CN112843038B - Application of medicine in preparation of medicine for treating diffuse large B cell lymphoma - Google Patents

Application of medicine in preparation of medicine for treating diffuse large B cell lymphoma Download PDF

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CN112843038B
CN112843038B CN202110344825.5A CN202110344825A CN112843038B CN 112843038 B CN112843038 B CN 112843038B CN 202110344825 A CN202110344825 A CN 202110344825A CN 112843038 B CN112843038 B CN 112843038B
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dlbcl
medicine
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apoptosis
drug
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CN112843038A (en
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徐林艳
刘梦迪
徐开林
桑威
秦园园
涂冬云
张猛
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Xuzhou Medical University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
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    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/50—Hydrolases (3) acting on carbon-nitrogen bonds, other than peptide bonds (3.5), e.g. asparaginase
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C12Y305/01—Hydrolases acting on carbon-nitrogen bonds, other than peptide bonds (3.5) in linear amides (3.5.1)
    • C12Y305/01001—Asparaginase (3.5.1.1)
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract

The invention discloses an application of a drug in preparing a drug for treating diffuse large B cell lymphoma, wherein the drug is PX-478 or PX-478 and L-Asparaginase, and the influence of the PX-478 on the proliferation and apoptosis of DLBCL cells is explored through in vitro experiments. Meanwhile, the invention discovers the effect of the combination of PX-478 and L-Asparaginase in DLBCL.

