CN117899083A - Application of buspirone hydrochloride as PD-1 inhibitor - Google Patents
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention provides application of buspirone hydrochloride as a PD-L1 inhibitor, and belongs to the field of biological medicine. The invention provides application of buspirone hydrochloride as a PD-L1 inhibitor, and researches prove that buspirone hydrochloride can effectively inhibit the expression of PD-L1 in melanoma cells, improve the ratio of CD4 + and CD8 + T lymphocytes in spleen and blood of tumor-bearing mice, strengthen the anti-tumor immune response of the tumor-bearing mice, obviously increase the expression of FBXO22 in tissues, further strengthen the anti-tumor effect of T lymphocytes of organisms, and can be used as the PD-L1 inhibitor and also be used for developing medicaments for diseases related to PD-1/PD-L1 signal paths.
Description
Technical Field
The invention relates to the technical field of biological medicines, in particular to application of buspirone hydrochloride as a PD-1 inhibitor.
Background
Programmed CELL DEATH ligand 1 (PD-L1), a transmembrane protein of 40kDa, also known as surface antigen cluster 274. It has been clarified by the current study that PD-L1 is an immunonegative molecule capable of binding to the apoptosis receptor-1 (Programmed cell deathprotein, PD-1), conducting an inhibitory signal, significantly inhibiting the anti-tumor effect of effector T cells. Furthermore, high expression of PD-L1 also inhibits the effects of neighboring macrophages in tumor tissue, participating in the formation of an immunosuppressive tumor microenvironment.
Recent studies have shown that monoclonal antibodies directed against immune checkpoint pathway PD-1/PD-L1 can effectively treat advanced melanoma, and have been FDA approved for the treatment of a variety of tumors in the clinic. However, most patients still have unsatisfactory therapeutic effects, and the antibody drugs have the disadvantages of immunogenicity problems, high production price, complex preparation process, and the like. Therefore, the search for new PD-1/PD-L1 pathway blocking drugs remains an important point of search. However, developing a new drug requires a lot of financial resources, material resources and manpower, and developing new functions of old clinical drugs becomes a hotspot of current research.
Buspirone hydrochloride (8-azaspiro [4,5] decane-7, 9-dione, 8- [4- (4-2-pyrimidinyl) -1-piperazinyl ] butyl-hydrochloride, buspirone hydrochloride) is used as a novel anxiolytic drug, mainly for the treatment of various anxiety disorders, depression, maladaptive behaviour and obsessive compulsive disorder by altering anxiety mood through activation of serotonin 1A receptor in the brain.
Disclosure of Invention
The invention aims to provide a novel PD-1/PD-L1 pathway blocking medicament.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides application of buspirone hydrochloride as a PD-L1 inhibitor.
The invention also provides the use of buspirone hydrochloride as the sole active ingredient in the manufacture of a medicament for the treatment, prevention, amelioration, control or alleviation of a disease associated with the PD-1/PD-L1 signalling pathway in a patient.
Preferably, the disease related to the PD-1/PD-L1 signaling pathway is cancer, an infectious disease or an autoimmune disease.
Preferably, the disease associated with the PD-1/PD-L1 signaling pathway is melanoma.
Preferably, the route of administration of the drug is oral or injectable.
Preferably, the medicine is emulsion, solution, granule, tablet, hard capsule, soft capsule, or emulsion, micelle solution, solution for intravenous injection and intramuscular injection.
Advantageous effects
The research of the invention proves that the buspirone hydrochloride can effectively inhibit the expression of PD-L1 in melanoma cells, improve the ratio of CD4 + and CD8 + T lymphocytes in spleen and blood of tumor-bearing mice, and enhance the anti-tumor immune response of the tumor-bearing mice.
According to the invention, the buspirone hydrochloride remarkably increases the expression of FBXO22 in tissues, wherein FBXO22 is a member of F-box family, forms subunits of E3 ubiquitin ligase complex, and the increased expression of FBXO22 can effectively promote ubiquitination and degradation of PD-L1. Buspirone hydrochloride is thought to degrade PD-L1 through the FBXO22 pathway, thereby enhancing the anti-tumor effect of T lymphocytes of the body. Thus, the buspirone hydrochloride can be used as a PD-L1 inhibitor for developing medicaments for diseases related to PD-1/PD-L1 signal paths.
Drawings
FIG. 1 shows the effect of buspirone hydrochloride on PD-L1 expression after 24h on melanoma cells.
FIG. 2 shows the effect of buspirone hydrochloride on PD-L1 expression after 48h of action on melanoma cells.
FIG. 3 is a graph showing the effect of buspirone hydrochloride on melanoma tumor growth.
FIG. 4 is a graph showing the effect of buspirone hydrochloride on CD4 + T cell rate in spleen of melanoma-bearing mice.
FIG. 5 is a graph showing the effect of buspirone hydrochloride on CD8 + T cell rate in spleen of melanoma-bearing mice.
