CN108815172A - Application of the ursodesoxycholic acid in the drug of preparation prevention or treatment liver cancer - Google Patents
Application of the ursodesoxycholic acid in the drug of preparation prevention or treatment liver cancer Download PDFInfo
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- CN108815172A CN108815172A CN201810933845.4A CN201810933845A CN108815172A CN 108815172 A CN108815172 A CN 108815172A CN 201810933845 A CN201810933845 A CN 201810933845A CN 108815172 A CN108815172 A CN 108815172A
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Abstract
The present invention provides application of the ursodesoxycholic acid in the drug of preparation prevention or treatment liver cancer, belong to biomedicine field, ursodesoxycholic acid of the invention has good effect to liver cancer treatment.
Description
Technical field
The invention belongs to biomedicine fields, prevent or treat the drug of liver cancer in preparation more particularly to ursodesoxycholic acid
In application.
Background technique
Liver cancer is the tumour that one of most common malignant tumour and the cancer-related death rate come second, Chinese liver
Cancer patient accounts for about the half of global liver cancer patient.Although clinical at present more using operation excision, trans-hepatic artery Chemoembolization etc.
Kind is treated, and curative effect is not satisfactory.Blood of liver cancer is abundant, and angiogenesis ability is that migration invasion occur simultaneously in it more by force
An important factor for causing tumor recurrence to shift, angiogenesis refer to derived from already present capillary and post capillary venules
New capillary blood vessel growth.Tumor Angiongesis is an extremely complex process, generally comprises blood vessel endothelium
Substrate degradation, endothelial cell migration, endothelial cell proliferation, endothelial cell pipeline branch form vascular circle and form new substrate
Film and etc..Due to this new vessels structure of tumor tissues and dysfunction, and vascular stroma is not perfect, and this capilary holds
It easily leaks, therefore tumour cell is not required to be directed through intravascular into blood flow and remote by complicated invasive procedure
It is formed and is shifted every position.More and more researches show that benign tumour angiogenesis is rare, angiogenic growth is slow；And it is most of
The angiogenesis of malignant tumour is intensive and growth is rapid.Therefore, angiogenesis plays important in the development transfer process of tumour
Effect, inhibits this process that will obviously prevent the development and diffusion transfer of tumor tissues.
The shortcomings that existing Control Technology：Clinical anti-angiogenic medicaments type is rare：Angiogenesis is liver cancer recurrence transfer
Essential condition, but first-line drug of the existing clinical approval for advanced liver cancer only has Sorafenib, can pass through and inhibit VEGF and blood
Platelet derived growth factor receptor and block tumor neovasculature formation.Drug side-effect is big, and patient is benefited limited：Suo Lafei
Buddhist nun can only make advanced liver cancer patient extend life cycle about 3 months, since it is there are side effects such as fash and gastrointestinal reactions,
Many patients can not adhere to treating, and its drug resistance is also one of limitation of the medicine.Clinical prevention hepatoma Metastasis recurs effect
It is poor：Existing clinic there is no the unified drug about the relapse and metastasis that prevents liver cancer, and clinic lacks the relapse and metastasis means that prevent liver cancer.
Therefore, above-mentioned technical problem how to be overcome to become those skilled in the art's technical problem urgently to be resolved.
Summary of the invention
It is an object of the invention to：In order to solve the problems, such as that above-mentioned existing clinical anti-liver cancer and anti-type is rare, the present invention is disclosed
A kind of application of ursodesoxycholic acid in the drug of preparation prevention or treatment liver cancer.
Goal of the invention of the invention is achieved through the following technical solutions：
Application of the ursodesoxycholic acid in the drug of preparation prevention or treatment liver cancer.
Preferably, ursodesoxycholic acid is to be applied to the system for the drug for preventing or treating liver cancer as unique active constituent
In standby.
Preferably, ursodesoxycholic acid is to be applied to inhibit human umbilical vein endothelial cell as unique active constituent
In the preparation of the drug of EA, hy926 cell.
Preferably, ursodesoxycholic acid is to be applied to inhibit liver cancer cells IL-8 and VEGF as unique active constituent
In the preparation of the drug of secretion.
