CN113694205B - Application of 5-HT receptor inhibitor and cisplatin in preparation of medicines for treating liver cancer - Google Patents
Application of 5-HT receptor inhibitor and cisplatin in preparation of medicines for treating liver cancer Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds thereof
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
The invention provides application of a serotonin receptor inhibitor (5-HT receptor inhibitor) and Cisplatin (Cisplatin) in preparing medicines for treating liver cancer, belonging to the technical field of biological medicines. The combination of the 5-HT receptor inhibitor and the Cisplatin can be used for treating liver cancer with high expression of RECQL4, can generate a synergistic effect, can enhance the sensitivity of the liver cancer with high expression of RECQL4 to the Cisplatin, enhance the anti-liver cancer effect of the Cisplatin and weaken the drug resistance of the liver cancer to the Cisplatin.
Description
Technical Field
The invention relates to the technical field of tumor treatment, in particular to application of a 5-HT receptor inhibitor and cisplatin in preparation of a medicine for treating liver cancer.
Background
Liver cancer is cancer with incidence and mortality rate in the front of the world, and at present, most of the clinical treatment of liver cancer is chemotherapy with drugs represented by platinum, but due to individual differences of liver cancer patients, the chemotherapy effects of patients in the same pathological period are obviously different. At present, through cancer genome map (The Cancer Genome Atlas, TCGA) analysis, four gene changes of Rad21, rad54B, rad and RECQL4 are found to be related to the size, clinical stage and prognosis of tumors in clinical liver cancer samples, particularly in liver cancer of stage iii and stage iv, the changes of the four genes of Rad21, rad54B, rad and RECQL4 are greatly related to prognosis, and in liver cancer samples with poor prognosis, the Rad21, rad54B, rad and RECQL4 genes all show high expression. The four genes Rad21, rad54B, rad, RECQL4 are all involved in DNA replication and damage repair, and play roles in different stages of DNA double strand break repair. The RECQL4 gene has stronger repair capability, and the expression level of the RECQL4 gene is positively related to other repair genes; the higher the RECQL4 expression of the patient, the worse the prognosis, and the susceptibility to drug resistance to many chemotherapeutics (such as Cisplatin, cis) that cause DNA damage clinically (Thomassen M, tan Q, kruse T A. Gene expression meta-analysis identifies chromosomal regions and candidate genes involved in breast cancer metastasis [ J ]. Breast Cancer Res Tr,2009,113 (2): 239-249.); as chemotherapy goes deep, patient resistance to chemotherapeutic agents results in treatment failure.
Serotonin receptor inhibitors (5-HT receptor inhibitors) are currently clinically used antidepressants, and are used clinically to treat moderate to mild depression. There is no report on the treatment of liver cancer by combining a serotonin receptor inhibitor with a chemotherapeutic agent.
Disclosure of Invention
The invention aims to provide an application of a 5-HT receptor inhibitor and Cisplatin in preparing medicines for treating liver cancer, wherein the 5-HT receptor inhibitor can enhance the anti-liver cancer effect of Cisplatin and weaken the drug resistance of liver cancer to Cisplatin.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides application of serotonin receptor inhibitor and cisplatin in preparing medicines for treating liver cancer.
The invention also provides application of the serotonin receptor inhibitor in preparing medicaments for weakening drug resistance of liver cancer to cisplatin.
The invention also provides application of the serotonin receptor inhibitor in preparing medicaments for reducing toxic and side effects of cisplatin in treating liver cancer.
The invention also provides application of the serotonin receptor inhibitor and cisplatin in preparing medicines for inhibiting proliferation of liver cancer cells.
Preferably, the liver cancer comprises RECQL4 high expression liver cancer.
The invention provides a medicine for treating liver cancer, which comprises a serotonin receptor inhibitor and cisplatin.
Preferably, the serotonin receptor inhibitor comprises one or more of metacetirizine, N- [3- (2-dimethylamino) ethoxy-4-methoxyphenyl ] -2' -methyl-4 ' - (5-methyl-1, 2, 4-oxadiazol-3-yl) - (1, 1' -biphenyl) -4-carboxamide, 5- ((4- (6-chlorothiophene [2,3-d ] pyrimidin-4-ylamino) piperidin-1-yl) methyl) -2-fluorobenzonitrile monofumarate and aripiprazole.
