CN116870014B - Application of peimine in preparation of oncolytic virus antitumor synergist and composition containing peimine - Google Patents
Application of peimine in preparation of oncolytic virus antitumor synergist and composition containing peimine Download PDFInfo
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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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/76—Viruses; Subviral particles; Bacteriophages
- A61K35/763—Herpes virus
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
The invention discloses an application of peimine in preparing an oncolytic virus antitumor synergist and a composition containing the peimine. The peimine can enhance the killing effect of the oncolytic virus, particularly the oncolytic virus oHSV-1, on the brain glioma cells, particularly under the concentration of the peimine which does not influence the activity of the tumor cells, and can also enhance the killing effect of the oncolytic virus on the brain glioma cells. The peimine can be used as an anti-tumor synergist of oncolytic viruses.
Description
Technical Field
The invention relates to the technical field of tumor medicaments, in particular to application of peimine in preparation of an oncolytic virus antitumor synergist and a composition containing the peimine.
Background
Brain glioma is a common intracranial tumor, accounting for about 70-80% of the intracranial tumor, wherein malignant brain glioma accounts for about 40-45%, and the survival rate of 5 years is less than 5%. Although comprehensive treatment such as surgery, radiotherapy and chemotherapy is performed, the life cycle of the patient is short, and the median life cycle is only 12-15 months. At present, malignant gliomas lack an effective treatment method, and bring heavy burden to families and countries of patients. Oncolytic virus therapy is one of the most promising approaches in the current treatment of malignant brain gliomas. Oncolytic type I herpes simplex virus (oncotic HSV-1, oHSV-1) is a virus commonly used in brain glioma virus therapy.
The oHSV-1 oncolytic virus causes tumor cell reaction, stimulates immune cells in microenvironment and the interaction of the tumor cells and the immune cells in the process of treating the brain glioma, and simultaneously stimulates the immune function of the tumor microenvironment when oncolytic, so that cold tumor is changed into hot tumor. However, the oHSV-1 has different therapeutic effects on different tumor cells or different cell lines of the same tumor cell, and therefore, the therapeutic effect and the sensitivity of oncolytic viruses need to be improved by screening medicines. The following technical effects are achieved: 1) The screened medicine can enhance the curative effect of the oncolytic virus and reduce the using amount of the oncolytic virus; 2) The screened medicine can make the tumor cell strain insensitive to the oncolytic virus become sensitive, and expand the application range of the oncolytic virus.
In view of this, the present invention has been made.
Disclosure of Invention
Aiming at the problems existing in the oncolytic virus in the prior art when tumor treatment is carried out, one of the purposes of the invention is to provide an application of peimine in preparing an oncolytic virus antitumor synergist, which can enhance the killing effect of oncolytic viruses on tumor cells, and belongs to a compound capable of enhancing the curative effect of oncolytic viruses.
The second object of the present invention is to provide a pharmaceutical composition for anti-tumor based on the above application.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
the first aspect of the invention provides an application of peimine in preparing an oncolytic virus antitumor synergist, wherein the tumor is brain glioma.
In the use of the first aspect, the tumor is an in vivo glioma, an in vitro glioma cell, or an in vitro glioma mass. As a preferred embodiment, the cell type of the glioma is at least one of LN229, U251 and BT-1207.
In the application of the first aspect, the oncolytic virus may be a common oncolytic virus type for treating brain glioma, and as a preferred embodiment, the oncolytic virus is an oncolytic type i herpes simplex virus (ohv-1) or a recombinant virus genetically engineered on the basis of the oncolytic type i herpes simplex virus.
In a second aspect, the present invention provides a pharmaceutical composition for anti-tumour comprising: fritillary bulb A and oncolytic virus, wherein the tumor is brain glioma.
In the pharmaceutical composition of the second aspect described above, the pharmaceutical composition may be used for treating glioma of various cell types, as a preferred embodiment, the cell type of the glioma is at least one of LN229, U251 and BT-1207.
In the pharmaceutical composition according to the second aspect, as a preferred embodiment, the oncolytic virus is an oncolytic type i herpes simplex virus or a recombinant virus genetically engineered on the basis of the oncolytic type i herpes simplex virus.
In the pharmaceutical composition of the above second aspect, as an alternative, the pharmaceutical composition is in the form of a mixture of peimine and oncolytic virus, or in the form of separate packages of peimine and oncolytic virus.
In the pharmaceutical composition of the second aspect, as an alternative, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
In the pharmaceutical composition of the second aspect, as an alternative, the pharmaceutical composition is in a form of lyophilized powder for injection, tablet, capsule or drop.
Compared with the prior art, the invention has the following beneficial effects:
the inventor finds that when the peimine and the oncolytic virus are combined for use, the peimine can enhance the killing effect of the oncolytic virus, particularly oncolytic virus oHSV-1, on brain glioma cells, particularly under the concentration of the peimine which does not influence the activity of tumor cells, and can also enhance the killing effect of the oncolytic virus on brain glioma cells. The peimine can be used as an anti-tumor synergist of oncolytic viruses.
