ml cell suspension is injected in right side of mice oxter with asepsis injector.
2.2 administrations: second day beginning gastric infusion glycocholic acid 15mg/kg (2 times/day) after modeling, every time
0.2mL, control group is to equal amount of distilled water, and successive administration two weeks.Last dose that night gives mouse fasting, on 15th using de- neck
Method execution mouse, sterile removing mouse oxter tumor tissues, Calculate tumour inhibiting rate.
3. result: experimental mice tumour average quality: 0.247 ± 0.08g, control group mice Mean tumor mass:
0.431 ± 0.167g, experimental mice tumour are obviously reduced compared with control group, inhibitory rate to 42.83%.
4 Real-time PCR of embodiment measures glycocholic acid specificity target spot rna expression amount in tumour cell
1. material: 4T1 mouse mastopathy cell is purchased from Chinese Academy of Sciences Shanghai cell bank.
2. method: extracting the RNA of 4T1 cell after glycocholic acid is intervened, it is sweet that Real-time PCR measurement is carried out after reverse transcription
The variation of ammonia cholic acid specificity target spot rna expression amount.
3. result: after glycocholic acid is intervened, related RNA amount expression improves 1.5 times, sees Figure 13, Figure 14.It is demonstrate,proved from rna level
Real glycocholic acid for tumour cell intervention as a result, disclosing the growth mechanism that glycocholic acid inhibits tumour cell.
The glycocholic acid specific target of tumour cell after 5 Western blot measuring glycocholic acid of embodiment is intervened
The expression quantity variation of point albumen
1. material: 4T1 mouse mastopathy cell is purchased from Chinese Academy of Sciences Shanghai cell bank.
2. extracting after glycocholic acid is intervened after the albumen of 4T1 cell, by denaturation treatment, according to Western blot process
Measure the expression quantity variation of GAP-associated protein GAP.
As a result: the glycocholic acid specificity target spot protein expression of Western blot experiment tumor cells showed increases, and sees
Figure 15, Figure 16.Confirm glycocholic acid for the intervention of tumour cell as a result, disclosing glycocholic acid inhibits swollen from protein level
The growth mechanism of oncocyte.
Claims (8)
1. glycocholic acid application in preparation of anti-tumor drugs, which is characterized in that the anti-tumor drug is behaved with antitumor
Drug or animal anti-tumor drug, the tumour is breast cancer, oophoroma, one or more kinds of in carcinoma of endometrium.
2. application according to claim 1, which is characterized in that the animal is primate and rodent.
3. application according to claim 1, which is characterized in that the anti-tumor drug is growth of tumour cell inhibition
Agent.
4. a kind of anti-tumor drug for being converted into glycocholic acid in vivo containing glycocholic acid or derivatives thereof, which is characterized in that institute
Stating anti-tumor drug includes the glycocholic acid of effective therapeutic dose and the pharmaceutically acceptable carrier of surplus.
5. the anti-tumor drug according to claim 4 containing glycocholic acid and its derivative, which is characterized in that the mouse
The effective therapeutic dose of breast cancer cell 4T1 is 0.4~1.6nmol/L.
6. the anti-tumor drug according to claim 4 containing glycocholic acid and its derivative, which is characterized in that the human milk
The effective therapeutic dose of adenocarcinoma cell MCF-7 is 0.16~1.28 μm of ol/L.
7. the anti-tumor drug according to claim 4 containing glycocholic acid and its derivative, which is characterized in that the human milk
The effective therapeutic dose of adenocarcinoma cell MDA-MB-468 is 0.08~1.32 μm of ol/L.
8. the anti-tumor drug according to claim 4 containing glycocholic acid and its derivative, which is characterized in that the drug
It is oral preparation, suppository, injection or transdermal agent.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020186392A1 (en) * | 2019-03-15 | 2020-09-24 | 大连大学 | Application of glycocholic acid in preparation of antitumor drugs |
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| CN105263475A (en) * | 2013-03-15 | 2016-01-20 | 制药创源有限公司 | Intravenous emulsions of triptolide as immunomodulators and anticancer agents |
| CN109575100A (en) * | 2018-10-25 | 2019-04-05 | 大连大学 | Glycocholic acid application in preparation of anti-tumor drugs |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2020186392A1 (en) * | 2019-03-15 | 2020-09-24 | 大连大学 | Application of glycocholic acid in preparation of antitumor drugs |
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Application publication date: 20190521 |