Preferably, the mass ratio of the serotonin receptor inhibitor to the cisplatin in the medicament is (1.5-2.5) to 5.
Preferably, the dosage form of the medicament comprises an injection.
Preferably, the concentration of the serotonin receptor inhibitor in the medicament is 1.5-2.5 mg/ml; the concentration of cisplatin in the medicine is 4.5-5.5 mg/ml.
The invention provides application of serotonin receptor inhibitor and cisplatin in preparing medicines for treating liver cancer. The combination of the 5-HT receptor inhibitor and the Cisplatin can be used for treating liver cancer with high expression of RECQL4, can generate a synergistic effect, can enhance the sensitivity of the liver cancer with high expression of RECQL4 to the Cisplatin, enhance the anti-liver cancer effect of the Cisplatin, weaken the drug resistance of the liver cancer to the Cisplatin and weaken the toxicity of Cisplatin.
Drawings
FIG. 1 shows the quantitative effect relationship of PRX, cis, PRX +cis on SNU398 cell proliferation;
FIG. 2 is a Fa-CI diagram of PRX+cis combined inhibition of SNU398 cell proliferation (< 0.05; P < 0.01);
FIG. 3 is a graph showing the quantitative effect of APZ, cis, APZ +cis on SNU398 cell proliferation;
FIG. 4 is a Fa-CI diagram of the combined inhibition of SNU398 cell proliferation by APZ+cis (< 0.05; P < 0.01);
FIG. 5 is a graph showing the quantitative effect of MET, cis, MET +cis on SNU398 cell proliferation;
FIG. 6 is a graph of Fa-CI for the combined inhibition of SNU398 cell proliferation by MET+cis (P <0.05; P < 0.01);
FIG. 7 is a graph showing the quantitative effect of SB, cis, SB +cis on SNU398 cell proliferation;
FIG. 8 is a Fa-CI diagram of SB+cis combined inhibition of SNU398 cell proliferation (P <0.05; P < 0.01);
fig. 9 shows tumor inhibition rates (P <0.05; P < 0.01) of different administration groups in example 5;
FIG. 10 is a survival curve of different dosing groups of nude mice in example 5.
Detailed Description
The invention provides application of serotonin receptor inhibitor and cisplatin in preparing medicines for treating liver cancer.
The invention provides application of a serotonin receptor inhibitor in preparing a medicament for weakening drug resistance of liver cancer to cisplatin.
The invention provides application of a serotonin receptor inhibitor in preparing a medicament for reducing toxic and side effects of cisplatin in treating liver cancer.
The invention provides application of serotonin receptor inhibitor and cisplatin in preparing medicines for inhibiting liver cancer cell proliferation.
In the present invention, the serotonin receptor inhibitor preferably comprises one or more of metacetirizine (Methiothepin maleate), N- [3- (2-dimethylamino) ethoxy-4-methoxyphenyl ] -2' -methyl-4 ' - (5-methyl-1, 2, 4-oxadiazol-3-yl) - (1, 1' -biphenyl) -4-carboxamide (SB 216641 hydro-chloride), 5- ((4- (6-chlorothiophene [2,3-d ] pyrimidin-4-ylamino) piperidin-1-yl) methyl) -2-fluorobenzonitrile monofumarate (PRX-08066 Maleic acid) and Aripiprazole (Aripiprazole). In the present invention, the Methiothepin maleate, SB 216641 hydrochlorides, PRX-08066Maleic acid and Aripiprazole are commercially available.
In the present invention, the liver cancer preferably includes RECQL4 high expression liver cancer.
In the present invention, the dosage form of the drug preferably includes an injection; the injection is preferably an intraperitoneal injection or an intravenous injection.