Drawings
FIG. 1 is a statistical graph showing the activities of three kinds of cells LN229, U251 and BT-1207 after different treatments in the test example; (a) is the activity proportion of LN229 cells in the peimine group and the peimine combined oHSV-1 group, (b) is the activity proportion of U251 cells in the peimine group and the peimine combined oHSV-1 group, and (c) is the activity proportion of BT-1207 cells in the peimine group and the peimine combined oHSV-1 group.
FIG. 2 shows the morphology of BT-1207 cells from different treatment groups in the experimental example.
FIG. 3 is a graph showing cell activities of LN229, U251, and BT-1207 in each of the treatment groups in the comparative example.
Detailed Description
In order to make the technical content of the present invention more clearly understood, the following detailed description of the technical solution of the present invention will be given with reference to the accompanying drawings and test examples. It should be understood that the detailed description and specific examples are intended for purposes of illustration only and are not intended to limit the scope of the invention.
Conditions and procedures not noted in the examples below are generally carried out in accordance with conventional conditions and procedures, and may be carried out with reference to those described in the molecular cloning Experimental guidelines, by Sambrook et al, or in accordance with the experimental conditions and instructions recommended by the vendor. The chemical reagents not illustrated are conventional commercial products.
In the screening of tumor therapeutic drugs, in order to screen out drugs capable of improving the curative effect and sensitivity of oncolytic viruses, the inventor finds out that the peimine can enhance the killing effect of oncolytic viruses oHSV-1 on glioma cells through a large number of experiments, and the in vitro killing effect is stronger along with the increase of the concentration of the peimine drugs. In the fritillary bulb first screening process, the inventor also screens other clinical antitumor drugs, such as matrine with antitumor effect, but matrine can not enhance the killing effect of oncolytic virus oHSV-1 on glioma cells. Specific screening procedures and results will be described in detail below. Three sets of replicates were run for each concentration in the following test examples, and the results averaged.
Test materials
The oncolytic I type herpes simplex virus lacks a neurovirulence gene ICP34.5 and an antigen presenting inhibitor ICP47; of course, the oncolytic virus of the present invention may be a recombinant oncolytic herpes simplex virus in which the neurovirulence gene ICP34.5 and the antigen presenting inhibitor ICP47 are deleted, but glycoprotein US11 is present, and the gene encoding cytosine deaminase is inserted into the position of neurovirulence gene ICP 34.5. Oncolytic virus ohv-1 (i.e., oncolytic herpes simplex virus type i) used in the following test examples was offered by beijing neurosurgery institute Zhang Junwen and its colleagues and is freely available to the public; the oHSV-1 can also be obtained by engineering a commercially available virus strain HSV-1 (F), i.e.copies of the 1,000bp gamma 134.5 gene and ICP47 gene per coding domain are deleted. All viruses were grown and titrated in Vero cells, and the viruses were stored at-80 ℃ avoiding freeze-thaw cycles.
Peimine is a natural compound with the effects of clearing heat, moistening lung, relieving cough and reducing sputum. Recent researches show that the peimine plays a role by inhibiting an active efflux pump on a bacterial cell membrane and has a strong reversing effect on drug-resistant staphylococcus aureus. In addition, high concentration fritillary bulb extract has the functions of inhibiting proliferation and metastasis of tumor cells, inhibiting proliferation of orbital fibroblasts of thyroid-related eye disease patients, and the like. It is commercially available, and the peimine used in the test example of the present invention is purchased from MCE company under the product number HY-N0212.
Matrine is one of the main active ingredients of Chinese medicinal materials of radix sophorae flavescentis and radix sophorae tonkinensis, and research in recent years shows that matrine plays an anti-tumor role by inducing apoptosis, cell cycle retardation, inducing autophagy, inhibiting tumor cell metastasis and invasion, inhibiting angiogenesis and other ways, and matrine used in the following experimental examples is purchased from microphone company with the product number of M813524.
Glioma cells LN229 and U251 used in the test examples of the invention were purchased from ATCC; BT-1207 is a primary cultured glioma cell line, which is preserved in China general microbiological culture Collection center (CGMCC) with the preservation number of 16693, and is shown in patent number CN 201811535397.9.
Experimental example investigation of killing effect of peimine and oHSV-1 on glioma cells
Fritillary bulb extract was prepared as a mother liquor at a concentration of 20mM with DMSO solvent.
LN229, U251 and BT-1207 were planted in 96-well plates, 2000 cells per well, three cells were cultured overnight in DMEM (10 wt% FBS+1wt% Streptomyces lividans) at 37℃in an environment containing 5% carbon dioxide (i.e., 24 hours), then each cell was divided into peimine group and peimine-combined oHSV-1 group, and a control group without any treatment was set, wherein, in the peimine group, different amounts of peimine were added to the cell culture liquid, so that the final concentrations in the cell culture liquid were 0, 1, 2.5, 5, 10, 20. Mu.M, respectively. The cell culture solution of the combination of peimine and ohv-1 group was added with ohv-1 (moi=0.1) in addition to peimine in the above manner. The two sets of cell cultures were then incubated at 37℃in an environment containing 5% carbon dioxide for a further 48 hours. The cell activity was then examined and the morphology of the cells was observed.
