CN111544595A - Application of ubiquitin-conjugating enzyme E2 inhibitor and oncolytic virus in preparation of antitumor drugs - Google Patents
Application of ubiquitin-conjugating enzyme E2 inhibitor and oncolytic virus in preparation of antitumor drugs Download PDFInfo
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Abstract
The invention discloses that the ubiquitin conjugating enzyme E2 inhibitor can be used as an anti-tumor synergist/drug resistance reversal agent of oncolytic virus for the first time. The inventors could significantly enhance the oncolytic effect of oncolytic viruses by inhibiting ubiquitin conjugating enzyme E2. The inventor adopts a compound Bay11-7082 for inhibiting the activity of ubiquitin conjugated enzyme E2 to act on tumor cells in a synergistic way with oncolytic virus, particularly M1 virus, and the experimental result shows that Bay11-7082 can enhance the anti-tumor effect in a synergistic way with the oncolytic virus.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to an application of an ubiquitin-conjugating enzyme E2 inhibitor and an oncolytic virus in preparation of an anti-tumor medicine.
Background
Oncolytic viruses (oncolytics) are a class of replication-competent viruses that target infection and kill tumor cells without damaging normal cells. Oncolytic virus therapy (oncolytical virotherapy) is an innovative tumor-targeted therapeutic strategy that utilizes natural or genetically engineered viruses to selectively infect and replicate in tumor cells to achieve the effects of targeted lysis and killing of tumor cells, but without damage to normal cells.
Oncolytic virus M1 is a Togaku virus of genus Alavirus of Togaviridae, isolated from Moso mosquitos of genus Katsu, Hainan, China. For example, chinese patent application CN104814984A discloses that oncolytic virus M1 can selectively cause tumor cell death without affecting normal cell survival. However, different tumors have different sensitivities to the M1 virus, and for some tumors, the oncolytic effect of the M1 virus alone is not ideal. For example, as described in chinese patent application CN104814984A, when M1 is used as an antitumor agent, the effect on colorectal cancer, liver cancer, bladder cancer and breast cancer is not as significant as that on pancreatic cancer, nasopharyngeal cancer, prostate cancer and melanoma; glioma, cervical cancer and lung cancer are the second; gastric cancer is the least significant. If the compound capable of increasing the tumor treatment effect of the oncolytic virus can be screened, the anti-tumor spectrum and anti-tumor strength of the oncolytic virus are expected to be increased.
Disclosure of Invention
The first aspect of the invention aims to provide the application of the ubiquitin conjugated enzyme E2 inhibitor in preparing an oncolytic virus anti-tumor synergist or a drug resistance reversal agent aiming at the defect of low-toxicity oncolytic virus synergist which is not toxic to normal cells in the prior art.
In a second aspect of the present invention, an anti-tumor pharmaceutical composition is provided.
The technical scheme adopted by the invention is as follows:
in a first aspect of the invention, there is provided the use of an inhibitor of ubiquitin-conjugating enzyme E2 in the preparation of an oncolytic virus anti-tumour potentiator or a drug resistance reversal agent.
The ubiquitin conjugated enzyme E2 inhibitor is a substance for inhibiting the activity of E2 conjugated enzyme, or a substance for degrading E2 conjugated enzyme, or a gene tool for reducing the level of E2 conjugated enzyme. The ubiquitin conjugating enzyme E2, also known as the E2 enzyme, the E2 enzyme interacts with selective proteins of the E3 enzyme through the E1 enzyme and links activation to covalent modifications. The E2 enzyme can differentiate the effect on downstream substrates by a single Ub/UBL molecule or in the form of a chain. Although the E3 enzyme is involved in substrate selection, the E2 enzyme is the main determinant in selecting lysine to construct ubiquitin chains, thereby directly controlling the cell fate of the substrate. About 40 ubiquitin conjugated enzymes E2 are found, compared with the activating enzyme E1, the inhibitor of the conjugated enzyme E2 has stronger specificity and also has greater value in the aspect of tumor treatment. For example, the compound CC0651 is an inhibitor of the binding enzyme E2 CDC34, which upon binding to CDC34 causes a conformational change such that delivery of UB is not achieved.