In the invention, the mass ratio of the serotonin receptor inhibitor to the cisplatin in the medicament is preferably (1.5-2.5) to 5. In the invention, the concentration of the serotonin receptor inhibitor in the medicament is preferably 1.5 to 2.5mg/ml; the concentration of cisplatin in the medicine is preferably 4.5-5.5 mg/ml. In the present invention, the solvent used for the drug is preferably sterile physiological saline or sterile PBS.
The invention also provides a medicine for treating liver cancer, which comprises a serotonin receptor inhibitor and cisplatin.
The technical solutions of the present invention will be clearly and completely described in the following in connection with the embodiments of the present invention. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The sources of materials in the examples of the present invention are as follows:
LO2 (human normal hepatocytes): purchased from south Beijing Kaiki Biotechnology development Co. SNU398 (human hepatoma cell): purchased from Guangzhou Saikovia Biotechnology Co. SB 216641 hydro-chloride (SB for short) and Methiothepin maleate (5-HT Receptors for short, non-Selective, MET for short) are purchased from TOCRTS company; PRX-08066 Maleric acid (5-HT 2B receptors 1 antagonit, PRX for short), aripiprazole (a high-affinity 5-HT receptor partial agonist, APZ for short) were purchased from Selleck corporation. Cisplatins (Cis) are purchased from Solarbio.
EXAMPLE 1 inhibition of cells by Cis and PRX alone and in combination
1. Cell seed plate
Selecting LO2 cells and SNU398 cells in logarithmic growth phase, digesting with 0.25% trypsin, centrifuging, collecting cells, counting, diluting to 5×10 3 3 parallel wells were placed per ml, 100. Mu.l of cell suspension was plated in 96-well plates at 37℃in 5% CO 2 After culturing in an incubator for 24 hours, the cells were observed under a microscope for adhesion.
2. Combination drug
Experimental grouping:
(1) Blank group: no cells and only culture medium are added;
(2) DMSO negative group: no medicine is added;
(3) Group of individual doses: 10 concentration levels (see Table 1) were set with a 2-fold relationship between adjacent concentrations.
(4) Combination group: according to the general principle of the experimental design of the Chou-Talay combined index method, the medicine is provided with 10 concentration levels, and PRX and Cis are combined at different concentrations, namely the level 1: PRX concentration 1+cis concentration 1; level 2: PRX concentration 2+cis concentration 2; sequentially to level 10: PRX concentration 10+cis concentration 10. (see Table 1).
TABLE 1 influence of Cis and PRX alone and in combination on cell proliferation
And observing the cells in the 96-well plate under a microscope, wherein the cells are good in adhesion and full in shape, and are ready for dosing. Ultraviolet irradiating the super clean bench for 30min, circularly ventilating for 15min, taking out the prepared medicine mother liquor from the refrigerator, spraying 75% alcohol, and placing in the super clean bench. And according to the set drug concentration, performing drug calculation and configuration. First, separate drug groups (PRX, cis) were formulated, each at 10 concentrations, and Cis and PRX were combined. The 96-well plate was removed from the incubator, kong Nayuan medium was aspirated using a syringe, and different concentrations of each drug were added to the 96-well plate separately in separate drug wells, 100 μl per well. When Cis and PRX are combined, the combined volume ratio of the two medicines is 1:1, and the total medicine adding amount of each hole is 100 mu l, namely, the concentration of single medicine is doubled and 50 mu l is added respectively, and the corresponding concentration is shown in the table 1 after the doubling ratio is diluted.