(1) CCK8 (syngeneic DOJINDO) detected cell activity.
The test results are shown in FIG. 1, (a) the ratio of LN229 cells in the peimine group and the peimine combined oHSV-1 group, (b) the ratio of U251 cells in the peimine group and the peimine combined oHSV-1 group, and (c) the ratio of BT-1207 cells in the peimine group and the peimine combined oHSV-1 group. As can be seen from fig. 1, the use of peimine alone at low concentration (less than 5 μm) did not affect glioma cell activity, whereas at high concentration (10 and 20 μm) there was anti-tumor activity among the three cells. The low concentration (less than 5 mu M) of peimine can obviously enhance the capability of the oncolytic virus to kill tumor cells after being added into a cell culture medium containing the oHSV-1 oncolytic virus (MOI=0.1), and the higher the concentration of peimine is, the stronger the killing capability is. At peimine concentrations below 5 μm, preferably below 2.5 μm, the synergistic effect of peimine and ohv-1 oncolytic virus on tumor killing is more pronounced. In contrast, for LN229 cells, whether peimine is at high or low concentration (20. Mu.M or less), it has an enhancing effect on the tumor killing of oHSV-1 oncolytic virus.
(2) BT-1207 cell morphology treated with 5 μm peimine alone (i.e. peimine group in fig. 2), BT-1207 cell morphology treated with ohv-1 alone (moi=0.1) was observed (i.e. ohv-1 in fig. 2), and BT-1207 cell morphology treated with 5 μm peimine+ohv-1 (moi=0.1) (i.e. peimine in fig. 2 in combination with ohv-1) was observed, while BT-1207 cell morphology without any treatment (i.e. control group) was observed.
As can be seen from fig. 2, the cell morphology was not substantially changed after 5 μm peimine (without affecting cell activity), and was not significantly different from that of the control group, and the cell morphology was changed after ohv-1 (moi=0.1) treatment. The cell morphology change of the combination therapy group of the peimine and the oHSV-1 is obviously different from that of the peimine group and the oHSV-1 group, and further proves that the peimine enhances the killing effect of the oHSV-1 on glioma cells.
Comparative example matrine and oHSV-1 studies on glioma cell killing action
Three types of glioma cells LN229, U251 and BT-1207 were cultured according to the method of the peimine test example, and each cell was divided into four groups, specifically: the control group without any treatment was added with only ohv-1 (moi=0.1) and with 5 μm peimine in combination with ohv-1, and with ohv-1 (moi=0.1) and 10 μm matrine in combination with ohv-1, and after the above-mentioned group addition of the corresponding substances, the culture was continued for 48 hours at 37 ℃ in an environment containing 5% carbon dioxide, and then cell activity was examined. Here, the inventors also conducted experiments in which 5. Mu.M matrine was added, but the effect on cell activity was smaller, so that 10. Mu.M matrine was used as an example.
The results are shown in fig. 3, which shows: matrine inhibits the anti-tumor activity of oHSV-1, can not enhance the killing of oHSV-1 to tumor cells, and fritillary bulb A enhances the anti-tumor activity of oHSV-1, thereby further proving that fritillary bulb A can enhance the anti-tumor activity of oHSV-1.
Claims (6)
1. The application of peimine in preparing an oncolytic virus antitumor synergist is characterized in that the tumor is brain glioma, the cell type of the brain glioma is LN229, and the oncolytic virus is oncolytic I type herpes simplex virus.
2. Use of a pharmaceutical composition for the preparation of an anti-neoplastic agent, said pharmaceutical composition comprising: fritillary bulb A and oncolytic virus, wherein the tumor is brain glioma, the cell type of the brain glioma is LN229, and the oncolytic virus is oncolytic type I herpes simplex virus.
3. The use according to claim 2, wherein the pharmaceutical composition is in the form of a mixture of peimine and oncolytic virus or in the form of separate packages of peimine and oncolytic virus.
4. The use according to claim 2 or 3, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
5. The use according to claim 4, wherein the pharmaceutical composition is in the form of an injection, a tablet, a capsule or a drop.
6. The use according to claim 4, wherein the pharmaceutical composition is in the form of a lyophilized powder for injection.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202310727213.3A CN116870014B (en) | 2023-06-19 | 2023-06-19 | Application of peimine in preparation of oncolytic virus antitumor synergist and composition containing peimine |
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Non-Patent Citations (3)
| Title |
|---|
| Peiminine Inhibits Glioblastoma in Vitro and in Vivo Through Cell Cycle Arrest and Autophagic Flux Blocking;Boxian Zhao等;《Cellular Physiology and Biochemistry》;第51卷;第1566-1583页 * |
| Stabilizing parallel G-quadruplex DNA by a new class of ligands: Two non-planar alkaloids through interaction in lateral grooves;Qian Li等;《Biochimie》;第91卷;第811-819页，尤其是第812页左栏第2段，第818页右栏第2段 * |
| 溶瘤I型单纯疱疹病毒的研究进展;由鹏飞等;《微生物学通报》;第42卷(第9期);第1795-1801页，尤其是第1795页摘要，第1797页左栏倒数第1段，右栏第2段 * |
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