Further, according to the use of the first aspect of the present invention, the oncolytic virus is selected from one or more of alphavirus, adenovirus, vaccinia virus, measles virus, vesicular stomatitis virus, and herpes simplex virus; preferably, the alphavirus is at least one selected from the group consisting of M1 virus and togavirus.
Further, according to the use of the first aspect of the present invention, the inhibitor of ubiquitin conjugated enzyme E2 is a substance inhibiting the activity of ubiquitin conjugated enzyme E2, or a substance degrading ubiquitin conjugated enzyme E2, or a gene tool reducing the expression level of ubiquitin conjugated enzyme E2; preferably, said substance inhibiting the activity of ubiquitin conjugating enzyme E2 is selected from the group consisting of compounds; the gene tool for reducing the expression level of ubiquitin-conjugated enzyme E2 is a tool for gene silencing, gene editing or gene knockout.
Preferably, the substance inhibiting the activity of ubiquitin conjugating enzyme E2 is Bay11-7082 or a pharmaceutically acceptable salt, solvate, tautomer, isomer thereof according to the use according to the first aspect of the invention.
Or more preferably, according to the use of the first aspect of the present invention, the gene means for reducing the expression level of ubiquitin-conjugating enzyme E2 is siRNA, dsRNA, miRNA, ribozyme or shRNA.
Further, according to the use of the first aspect of the present invention, the tumor comprises a solid tumor or a hematological tumor; preferably, the solid tumor is liver cancer, colorectal cancer, bladder cancer, breast cancer, cervical cancer, prostate cancer, glioma, melanoma, pancreatic cancer, nasopharyngeal cancer, lung cancer, or gastric cancer.
In a second aspect of the present invention, there is provided an anti-tumor pharmaceutical composition comprising an inhibitor of ubiquitin conjugating enzyme E2 and an oncolytic virus.
Further, according to the pharmaceutical composition of the second aspect of the present invention, the ubiquitin conjugated enzyme E2 inhibitor is a substance inhibiting the activity of ubiquitin conjugated enzyme E2, or a substance degrading ubiquitin conjugated enzyme E2, or a gene tool reducing the expression level of ubiquitin conjugated enzyme E2;
preferably, said substance inhibiting the activity of ubiquitin conjugating enzyme E2 is selected from the group consisting of compounds; the gene tool for reducing the expression level of ubiquitin-conjugated enzyme E2 is a tool for gene silencing, gene editing or gene knockout.
More preferably, according to the pharmaceutical composition of the second aspect of the present invention, the substance inhibiting the activity of ubiquitin conjugating enzyme E2 is Bay 11-7082.
Or more preferably, according to the pharmaceutical composition of the second aspect of the present invention, the gene means for reducing the expression level of ubiquitin conjugated enzyme E2 is siRNA, dsRNA, miRNA, ribozyme or shRNA.
Further, according to the pharmaceutical composition of the second aspect of the present invention, the oncolytic virus is selected from one or more of alphavirus, adenovirus, vaccinia virus, measles virus, vesicular stomatitis virus, and herpes simplex virus; preferably, the alphavirus is at least one selected from the group consisting of M1 virus and togavirus.
Further, according to the pharmaceutical composition of the second aspect of the present invention, the tumor comprises a solid tumor or a hematological tumor; preferably, the solid tumor is liver cancer, colorectal cancer, bladder cancer, breast cancer, cervical cancer, prostate cancer, glioma, melanoma, pancreatic cancer, nasopharyngeal cancer, lung cancer, or gastric cancer.
The invention has the beneficial effects that:
the invention discovers for the first time that the ubiquitin conjugating enzyme E2 inhibitor can be used as an anti-tumor synergist/drug resistance reversal agent of oncolytic virus.