The 96-well plate was removed from the cell incubator, the crude medium was aspirated from each well using a syringe, fresh drug-containing medium was added, 100. Mu.l per well, and the 96-well plate was placed in the cell incubator for continuous culture. Sterile operation is noted in the process of adding medicine, so that cell pollution is prevented. And observing the cell morphology after the drug intervention for 24 hours and 48 hours respectively, and photographing and storing. After the medicine is intervened for 48 hours, the medicine-containing culture medium is discarded, a certain amount of 10% of CCK-8 working solution is prepared, 100 μl of each hole is added, after the cell culture box is incubated for 2-4 hours, the OD value of each hole under the wavelength of 450nm is measured by a multifunctional enzyme-labeled instrument, and the data is stored and processed. The data is taken into the following formula:
cell Viability) = (OD Medicine group -OD Blank group )/(OD Negative group -OD Blank group )×100％；
OD Medicine group Adding a compound to be detected into the cell hole to obtain the final solution absorbance value of the cell hole after co-culture;
OD negative group The final solution absorbance of the cell well measured after the co-culture with the complete medium is added;
OD blank group Is the final solution absorbance of the blank wells of the medium without cells and without test compound;
taking the drug concentration as the abscissa and the cell survival rate as the ordinate, performing data processing by using GraphPad Prism 6.0, and obtaining the IC of each cell corresponding to each drug 50 The value, i.e. the concentration of compound that induces 50% of tumor cell death, referred to as the median inhibitory concentration, is used to measure the ability of the drug to intervene in tumor cell proliferation, IC 50 The lower the value, the more potent the drug intervention, indicating that the cell is more sensitive to the drug.
3. Chou-Talalay equation and determination of combined drug effect
According to the Chou-Talalay equation, fa/fu= [ D/Dm ] m, (D is drug concentration; dm is medium-effective concentration, i.e. drug concentration when fa=0.5), taking the logarithm of both sides of the linear equation: y=mx+a (where y=log [ fa/fu ], x=log d, m is the slope of the equation and a is the intercept of the equation). And calculating the corresponding Dm (logDm= -a/m) when the two medicaments are used singly or in combination respectively, and then calculating the effect relationship when the two medicaments are used together according to a dose-effect formula = D1/Dx1+D2/Dx2+alpha D1D2/Dx1Dx2 in a combined index method. ( D1 and D2 are the concentrations of the two drugs at which the drug effect X is achieved, and Dx1 and Dx2 are used separately. Interaction of two drugs: CI <1 is the synergistic effect when two drugs are combined, ci=1 is the additive effect when two drugs are combined, and CI >1 is the antagonistic effect when two drugs are combined. )
The SNU398 was subjected to drug intervention in the PRX, cis, prx+cis groups with LO2 cells as a control, as shown in fig. 1 and 2. The results of fig. 1 show that: the Cis group, the PRX group and the PRX+cis group have inhibition effect on proliferation of SNU398 cells, and the inhibition rate of cell proliferation is increased along with the increase of the drug concentration, so that the drug has a dose-effect relationship; compared with Cis group, the inhibition rate of PRX+cis group to SNU-398 cell is obviously increased, and there is obvious statistical difference (P < 0.01); when the same inhibition rate is achieved in the Cis group and the PRX+cis group, the PRX+cis group reduces the amount of Cis and enhances the sensitivity of SNU398 to Cis. The results in FIG. 2 show that the combination of PRX+cis showed a synergy at various concentrations with CI <1, and that the synergy of the combination of PRX+cis increased with increasing concentration.
EXAMPLE 2 inhibition of cells by Cis and APZ alone and in combination
The drug grouping situation is shown in table 2 and the remaining procedure is shown in example 1.
TABLE 2 influence of Cis and APZ alone and in combination on cell proliferation
The SNU398 was subjected to drug intervention by setting APZ, cis, APZ+cis groups against LO2 cells. As shown in FIG. 3, the Cis group, the APZ group and the APZ+cis group all have inhibition effect on proliferation of SNU398 cells, and the inhibition rate of cell proliferation is increased along with the increase of the drug concentration, so that the dose-effect relationship is realized; at medium and low concentrations, the inhibition rate of the APZ+cis group on SNU-398 cells was higher than that of Cis group, and there was a statistical difference (P < 0.05), indicating that the combination of APZ+cis increases the sensitivity of SNU398 to Cis; with the increase of the drug concentration, the inhibition rate of the Cis group and the APZ+cis group on the SNU398 is not obviously different; see fig. 4, where the apz+cis group exhibits synergy at low concentrations in combination with CI values < 1; with increasing concentrations of APZ+cis combination, CI >1 exhibited antagonism.
EXAMPLE 3 inhibition of cells by Cis and MET alone and in combination
Drug grouping is shown in table 3 and the remaining procedure is shown in example 1.