Preferably, ursodesoxycholic acid is to be applied to inhibit the generation of IL-8 induction of vascular as unique active constituent
In the preparation of drug.
Compared with prior art, the present invention is experimentally confirmed：UDCA can effectively inhibit in Hepatocellular carcinoma cell line
The expression of IL-8 and VEGF, and then inhibit angiogenesis, specific mechanism may be by inhibiting the expression of p-I κ B, and then promotes
P65 enters nuclear expression, while by regulation p-ERK signal path, finally inhibiting the secretion of IL-8 and playing inhibition angiogenesis
Effect, be conducive to the excavation of this clinical new effect of common medicine of UDCA, be conducive to the prevention and treatment of liver cancer patient relapse and metastasis.
Detailed description of the invention
Fig. 1 is the structural formula figure of ursodesoxycholic acid；
Fig. 2 is that ursodesoxycholic acid influences schematic diagram to 7721 ability of cell proliferation of SMMC；
Fig. 3 is that ursodesoxycholic acid influences schematic diagram to 926 ability of cell proliferation of EA.hy；
Fig. 4 is that ursodesoxycholic acid inhibits 7721 cell IL-8 of SMMC under anoxia condition to secrete schematic diagram；
Fig. 5 is that ursodesoxycholic acid inhibits 7721 cell VEGE of SMMC under anoxia condition to secrete schematic diagram；
Fig. 6 is that ursodesoxycholic acid inhibits angiogenesis schematic diagram under the conditions of IL-8；
Fig. 7 is that ursodesoxycholic acid inhibits angiogenesis node number schematic diagram under the conditions of IL-8；
Fig. 8 is that ursodesoxycholic acid inhibits angiogenesis blood vessel segment length schematic diagram under the conditions of IL-8；
Fig. 9 is that ursodesoxycholic acid inhibits angiogenesis screening area schematic diagram under the conditions of IL-8；
Figure 10 is that internal ursodesoxycholic acid inhibits angiogenesis schematic diagram under the conditions of IL-8；
Figure 11 is that internal ursodesoxycholic acid inhibits hemoglobin concentration schematic diagram under the conditions of IL-8；
Figure 12 is that internal ursodesoxycholic acid inhibits angiogenesis immunohistochemistry schematic diagram under the conditions of IL-8；
Figure 13 is that Western Blot method detects ursodesoxycholic acid effect associated signal paths schematic diagram.
Specific embodiment
The present invention is described in detail with specific embodiment below in conjunction with the accompanying drawings.
Embodiment
The reagents and materials used in the present invention are commercially available or can prepare by literature method.
Ursodesoxycholic acid (Ursodeoxycholic acid) is purchased from Sigma Co., USA, purity >=99%, and molecular formula is
C24H40O4, molecular mass 392.57g/moL, structural formula is as shown in Figure 1.
This product is dissolved in dimethyl sulfoxide (dimethylsulfoxide, DMSO), is made into 180mmol/L mother liquor, is being tested
It is diluted to respective concentration according to schedule in the process.