The invention provides application of an inhibitor of ubiquitin-conjugating enzyme E2 in preparing an oncolytic anti-tumor synergist/drug resistance reversal agent.
Resistance reversers are defined as tumors that are not very sensitive to oncolytic viruses or are resistant to oncolytic viruses when used as an antineoplastic agent, and in such cases, resistance of tumors to said oncolytic viruses can be reversed by combining the oncolytic virus with an inhibitor of ubiquitin-binding enzyme E2 (acting as a resistance reversal agent).
The inventors could significantly enhance the oncolytic effect of oncolytic viruses by inhibiting ubiquitin conjugating enzyme E2. The inventor adopts a compound Bay11-7082 for inhibiting the activity of ubiquitin conjugated enzyme E2 to act on tumor cells in a synergistic way with oncolytic virus, particularly M1 virus, and the experimental result shows that Bay11-7082 can enhance the anti-tumor effect in a synergistic way with the oncolytic virus.
The invention discovers that the ubiquitin conjugating enzyme E2 inhibitor, especially Bay11-7082 can increase the anti-tumor effect of the oncolytic virus so as to improve the treatment effectiveness of the oncolytic virus as an anti-tumor medicament. Cytological experiments prove that the combined application of the M1 virus and Bay11-7082 can obviously cause morphological lesion of tumor cells, thereby obviously enhancing the inhibiting effect on the tumor cells.
The inventor combines Bay11-7082 and M1 viruses to act on a human hepatocellular carcinoma Hep3B strain, and unexpectedly finds that when the antiviral compounds Bay11-7082 and M1 viruses are combined for use, the morphological lesion of tumor cells is remarkably increased, and the survival rate of the tumor cells is remarkably reduced. For example, in one embodiment of the invention, tumor cell survival was 72% when hepatoma cells were treated with M1 virus alone (MOI ═ 0.001), and decreased to 44.1% when Bay11-7082 at 1 μ M was used in combination with M1 virus at the same MOI. Compared with the anti-tumor effect of the single M1 virus, the combined use of Bay11-7082 and M1 has obviously improved tumor-dissolving effect.
The present invention has found that the combined use of Bay11-7082 with oncolytic virus to treat tumor cells has significantly better tumor cell killing than Bay11-7082 alone at the same concentration, e.g., when tumor cells are treated with Bay11-7082 at 1 μ M, for example, the survival rate of tumor cells is still as high as 87.7%, and when Bay11-7082 at 1 μ M is used in combination with M1 virus, the survival rate of tumor cells is greatly reduced to 44.1%. It can be seen that the greatly enhanced oncolytic effect of Bay11-7082 in combination with M1 benefits from the synergistic mechanism between Bay11-7082 and M1 viruses, and does not simply work through the anti-tumor mechanism of Bay 11-7082.
The oncolytic virus synergist adopted by the invention also has the characteristic that the obvious effect of synergizing the oncolytic virus can be obtained with extremely low application dosage. For example, the killing rate of Bay11-7082 on cancer cells is almost negligible despite such low (e.g., as low as 50uM) doses (liver cancer cell survival rates are still as high as 87.7%). However, when combined with M1 virus also at such low doses, tumor cell survival dropped dramatically to 44.1%. The use of extremely low dosage can greatly reduce other toxic and side effects possibly caused by the medicament, so that the influence of the medicament on the body is reduced. This is important for patients undergoing cancer therapy.
Drawings
FIG. 1 Effect of Bay11-7082 treatment in combination with M1 virus on survival of human hepatocellular carcinoma strain Hep 3B.
Detailed Description
In order to clearly understand the technical contents of the present invention, the following embodiments are described in detail with reference to the accompanying drawings. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures without specific conditions noted in the following examples, generally followed by conventional conditions, such as Sambrook et al, molecular cloning: the conditions described in the Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the manufacturer's recommendations. The various chemicals used in the examples are commercially available.