TABLE 3 influence of Cis and MET alone and in combination on cell proliferation
The SNU398 and the MET group, the Cis group and the MET+cis group are set by taking LO2 cells as a control, and the drug intervention is carried out. As shown in FIG. 5, the Cis group, the MET group and the MET+cis group all have inhibition effect on proliferation of SNU398 cells, and the inhibition rate of cell proliferation is increased along with the increase of the drug concentration, so that the inhibition rate has a dose-effect relationship; the inhibition rate of the MET+cis group on the SNU398 is obviously higher than that of the Cis group in a certain concentration range, and the inhibition rate has obvious statistical difference (P < 0.01); as shown in fig. 6, when the met+cis group is used in combination with low concentration, CI value >1 shows antagonism, and when the met+cis group is used in combination with high concentration, CI value <1 shows synergy.
EXAMPLE 4 inhibition of cells by Cis and SB alone and in combination
The drug grouping situation is shown in table 4 and the remaining procedure is shown in example 1.
TABLE 4 influence of Cis and SB alone and in combination on cell proliferation
The SNU398 was subjected to drug intervention in SB, cis, SB+cis groups with LO2 cells as controls. As shown in FIG. 7, the Cis group, the SB group and the SB+cis group have inhibition effect on proliferation of SNU398 cells, and the inhibition rate of cell proliferation increases with the increase of the drug concentration, and have a dose-effect relationship; the inhibition rate of SNU398 is obviously increased in the SB+cis group compared with the Cis group in a certain concentration range, and the statistical difference is obvious (P < 0.01); as shown in FIG. 8, the combination of low concentration in SB+cis group showed antagonism of CI >1, and the combination of high concentration in SB+cis group showed synergy of CI < 1.
EXAMPLE 5 pharmacodynamic detection of nude mice allograft tumor model by APZ and Cis combination
(1) The operation steps are as follows:
after BALB/C-Nu nude mice were cultured in SPF environment for 1 week, 40 nude mice were weighed one by one and labeled. Sterile PBS and Matrigel are prepared according to a volume ratio of 1:1 on ice, the sterile PBS and Matrigel are uniformly mixed, SNU398 cells are subjected to constant volume cell suspension, the suspension is injected under the right forelimb armpit of a nude mouse, 200 mu l of mixed solution (PBS: matrigel=1:1, volume ratio) is injected into a Blank group nude mouse, and 7×10 nude mice of an experimental group are injected 6 200 μl of hepatoma cell SNU398. After nude mice are subcutaneously injected with SNU398 cells, the growth condition of tumors is observed every day, and the tumor volume of the nude mice is about 100-150 mm 3 And when the tumor is in a small size, the nude mice with oversized tumor are removed according to the size of the tumor and the weight of the nude mice, and the nude mice with oversized tumor are randomly grouped for intraperitoneal injection. The experimental groups were divided into 5 groups: (1) Cis administration group: the dosage is 25mg/kg, and the medicine is administered once every five days; (2) APZ drug group: the dosage is 10mg/kg, and the medicine is administered once every two days; (3) Cis and APZ combination: dosing was performed every five days at a dose of Cis (25 mg/kg) +APZ (10 mg/kg); (4) DMSO control: injection of DMSO solvent once every two days; (5) Blank group.
Auxiliary materials of the medicine: preparing the medicament with sterile PBS (pH 7.2); configuration of Cisplatins: 50mg of Cis is added with 50 μl of DMSO, 9950 μl of PBS is supplemented, and a 50mg/10ml solution is prepared, and the solution is split into 10 EP tubes of 1.5ml, and frozen at-20deg.C for use. The dosage of each tumor-bearing mouse is as follows: 100 μl/20g. Configuration of APZ: 20mg of APZ was prepared as a 10ml solution, and the other procedures were the same as Cis. The dosage of each tumor-bearing mouse is as follows: 100 μl/20g.