Embodiment one
Liver cancer cells are inoculated in orifice plate, orifice plate is placed in incubator, after cell is adherent, sops up original fluid, is compareed
100 μ L of DMEM complete medium is added in group, and experimental group is added the DMEM containing different ursodesoxycholic acid concentration doses and cultivates completely
100 μ L of base, while the zeroing group of cell is not added in setting, continues to be placed in 37 DEG C of cell incubators and cultivate, administration timing of drug point is calculated as
0h, for 24 hours and after 48h, culture medium is sucked, 100 culture mediums of the μ L containing 0.5%MTT are added in each hole, are placed in after incubator is incubated for 4h and add
Enter three solution, low speed concussion 10min is placed in incubator overnight, finally surveys light absorption value at 570nm in multi-function microplate reader
Calculate cell proliferation rate；
By human umbilical vein endothelial cell EA, hy926 cell inoculation is placed in incubator in orifice plate, orifice plate, to cell
After adherent, original fluid is sopped up, 100 μ L of DMEM complete medium is added in control group, and experimental group, which is added, contains different ursodeoxycholics
The 100 μ L of DMEM complete medium of acid concentration dosage, while the zeroing group of cell is not added in setting, continues to be placed in 37 DEG C of cell culture
It is cultivated in case, administration timing of drug point is calculated as 0h, for 24 hours and after 48h, sucks culture medium, and 100 cultures of the μ L containing 0.5%MTT are added in each hole
Base is placed in after incubator is incubated for 4h and three solution is added, and low speed concussion 10min is placed in incubator overnight, finally in more function
Energy microplate reader surveys light absorption value at 570nm and calculates cell proliferation rate；
Use CoCl2Anaerobic environment is simulated, liver cancer cells are inoculated in orifice plate, orifice plate is placed in incubator, adherent to cell
Afterwards, original fluid is sopped up, 100 μ L of DMEM complete medium is added in control group, and experimental group is added dense containing different ursodesoxycholic acid
The 100 μ L of DMEM complete medium for spending dosage, continues to be placed in 37 DEG C of cell incubators and cultivate for 24 hours, finally uses enzyme linked immunological
The secretion of determining adsorption kit measurement liver cancer cells IL-8 and VEGF；
Orifice plate is taken to be placed on ice, by high concentration matrigel and DMEM culture medium according to 1:After 1 ratio mixes, it is uniformly laid on hole
In plate, then every 60 μ L of hole will go it to place 30min in 37 DEG C of incubators, by EA, the digestion of hy926 vascular endothelial cell and from
The DMEM culture medium for being free of serum is added after discarding former culture medium, by cell quantification to 4 × 10 in the heart5A/mL, while by 100 μ
The IL-8 of g/mL and the ursodesoxycholic acid of various concentration are added in different groups, are rocked uniformly to be placed in incubator and be cultivated
16h is finally placed in microscope and observes.
The thing of all experiments is put in -20 DEG C of pre-coolings, by EA, hy926 vascular endothelial cell is digested and is centrifuged, and discards original
The DMEM culture medium for being free of serum is added after culture medium, by cell quantification to 2 × 107A/mL, while by the IL-8 of 100 μ g/mL
And IL-8 group and IL-8+ medicine group is added in 50 μM of ursodesoxycholic acid, and blank group is arranged, and forms cell suspension, cell is mixed
Suspension is mixed with without phenol red matrigel, and the male nude mouse left lower extremity for being injected in 4 week old is subcutaneous, takes out base after 10 days to be grown
Matter glue detects matrigel with hemoglobin detection kit.
By EA, hy926 vascular endothelial cell is taped against in orifice plate, and extracts egg after medicine irritation corresponding time point is added
It is white, cell pyrolysis liquid is added to the cell handled well, takes supernatant after centrifugation, protein content is detected by BCA method, is then passed through
SDS-PAGE runs electrophoresis, will run and carries out protein transferring film using sandwich device after complete offset plate is removed, by Protein transfer
It to pvdf membrane, then passes sequentially through 5% skimmed milk solution and is closed, different primary antibodies is then added is placed on 4 DEG C of refrigerators and shake
It shakes overnight, film is then washed using TBST, adds secondary antibody to rock 2h at room temperature, TBST washes film, and color developing agent is added to be developed the color and taken pictures；
Embodiment two
Experiment one
Take that growth conditions are good, logarithmic growth phase SMMC-7721 liver cancer cells (purchased from American ACT T Culture Collection Center)
According to 5 × 103The concentration in a/hole is inoculated with 96 orifice plates, is placed in 37 DEG C, in the incubator containing 5%CO2, after cell is adherent, sops up
100 μ L of DMEM complete medium is added in original fluid, control group, and experimental group is separately added into containing 25,50,100,200,400 μM of agent
The DMEM complete medium of the ursodesoxycholic acid (each dosage sets 3 multiple holes) of amount, while the zeroing group of cell is not added in setting, after
Continuous be placed in 37 DEG C of cell incubators is cultivated, and administration timing of drug point is calculated as 0h, for 24 hours and after 48h, sucks culture medium, and each hole is added 100
Culture medium of the μ L containing 0.5%MTT is placed in after incubator is incubated for 4h and three solution is added, and low speed concussion 10min is placed on incubator
In overnight, finally multi-function microplate reader survey 570nm place light absorption value (A value) calculating cell proliferation rate.