Description

Application of medicine in preparation of medicine for treating diffuse large B cell lymphoma
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to an application of a medicine in preparation of a medicine for treating diffuse large B cell lymphoma.
Background
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL), accounts for about 30-40% of NHL, and is a group of malignant invasive lymphomas with strong heterogeneity in various aspects such as clinical manifestation, tissue morphology and prognosis. The R-CHOP regimen and various immunotherapies, while significantly improving the survival rate of DLBCL, still 20-25% of patients relapse within 2 years, with about 40% of relapsed patients being ineffective for high dose chemotherapy or in combination with autologous hematopoietic stem cell transplantation therapy. Therefore, the pathogenesis of DLBCL is deeply explored, potential new molecular targets and treatment strategies for DLBCL treatment are sought, and the DLBCL has important practical significance for DLBCL.
Disclosure of Invention
This section is for the purpose of summarizing some aspects of embodiments of the invention and to briefly introduce some preferred embodiments. In this section, as well as in the abstract and the title of the invention of this application, simplifications or omissions may be made to avoid obscuring the purpose of the section, the abstract and the title, and such simplifications or omissions are not intended to limit the scope of the invention.
In one aspect, the present invention provides a use of a medicament for the preparation of a medicament for the treatment of diffuse large B-cell lymphoma: the medicine is PX-478.
The preferable scheme of the application of the medicine in preparing the medicine for treating diffuse large B cell lymphoma is as follows: the concentration of the PX-478 is 2.5-40 mu M.
As a preferable scheme of the application of the medicine in preparing the medicine for treating diffuse large B cell lymphoma, the medicine comprises the following components: the concentration of the PX-478 is 10 mu M.
As another aspect of the present invention, the present invention provides an application of a medicament in preparing a medicament for treating diffuse large B cell lymphoma: the medicines are PX-478 and L-Asparaginase.
The preferable scheme of the application of the medicine in preparing the medicine for treating diffuse large B cell lymphoma is as follows: the concentration of the PX-478 is 2.5-40 mu M; the concentration of the L-Asparaginase is 0.2-10U.
The preferable scheme of the application of the medicine in preparing the medicine for treating diffuse large B cell lymphoma is as follows: the concentration of the PX-478 is 10 mu M; the concentration of the L-Asparaginase is 1U.
The invention has the beneficial effects that: the invention explores the influence of PX-478 on the proliferation and apoptosis of DLBCL cells through in vitro experiments. Meanwhile, the invention discovers the effect of the combination of PX-478 and L-Asparaginase in DLBCL.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the description of the embodiments will be briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings based on these drawings without inventive exercise. Wherein:
FIG. 1 shows that PX-478 inhibited DLBCL cell proliferation.
FIG. 2 shows that PX-478 blocked the DLBCL cell cycle.
FIG. 3 shows that PX-478 affected DLBCL cell cycle associated gene expression.
FIG. 4 shows that PX-478 induced apoptosis of DLBCL cells.
FIG. 5 shows that PX-478 induces exogenous apoptosis pathway of DLBCL
FIG. 6 shows that PX-478 induces the endogenous apoptosis pathway of DLBCL.
FIG. 7 shows that PX-478 and L-ASP are combined to induce DLBCL cell apoptosis.
FIG. 8 shows the result of the combined administration of PX-478 and L-ASP to activate the DLBCL apoptosis pathway.
FIG. 9 is a gray scale analysis of the PX-478 and L-ASP combined drug-activated DLBCL apoptosis pathway.
FIG. 10 shows the formula PX-478.
Detailed Description
In order to make the aforementioned objects, features and advantages of the present invention more comprehensible, embodiments accompanying specific embodiments of the present invention are described in detail below.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways than those specifically described and will be readily apparent to those of ordinary skill in the art without departing from the spirit of the present invention, and therefore the present invention is not limited to the specific embodiments disclosed below.
Furthermore, reference herein to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one implementation of the invention. The appearances of the phrase "in one embodiment" in various places in the specification are not necessarily all referring to the same embodiment, nor are separate or alternative embodiments mutually exclusive of other embodiments.
Effect of different concentrations of PX-478 on DLBCL cell proliferation: good and log-extended status of DLBCL cells (U2932, SUDHL2, WSU-DLCL2 and HBL-1) observed under a mirror at 2X 10 per well4The number of cells is respectively inoculated in a 96-well plate, the medicine PX-478 is added to ensure that the final concentration is 0, 2.5, 5, 10, 20 and 40 mu M in sequence, the cell state is observed after 48 hours, the CCK-8 reagent is added, and then the absorbance is detected by a microplate reader. The results show that the proliferation rates of the four cells are gradually reduced along with the increase of the concentration of the PX-478 medicament, and the medicament adding groups and the medicament adding pairs are comparedThe differences in cell proliferation for the control groups were all statistically significant (FIG. 1). FIGS. 1A-D: HBL1, WSU-DLCL2, SUDHL2 and U2932 cells were treated with PX-478 at different concentrations for 48h, and cell proliferation was detected by CCK-8 method (P compared with control group)<0.05，**P<0.01，***P<0.001）。
Effect of PX-478 on DLBCL cell cycle distribution: in order to explore the influence of a HIF-1 alpha inhibitor PX-478 on the cell cycle of DLBCL, a proper amount of DLBCL cells are inoculated into a six-well plate, PX-478 is added, the final concentration of the medicine is 0, 12.5 and 25 mu M respectively, and after 48 hours of action, the distribution condition of the cell cycle of DLBCL is detected by adopting a PI single staining method and a flow cytometer. The results show that after the DLBCL cells are treated by PX-478 with different concentrations, G2/M phase cells increase along with the increase of the drug concentration compared with the control group, and the comparison of cell cycle differences of each drug addition group and the control group has statistical significance, which indicates that PX-478 induces cell cycle arrest at the G2/M phase (figure 2). Fig. 2 a. different concentrations of PX-478 treated U2932, HBL1, SUDHL2 cells for 48h, PI flow cytometry examined cell cycle, fig. 2b. percentage of cells in different cell cycles (three independent experiments, # P <0.05, # P <0.01, # P < 0.001).