Observing whether the mental state of the mice is normal or not after the injection of the medicine, recording the death time by taking the administration days as a unit, drawing a life cycle curve, and evaluating the life cycle; the weight of the nude mice is observed and measured every other day, the long diameter and the short diameter of the tumor are measured by using a vernier caliper, and the tumor is recorded and analyzed. After the experiment is finished, the cervical vertebrae are removed, the animals are killed, dissected, tumors are peeled off, the weight and the tumor weight of the nude mice are weighed, the heart, the liver, the spleen, the lung and the kidney are obtained and weighed, the organ coefficients of each group are calculated respectively, and the results are processed statistically. Analysis data are expressed as mean.+ -. Standard deviation (mean.+ -. S.E.M), data comparison between groups is analyzed using One-Way analysis of variance (One Way ANOVA), comparison between groups is performed using student-t test, statistical analysis and mapping are performed using GraphPad Prism 6.0 statistical software.
(2) Results: inhibition of tumor by combination
After the experiment is finished, the nude mice are killed by cervical vertebra removal, the nude mice are dissected to strip out tumors, and the tumors are weighed. The tumor inhibition rate was calculated from the following formula: inhibition (%) = (tumor weight of control group-tumor weight of experimental group)/tumor mass of control group×100%. As shown in fig. 9 and table 5, the APZ group, cis group, and apz+cis group have inhibitory effect on tumor growth in mice, compared to DMSO control group, wherein the apz+cis group has the highest inhibition rate on tumor. The inhibition rates of the APZ group, the Cis group and the APZ+cis group on tumors are 25.02%, 82.33% and 91.23%, respectively.
TABLE 5 inhibition of tumor growth by APZ, cis, APZ and Cis
Compared to DMSO control group: p <0.05; * *: p <0.01.
(3) Results: survival curve analysis of nude mice
The survival period of the mice in the different drug groups was evaluated and plotted, as shown in fig. 10, and it can be seen that the survival period of the mice in Cis group, APZ group, apz+cis group was prolonged as compared with the mice in DMSO control group, wherein the survival period of the mice in apz+cis group was longest.
(4) Results: analysis of organ coefficients of nude mice
When tumor model mice were treated in the above experiments, hearts, livers, spleens, lungs, and kidneys were removed. Each organ was then weighed and the weight recorded. Calculating viscera coefficients according to the formula: organ coefficient=organ weight/body weight x 100%.
After each group of BALB/N-Cu nude mice are dissected and the viscera are weighed, statistics and analysis of main viscera coefficients are carried out, and the results are shown in a table 6, compared with the BALB/N-Cu nude mice in a DMSO control group, the viscera coefficients of the lungs of the Cis group and the APZ+cis group are respectively increased to different degrees, and the statistics difference is obvious (P < 0.01); the viscera coefficient of Cis group kidney is increased, and the Cis group kidney has obvious statistical difference (P < 0.01); the viscera coefficient of Cis group heart is increased, and the Cis group heart has obvious statistical difference (P < 0.01); compared with the Cis group BALB/N-Cu mice, the lung organ coefficients of the APZ group and the APZ+cis group are higher than those of the Cis group, and the lung organ coefficients have obvious statistical differences (P < 0.01); spleen organ coefficients of APZ group were higher than Cis group, with statistical differences (P < 0.01); the heart organ coefficients of the APZ group and the APZ+cis group are lower than those of the Cis group, and the significant statistical difference (P < 0.05) exists; there were no statistical differences in the viscera coefficients of liver and spleen compared with the DMSO control group in Cis group, APZ group, APZ+cis group.
TABLE 6 analysis of organ coefficients in BALB/C-Nu mice
Each group compared to DMSO control group: p <0.05; * *: p <0.01.
Through organ coefficient analysis, the organ coefficients of the kidney, the heart and the lung of the Cis group are higher than those of the DMSO group nude mice, so that the Cis group has larger toxic and side effects and can cause complications. The inhibition rate of APZ+cis combined drug group to tumor is highest, compared with Cis group, we find that the organ coefficients of kidney, heart and lung of APZ+cis group are smaller than Cis group, which shows that APZ can weaken toxic and side effect of Cis and strengthen sensitivity of tumor to Cis.