Cell proliferation rate=(experimental group A value-zeroing group A value)/(control group A value-zeroing group A value) × 100%
As a result as shown in Fig. 2, compared with the control group, the proliferation of the ursodesoxycholic acid of various concentration to SMMC-7721 cell
There is inhibiting effect, and its inhibiting effect has significance when ursodeoxycholic acid concentration is greater than 200 μM.
Experiment two
Take that growth conditions are good, human umbilical vein endothelial cell EA, hy926 of logarithmic growth phase are (purchased from Chinese science
Institute's cell bank) according to 5 × 103The concentration in a/hole is inoculated with 96 orifice plates, is placed in 37 DEG C, in the incubator containing 5%CO2, pastes to cell
After wall, sop up original fluid, control group is added 100 μ L of DMEM complete medium, experimental group is separately added into containing 25,50,100,
200, the DMEM complete medium of the ursodesoxycholic acid (each dosage sets 3 multiple holes) of 400 μM of dosage, while cell is not added in setting
Zeroing group, continue to be placed in 37 DEG C of cell incubators and cultivate, administration timing of drug point is calculated as 0h, for 24 hours and after 48h, suck culture medium,
100 culture mediums of the μ L containing 0.5%MTT are added in each hole, are placed in after incubator is incubated for 4h and three solution are added, low speed shakes 10min
It is placed in incubator overnight, finally surveys light absorption value (A value) at 570nm in multi-function microplate reader and calculate cell proliferation rate.
Cell proliferation rate=(experimental group A value-zeroing group A value)/(control group A value-zeroing group A value) × 100%
As a result as shown in figure 3, compared with the control group, to EA, the proliferation of hy926 cell has the ursodesoxycholic acid of various concentration
Inhibiting effect, and its inhibiting effect has significance when ursodeoxycholic acid concentration is greater than 100 μM.
Experiment three
Since anoxic is the promoting factor of angiogenesis, we simulate anoxic ring by CoCl2 in this experiment
Border, at the same it is dense to liver cancer and the vascular endothelial cell proliferation ability ursodesoxycholic acid without obvious effect by above-mentioned condition selection
It spends (25 and 50 μM), acts on SMMC-7721 liver cancer cells, detection ursodesoxycholic acid is tested to SMMC-7721 liver by ELISA
The influence of cancer cells secrete IL-8 and VEGF.
Take that growth conditions are good, SMMC-7721 cell of logarithmic growth phase is according to 5 × 103The concentration in a/hole is inoculated with 96 holes
Plate is placed in 37 DEG C, in the incubator containing 5%CO2, after cell is adherent, sops up original fluid, control group is added DMEM and trains completely
100 μ L of base is supported, experimental group is separately added into the ursodesoxycholic acid containing 25,50,100,200,400 μM of dosage, and (each dosage sets 3 again
Hole) DMEM complete medium, continue to be placed in 37 DEG C of cell incubators and cultivate for 24 hours.
It is operated then according to ELISA kit specification：
Sample-adding：Blank well, gauge orifice, sample to be tested hole are set respectively, and wherein sample and enzyme marking reagent is not added in blank well.In enzyme
It is loaded 50 μ L standard items on mark coating plate, adds 40 μ L sample dilutions, 10 μ L samples to be tested in sample to be tested hole respectively, mixing is equal
It is even, 37 DEG C of incubation 30min；Washing：Sealing plate film carefully to be taken away, liquid, drying are abandoned, each hole adds cleaning solution, it washs 3 times, each 3min,
Drying；Enzyme labeling antibody：In each reacting hole, 50 μ L enzyme marking reagents are added, wherein except blank well, sealing plate film sealing plate, 37 DEG C,
Incubate 30min；It washs again 3 times；Substrate is added to develop the color：In each hole, it is firstly added color developing agent A50 μ L, adds color developing agent B50 μ
L is mixed, 37 DEG C, and develop the color 15min, pays attention to being protected from light；Terminate reaction：50 μ L of terminate liquid is added in each reacting hole；In ELISA
It on detector, is returned to zero with blank well, 450nm wavelength sequentially measures the absorbance in each hole.