FIG. 6 is a graph showing the effect of buspirone hydrochloride on the CD4 + T cell rate in the blood of melanoma-bearing mice.
FIG. 7 is a graph showing the effect of buspirone hydrochloride on CD8+ T cell ratio in blood of melanoma-bearing mice.
FIG. 8 shows the effect of Western blot detection of buspirone hydrochloride on PD-L1 expression in tumor tissue of tumor-bearing mice.
FIG. 9 shows the effect of immunofluorescence detection of buspirone hydrochloride on PD-L1 expression in tumor tissue of tumor-bearing mice.
Fig. 10 is the effect of buspirone hydrochloride on FBXO22 expression in melanoma tumor tissue.
Detailed Description
In the present invention, buspirone hydrochloride is buspirone hydrochloride tablet (5 mg/tablet) of Yishu (enhua).
The technical solutions provided by the present invention are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention.
EXAMPLE 1Western blot detection of expression of cell PD-L1
After plating a six-well plate of melanoma B16 cells according to the cell density of 3.5X10 5 cells/well and incubating for 16 hours in a 5% CO 2 incubator at 37 ℃, buspirone hydrochloride (0,0.625,1.25,2.5,5, 10 ug/ml) acts on the cells for 24 hours and 48 hours according to different concentrations, and then cellular proteins are extracted respectively. Proteins were subjected to SDS-PAGE, electrotransferred, and the electrotransferred PVDF membranes were incubated with the corresponding PD-L1 antibodies (1:1000 dilution, bioworld Technology) overnight, washed, incubated with the corresponding secondary antibodies, washed again and exposed to light.
We used the Westernblot experiment to examine the effect of buspirone hydrochloride at various concentrations (0,0.625,1.25,2.5,5, 10 ug/ml) on PD-L1 expression in melanoma cells.
The results show that buspirone hydrochloride significantly inhibited the expression of PD-L1 in the cells after 24h (FIG. 1) and 48h (FIG. 2) of the melanoma cells.
Example 2 animal experiments
Establishment of melanoma mouse model
The cultured B16 cells were subjected to cell counting, and the cell concentration was adjusted to 1X 10 7 cells/mL. The right hind limb of the C57BL/6 mouse was selected to be subcutaneously injected with 100. Mu.L of the cell suspension, i.e., 1X 10 6 cells/mouse. And (5) observing whether the molding is successful or not about 7 days, if the protrusion is formed at the injection part, the molding is successful, and if the protrusion is not the molding failure.
Mouse treatment
When the tumors of the mice grow to 3-4 mm 3, the mice are randomly divided into four groups, namely, PBS group, 100 μg/group, 200 μg/group, 400 μg/group, and corresponding treatments are performed. PBS group was injected intratumorally with 100. Mu. LPBS solution, 100. Mu.g per group was injected intratumorally with 100. Mu.g buspirone hydrochloride, 200. Mu.g per group was injected intratumorally with 200. Mu.g buspirone hydrochloride, 400. Mu.g per group was injected intratumorally with 400. Mu.g buspirone hydrochloride. Once daily for 7 days. Mice were sacrificed 4 days after the last treatment, blood, spleen and tumor tissue of the mice were isolated, and tumor weights of the mice and T lymphocyte ratios in the blood, spleen were recorded.
Flow cytometry
3 Mice were sacrificed at random in different treatment groups and eyeball blood and spleen were removed.
(1) Peripheral blood flow type: 200. Mu.L of eyeball blood was taken, red blood cells were lysed, and the corresponding antibodies CD3 (BioLegend), CD4 (BioLegend) and CD8 (BioLegend) were added to the mixture, and after incubation for half an hour in the dark, the cells were washed with 4mL of cell staining Buffer, centrifuged to discard the supernatant, and the cells were resuspended with 0.4mL of cell staining Buffer, and were detected on a flow machine.
(2) Spleen cell flow-through: spleen was ground, spleen cell suspensions were prepared, erythrocytes were lysed, cell pellets were suspended in 1mL of medium, cell counts were performed, corresponding antibodies CD3 (BioLegend), CD4 (BioLegend) and CD8 (BioLegend) were added to each EP tube according to a cell volume of 2×10 6 cells/100 μl, after incubation at 4 ℃ for 30min in the absence of light, 500 μ LPBS solution was directly added, centrifugation was performed, after discarding the supernatant, cells were washed with 1mL of PBS solution, centrifuged, the supernatant was discarded, cells were resuspended with 300 μl of PBS solution, and flow-on-machine detection was performed.
Next we examined the effect of buspirone hydrochloride treatment at different doses (100 μg/g, 200 μg/g and 400 μg/g) on tumor growth in melanoma-bearing mice, on the ratio of CD4 + and CD8 + T lymphocytes in the spleen of melanoma-bearing mice, and on the ratio of CD4 + and CD8 + T lymphocytes in the blood of melanoma-bearing mice.