The side effects of Cisplatin are manifested by loss of appetite, nausea, vomiting, diarrhea, etc. Usually occurs 1-2 hours after injection, lasts for 4-6 hours or longer, and disappears after 2-3 days. This response is dose dependent. Cisplatin exhibits outstanding nephrotoxicity, mainly manifested as kidney-transitional lesions, including damage to tubular epithelial cells. It features that its blood urine and kidney function are damaged, serum creatinine is raised and its clearance rate is lowered.
The above examples show that the 5-HT receptor inhibitor can enhance the anti-liver cancer effect of Cisplatin and reduce the toxic and side effects of Cisplatin, thereby providing a new therapeutic concept and theoretical experimental basis for clinically treating liver cancer.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (4)
1. Application of serotonin receptor inhibitor and cisplatin in preparing medicine for treating liver cancer; the serotonin receptor inhibitor can enhance the anti-liver cancer effect of cisplatin;
the liver cancer isRECQL4High expression liver cancer;
the serotonin receptor inhibitor is one or more of metacetirizine, N- [3- (2-dimethylamino) ethoxy-4-methoxyphenyl ] -2' -methyl-4 ' - (5-methyl-1, 2, 4-oxadiazol-3-yl) - (1, 1' -biphenyl) -4-carboxamide and aripiprazole;
when the serotonin receptor inhibitor is metazizeine, the concentration of metazizeine is 20 mu M, and the concentration of cisplatin is 20 mu M;
or the concentration of the metacetirizine is 40 mu M, and the concentration of the cisplatin is 40 mu M;
or the concentration of the metacetirizine is 80 mu M, and the concentration of the cisplatin is 80 mu M;
when the serotonin receptor inhibitor is N- [3- (2-dimethylamino) ethoxy-4-methoxyphenyl ] -2 '-methyl-4' - (5-methyl-1, 2, 4-oxadiazol-3-yl) - (1, 1 '-biphenyl) -4-carboxamide, the concentration of N- [3- (2-dimethylamino) ethoxy-4-methoxyphenyl ] -2' -methyl-4 '- (5-methyl-1, 2, 4-oxadiazol-3-yl) - (1, 1' -biphenyl) -4-carboxamide is 20. Mu.M and the concentration of cisplatin is 20. Mu.M;
or the concentration of N- [3- (2-dimethylamino) ethoxy-4-methoxyphenyl ] -2' -methyl-4 ' - (5-methyl-1, 2, 4-oxadiazol-3-yl) - (1, 1' -biphenyl) -4-carboxamide is 40. Mu.M and the concentration of cisplatin is 40. Mu.M;
or the concentration of N- [3- (2-dimethylamino) ethoxy-4-methoxyphenyl ] -2 '-methyl-4' - (5-methyl-1, 2, 4-oxadiazol-3-yl) - (1, 1 '-biphenyl) -4-carboxamide is 80. Mu.M and the concentration of cisplatin is 80. Mu.M when the concentration of N- [3- (2-dimethylamino) ethoxy-4-methoxyphenyl ] -2' -methyl-4 '- (5-methyl-1, 2, 4-oxadiazol-3-yl) - (1, 1' -biphenyl) -4-carboxamide is 80. Mu.M;
when the serotonin receptor inhibitor is aripiprazole, the concentration of aripiprazole is 0.15625 μm and the concentration of cisplatin is 0.15625 μm;
or the concentration of aripiprazole is 0.3125 μm and the concentration of cisplatin is 0.3125 μm;
or the concentration of aripiprazole is 0.625 μm and the concentration of cisplatin is 0.625 μm;
or the concentration of aripiprazole is 1.25 μm and the concentration of cisplatin is 1.25 μm; .
2. The use of claim 1, wherein the effect of the serotonin receptor inhibitor further comprises reducing resistance of liver cancer to cisplatin.
3. The use of claim 1, wherein the serotonin receptor inhibitor further comprises reducing the toxic side effects of cisplatin in the treatment of liver cancer.
4. The use according to claim 1, wherein the effect of the serotonin receptor inhibitor and cisplatin further comprises inhibition of liver cancer cell proliferation.
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