CoCl2 can effectively facilitate the secretion of IL-8 and VEGF to ELISA as the result is shown, it was demonstrated that anoxia model success, and DUCA
The secretion of liver cancer cells IL-8 (as shown in Figure 4) and VEGF (as shown in Figure 5) can effectively be inhibited.
Experiment four
Since VEGF is vascular endothelial growth factor, according to the literature and above-mentioned experimental result, it is presumed that IL-8 is
The cell factor closely related with angiogenesis of secretion of hepatoma, therefore, we are deoxygenated by IL-8 cell factor and bear
Cholic acid detects its influence to angiogenesis.
96 orifice plates are taken to be placed on ice, by high concentration Matrigel matrigel and DMEM culture medium according to 1:After 1 ratio mixes,
It is uniformly laid in 96 orifice plates, every 60 μ L of hole, it then will be gone to place 30min in 37 DEG C of incubators, carried out after matrigel solidification
Subsequent experimental.By the good EA of growth conditions, 926 vascular endothelial cell of hy is digested and is centrifuged, is added not after discarding former culture medium
DMEM culture medium containing serum, by cell quantification to 4 × 105A/mL, while by the bear of the IL-8 of 100 μ g/mL and various concentration
Deoxycholic aicd is added in different groups (respectively 25,50,100,200 μM), jiggles uniformly to be placed in incubator and train
16h is supported, is then just being set in microscope again and is being observed and take pictures.
As a result, it has been found that IL-8 can effectively induction of vascular be generated, and the ursodesoxycholic acid of various concentration is equal relative to control group
The generation of blood vessel can effectively be inhibited.Fig. 6 represents angiogenesis image under mirror, and Fig. 7 represents angiogenesis node number, and Fig. 8 is represented
Angiogenesis length, Fig. 9 table angiogenesis area.
Experiment five
The thing of all experiments is put in -20 DEG C of pre-coolings in advance, by the good EA of growth conditions, 926 blood vessel endothelium of hy is thin
Born of the same parents digest and are centrifuged, and the DMEM culture medium for being free of serum are added after discarding former culture medium, by cell quantification to 2 × 107A/mL,
IL-8 and 50 μM of the ursodesoxycholic acid of 100 μ g/mL is added in different groups simultaneously, experiment is divided into blank group, IL-8
Above-mentioned cell suspension is mixed with without phenol red matrigel, is injected in the hero of 4 week old by group and IL-8+ ursodesoxycholic acid group
Property nude mice left lower extremity is subcutaneous, takes out after 10 days to be grown.Experimental result is as shown in Figure 10, IL-8 can effectively induction of vascular life
At, and ursodesoxycholic acid can the effective antagonism effect.
The matrix blob of viscose taken out is detected, testing result using hemoglobin detection kit (being purchased from Bei Bo company)
As shown in figure 11.
The immunohistochemistry detection of matrix blob of viscose is carried out by commission Shanghai Garrett Serviss Biotechnology Co., Ltd simultaneously, mainly
Detect marker CD31, VEGF, the vWF of angiogenesis, as the result is shown IL-8 can effective induction of vascular generation, and ursodeoxycholic
Acid can the effective antagonism effect (as shown in figure 12).
Experiment six
Using immunoblotting (Western Blot), IL-8 and ursodesoxycholic acid are detected to the shadow of unlike signal access
It rings, by the good EA of growth conditions, 926 vascular endothelial cell of hy is taped against in 6 orifice plates, and the medicine irritation corresponding time is added
Albumen is extracted after point, cell pyrolysis liquid is added to the cell handled well, supernatant is taken after centrifugation, protein content is detected by BCA method,
Then electrophoresis is run by SDS-PAGE, will runs and protein transferring film is carried out using sandwich device after complete offset plate is removed, by egg
White matter is transferred to pvdf membrane, then passes sequentially through 5% skimmed milk solution and is closed, and different primary antibodies are added afterwards and are placed on 4 DEG C of ice
Case rocks overnight, then washes film using TBST, adds secondary antibody to rock 2h at room temperature, TBST washes film, and color developing agent is added to be developed the color and clapped
According to.