The results show that:
1. buspirone hydrochloride treatment was effective in inhibiting melanoma growth (fig. 3);
2. Flow cytometry results of spleen showed that buspirone hydrochloride significantly increased the ratio of CD4 + T lymphocytes (fig. 4) to CD8 + T lymphocytes in the spleen of tumor-bearing mice (fig. 5);
3. consistent with the trend of the ratio of T cells in spleen, buspirone hydrochloride significantly increased the ratio of CD4 + T lymphocytes (fig. 6) and cd8+ T lymphocytes (fig. 7) in the blood of tumor-bearing mice.
EXAMPLE 3Western blot detection of PD-L1 expression in tumor tissue
Taking 0.1g of tumor tissues of different treatment groups, placing the tumor tissues into a 2mL grinding tube, adding cell lysate, grinding the tumor tissues by using a tissue grinder, continuously cracking the tissues on ice for 30min, and centrifuging to obtain cracked supernatants. Proteins were subjected to SDS-PAGE, electrotransferred, and the electrotransferred PVDF membranes were incubated with the corresponding PD-L1 antibodies (Bioworld Technology 1:1000 dilution) overnight, washed, incubated with the corresponding secondary antibodies, washed again and exposed to light.
Immunofluorescence detection of tissue PD-L1 expression
Paraffin sections were prepared, dewaxed and rehydrated. After thermal antigen retrieval with citrate buffer, incubation with 3% hydrogen peroxide, washing with PBS solution, removing residual liquid on slide, dripping 5% goat serum blocking solution, incubating at room temperature for 15min, removing blocking solution, dripping PD-L1 primary antibody (BioworldTechnology 1:200 dilution), placing in a light-shielding box at 4deg.C overnight, standing at room temperature for two hours the next day, and washing. Dripping fluorescent secondary antibody, incubating for 30min at room temperature in dark, washing, dripping DAPI staining solution, incubating for 10min at room temperature, and washing. The sheet was sealed with an anti-fluorescence quencher and photographed with a confocal fluorescence microscope.
The effect of different doses (100. Mu.g/dose, 200. Mu.g/dose, and 400. Mu.g/dose) of buspirone hydrochloride treatment on PD-L1 expression in mouse tumor tissue was examined by Western blot and immunofluorescence experiments.
The Westernblot and immunofluorescence experimental results (figures 8 and 9) both prove that buspirone hydrochloride can obviously inhibit the expression of PD-L1 protein in tumor tissues of tumor-bearing mice.
EXAMPLE 4Western blot detection of expression of tumor tissue FBXO22
Taking 0.1g of tumor tissues of different treatment groups, placing the tumor tissues into a 2mL grinding tube, adding cell lysate, grinding the tumor tissues by using a tissue grinder, continuously cracking the tissues on ice for 30min, and centrifuging to obtain cracked supernatants. Proteins were subjected to SDS-PAGE, electroblotted, incubated overnight with the corresponding FBXO22 primary antibodies (Proteintech 1:4000 dilution), washed, incubated with the corresponding secondary antibodies, washed again and exposed to light.
FBXO22 is a member of the F-box family and participates in the subunits that make up the E3 ubiquitin ligase complex. The high expression of the polypeptide can effectively promote ubiquitination and degradation of PD-L1. We examined the effect of different doses (100. Mu.g/g, 200. Mu.g/g and 400. Mu.g/g) of buspirone hydrochloride treatment on FBXO22 expression in mouse tumor tissue by Westernblot experiments.
The results showed that buspirone hydrochloride was effective in increasing FBXO22 protein expression in melanoma tumor tissue (fig. 10).
Taken together, buspirone hydrochloride is thought to increase the degradation of PD-L1 through the FBXO22 pathway, and by inhibiting the expression of PD-L1, the T cell anti-tumor immune response of tumor bearing mice is further improved. Buspirone hydrochloride can be used as a PD-L1 inhibitor and used for developing medicaments for diseases related to PD-1/PD-L1 signal paths.
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 (6)
1. Use of buspirone hydrochloride as PD-L1 inhibitor.
2. Use of buspirone hydrochloride as the sole active ingredient in the manufacture of a medicament for the treatment, prevention, amelioration, control or alleviation of a disease associated with the PD-1/PD-L1 signaling pathway in a patient.
3. The use according to claim 2, wherein the disease associated with the PD-1/PD-L1 signaling pathway is cancer, an infectious disease or an autoimmune disease.
4. The use according to claim 3, wherein the disease associated with the PD-1/PD-L1 signaling pathway is melanoma.
5. The use of claim 2, wherein the route of administration of the medicament is oral or injectable.
6. The use according to claim 5, wherein the medicament is in the form of an emulsion, solution, granule, tablet, hard capsule, soft capsule, or in the form of an emulsion, micelle solution, solution for intravenous injection or intramuscular injection.
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