Detecting the influence of PX-478 on the expression of DLBCL cell cycle related genes: PX-478 with different concentrations is respectively added into DLBCL cells, the cells are collected and RNA is extracted after the drug acts for 48 hours, and the influence of the PX-478 on the expression of genes related to the DLBCL cell cycle is detected after a series of operations such as reverse transcription and qPCR. The results show that, after PX-478 treatment,Cyclin D1、 Cyclin EandCyclin B1the gene expression of (2) was significantly reduced, i.e. PX-478 regulated DLBCL cell cycle by affecting Cyclin D1, Cyclin E and Cyclin B1 expression (fig. 3). FIGS. 3A-C: treating U2932 and WSU-DLCL2 cells for 48h by PX-478 with different concentrations, and detecting cell cycle related gene expression (P) by RT-qPCR experiment<0.001）。
Effect of PX-478 on DLBCL apoptosis: under the observation of good state and logarithmic growth period of DLBCL cells (U2932, SUDHL2, HBL-1 and WSU-DLCL 2), the DLBCL cells are respectively inoculated into a 6-well plate by the number of 2 x 106 cells per well, the drug PX-478 is added to ensure that the final concentration is 0, 12.5 and 25 mu M in sequence, the cells are collected after 48 hours, the cells are marked by Annexin V-PE/7-AAD in an apoptosis kit, and the apoptosis condition is detected by using a flow cytometer. The results show that the apoptosis rate is gradually increased along with the increase of the concentration of the PX-478 drug, and the difference of each drug-adding group compared with the control group has statistical significance (figure 4). FIG. 4A. different concentrations of PX-478 treated U2932, HBL1, SUDHL2 cells for 48h, Annexin V-PE/7-AAD flow cytometry to detect apoptosis. Figure 4b. percentage of cells that were apoptotic (three independent experiments, P <0.05, P <0.01, P < 0.001).
PX-478 induces activation of the extrinsic apoptotic pathway: in order to research the PX-478 induced apoptosis signal channel, the expression condition of related proteins in an exogenous apoptosis channel is detected by using a Western Blot technology. The results show that under the action of PX-478, the expression of the death receptor DR5 is gradually increased along with the increase of the drug concentration, the expression of the apoptosis inhibiting protein c-FLIPS is gradually reduced, the cleavage and activation of Caspase 8 are enhanced, and the hydrolysis of PARP is increased, which indicates that PX-478 can activate the exogenous apoptosis pathway of DLBCL cells, thereby promoting the apoptosis of the DLBCL cells (figure 5). FIG. 5 shows that PX-478 with different concentrations was used to treat SUDHL2 and WSU-DLCL2 cells for 48h, and western blot was used to detect the expression of DR5, c-FLIPS, Caspase 8, PARP and other proteins.
PX-478 induces activation of the endogenous apoptotic pathway: in order to determine whether an endogenous apoptosis pathway is activated in the process of inducing DLBCL apoptosis by PX-478, the expression condition of the BCL-2 family protein under the action of PX-478 is detected. The result shows that with the increase of the concentration of the drug PX-478, the expression of the pro-apoptotic proteins Bim and Bax in the DLBCL cell is gradually increased, and the expression of the anti-apoptotic protein Mcl-1 is gradually reduced, which indicates that PX-478 activates the endogenous apoptosis pathway of the DLBCL cell, thereby promoting the apoptosis of the DLBCL cell. (FIG. 6). FIG. 6 shows that PX-478 with different concentrations is used for treating SUDHL2 and WSU-DLCL2 cells for 48h, and western blot is used for detecting protein expressions such as Bim, Bax and Mcl-1.
Effect of PX-478 in combination with L-Asparaginase (Asparaginase) on DLBCL apoptosis: one of the main reasons that the drug resistance of tumors affects the curative effect and prognosis is that in order to improve drug resistance, a drug combination method is a common solution. Moreover, the proper combination may exert a better than single effectHas better anti-tumor effect. We therefore further investigated whether PX-478 combined with L-Asparaginase (L-ASP) had a synergistic effect, investigating the effect of PX-478 combined with L-Asparaginase on the apoptosis of DLBCL cells. An appropriate amount of DLBCL cells (U2932, SUDHL2, HBL1 and WSU-DLCL 2) that grew well and were in logarithmic growth phase were taken at 2 x 10 per well6The number of the cells is inoculated in a 6-well plate, 10 mu M of single-drug PX-478 and 1U of single-drug L-ASP are respectively added, 10 mu M of PX-478 and 1U of L-ASP are added, and the cells are collected and subjected to flow detection for apoptosis after 48 hours. The results show that the apoptosis rate of the DLBCL of the single drug group is obviously higher than that of the control group, the apoptosis rate of the combined group of the two drugs is more obviously higher than that of the single drug group, the difference of the apoptosis rates of the combined group of the two drugs is statistically significant (figure 7) compared with the single drug group and the control group, and the apoptosis is detected by combining the PX-478 and the L-ASP to treat the U2932, the SUDHL2, the HBL1 and the WSU-DLCL2 for 48 hours and by Annexin V-PE/7-AAD flow cytometry. Figure 7b. percentage of cells apoptotic (three independent experiments, P)<0.05，**P<0.01，***P<0.001）。
PX-478 enhanced L-Asparaginase to induce DLBCL apoptosis: and respectively taking SUDHL2 and WSU-DLCL2 cells which are treated by PX-478 and L-ASP independently and jointly, and detecting the expression condition of related proteins in an apoptosis channel by using a Western Blot technology. The results show that the expression of the anti-apoptotic protein Mcl-1 of the PX-478 combined L-ASP group is reduced, Caspase3 cleavage is activated most strongly, and the PARP hydrolysis degree is enhanced, which indicates that the PX-478 combined L-ASP is easier to activate the apoptosis pathway of DLBCL cells than a single drug (FIG. 8 and FIG. 9). FIG. 8 shows that PX-478 combined with L-ASP treats U2932, SUDHL2 and WSU-DLCL2 cells for 48h, and western blot detects protein expression of Mcl-1, caspase3, PARP and the like. Fig. 9 shows the gradation analysis result.
In conclusion, the invention explores the influence of PX-478 on the proliferation and apoptosis of DLBCL cells through in vitro experiments. Meanwhile, the invention discovers the effect of the combination of PX-478 and L-Asparaginase in DLBCL.
It should be noted that the above-mentioned embodiments are only for illustrating the technical solutions of the present invention and not for limiting, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, which should be covered by the claims of the present invention.

Claims (2)

1. The application of a medicine in preparing a medicine for treating diffuse large B cell lymphoma is characterized in that: the medicines are PX-478 and L-Asparaginase;
the concentration of the PX-478 is 2.5-40 mu M; the concentration of the L-Asparaginase is 0.2-10U.
2. The use of a medicament according to claim 1 for the preparation of a medicament for the treatment of diffuse large B-cell lymphoma, wherein: the concentration of the PX-478 is 10 mu M; the concentration of the L-Asparaginase is 1U.
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