As a result as shown in figure 13, ursodesoxycholic acid inhibits the specific mechanism of angiogenesis may be by the table of inhibition p-I κ B
It reaches, and then P65 is promoted to enter nuclear expression, while by regulation p-ERK signal path, finally inhibiting the secretion of IL-8 and playing suppression
The effect of angiogenesis processed.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all in essence of the invention
Made any modifications, equivalent replacements, and improvements etc., should all be included in the protection scope of the present invention within mind and principle.With
The upper only presently preferred embodiments of the present invention, is not intended to limit the invention, it is noted that all of the invention
Made any modifications, equivalent replacements, and improvements etc., should all be included in the protection scope of the present invention within spirit and principle.
Claims (5)
1. application of the ursodesoxycholic acid in the drug of preparation prevention or treatment liver cancer.
2. application according to claim 1, it is characterised in that：Ursodesoxycholic acid is applied to as unique active constituent
In the preparation of the drug of prevention or treatment liver cancer.
3. application according to claim 1, it is characterised in that：Ursodesoxycholic acid is applied to as unique active constituent
Inhibit human umbilical vein endothelial cell EA, in the preparation of the drug of hy926 cell.
4. application according to claim 1, it is characterised in that：Ursodesoxycholic acid is applied to as unique active constituent
In the preparation for inhibiting the drug of the secretion of liver cancer cells IL-8 and VEGF.
5. application according to claim 1, it is characterised in that：Ursodesoxycholic acid is applied to as unique active constituent
In the preparation for inhibiting the drug of the generation of IL-8 induction of vascular.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109288850A (en) * | 2018-11-21 | 2019-02-01 | 浙江大学 | Ursodesoxycholic acid or its pharmaceutical salts application in preparation of anti-tumor drugs and anti-tumor drug |
| CN113143936A (en) * | 2021-02-10 | 2021-07-23 | 北京蕴汇医药科技有限公司 | Application of chenodeoxycholic acid or derivative thereof in preparation of EGFR and/or STAT3 inhibitor |
| CN114867482A (en) * | 2019-12-13 | 2022-08-05 | 首尔大学校产学协力团 | Pharmaceutical composition for preventing or treating cancer |
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| CN103772466A (en) * | 2014-03-04 | 2014-05-07 | 厦门大学 | Mammalian target of rapamycin (mTOR) inhibitor as well as preparation method and application thereof in preparation of antitumor drug |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109288850A (en) * | 2018-11-21 | 2019-02-01 | 浙江大学 | Ursodesoxycholic acid or its pharmaceutical salts application in preparation of anti-tumor drugs and anti-tumor drug |
| CN109288850B (en) * | 2018-11-21 | 2019-10-29 | 浙江大学 | Ursodesoxycholic acid or its pharmaceutical salts application in preparation of anti-tumor drugs and anti-tumor drug |
| WO2020103531A1 (en) * | 2018-11-21 | 2020-05-28 | 浙江大学 | Application of ursodeoxycholic acid or medicinal salt thereof in preparing anti-tumor drug and anti-tumor drug |
| CN114867482A (en) * | 2019-12-13 | 2022-08-05 | 首尔大学校产学协力团 | Pharmaceutical composition for preventing or treating cancer |
| EP4074316A4 (en) * | 2019-12-13 | 2023-12-27 | Veritasbiotherapeutics Co., LTD | Pharmaceutical composition for preventing or treating cancer |
| CN113143936A (en) * | 2021-02-10 | 2021-07-23 | 北京蕴汇医药科技有限公司 | Application of chenodeoxycholic acid or derivative thereof in preparation of EGFR and/or STAT3 inhibitor |
| CN113143936B (en) * | 2021-02-10 | 2022-03-25 | 北京蕴汇医药科技有限公司 | Application of chenodeoxycholic acid or derivative thereof in preparation of EGFR and/or STAT3 inhibitor |
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Application publication date: 20181116 |