Example 1BAY11-7082 combined with M1 virus treatment significantly reduced survival rate of human hepatocellular carcinoma strain Hep3B
Materials:
human hepatocellular carcinoma Hep3B (purchased from ATCC), M1 virus (collection number CCTCC V201423), high-sugar DMEM medium (purchased from Corning), multifunctional microplate reader.
In a preferred embodiment of the invention, the inhibitor of ubiquitin conjugating enzyme E2 is Bay11-7082, which has the formula shown in formula 1:
formula 1: bay 11-7082.
The method comprises the following steps:
a) cell inoculation and administration treatment: cells in logarithmic growth phase were selected, and a cell suspension was prepared in DMEM complete medium (containing 10% fetal bovine serum and 1% double antibody), and seeded in a 96-well plate at a density of 4X 103 cells per well. After 12 hours, the cells are completely attached, and the experiment is divided into a control group, a BAY11-7082 single-use group, an M1 infection group and a BAY 11-7082/M1 combination group. The dosages used were: m1 virus (MOI ═ 0.001) infected cells; BAY11-7082 was 1. mu.M.
b) Reaction of tetramethylazoazolium salt (MTT) with succinate dehydrogenase in cells: at 48h drug treatment, 20 μ L of MTT (5mg/mL) was added to each well and incubation continued for 4 hours, at which time microscopic examination of the particulate blue-violet formazan crystals formed within the viable cells could be observed.
c) Dissolving formazan particles: the supernatant was carefully aspirated, the crystals formed were dissolved by adding DMSO (100. mu.L/well), shaken on a micro-shaker for 5min, and then the optical density (OD value) of each well was measured on an enzyme-linked detector at a wavelength of 570 nm. Cell survival rate-OD value of drug-treated group/OD value of control group × 100%.
As a result:
as shown in fig. 1, M1 virus (MOI ═ 0.001) alone has a small inhibitory effect on tumor cell survival rate of Hep3B, and the survival rate of tumor cells reached 72.0%, and the survival rate of tumor cells in 1 μ M BAY11-7082 treated group was still as high as 87.7%, however, when the same 1 μ M BAY11-7082 was used in combination with M1 virus (MOI ═ 0.001) (BAY11-7082+ M1), the survival rate of tumor cells dropped to 44.1%, indicating that BAY11-7082 could significantly enhance the oncolytic effect of M1 virus.
Example 2
A pharmaceutical composition for the treatment of a tumor comprising an inhibitor of ubiquitin conjugating enzyme E2 and an oncolytic virus.
It may also be a kit for the treatment of tumors comprising an inhibitor of ubiquitin conjugating enzyme E2 or a derivative or combination thereof, and an oncolytic virus. The pharmaceutical package differs from the composition in that the ubiquitin-conjugating enzyme E2 inhibitor is in a different dosage form than the oncolytic virus but is packaged separately (e.g., in a pill, or capsule, or tablet or ampoule containing the ubiquitin-conjugating enzyme E2 inhibitor; another pill, or capsule, or tablet or ampoule containing the oncolytic virus). In some embodiments, oncolytic viruses, ubiquitin-conjugating enzyme E2 inhibitors, and combinations of oncolytic viruses and ubiquitin-conjugating enzyme E2 inhibitors, may also contain one or more adjuvants. The adjuvant refers to a component which can assist the curative effect of the medicament in the medicament composition. The pharmaceutical kit may also comprise an independently packaged inhibitor of ubiquitin conjugating enzyme E2, and an independently packaged oncolytic virus. The administration of the ubiquitin conjugating enzyme E2 inhibitor and the oncolytic virus in the pharmaceutical kit may be simultaneous or in any order before or after the oncolytic virus, e.g. the ubiquitin conjugating enzyme E2 inhibitor is administered before the oncolytic virus, or the ubiquitin conjugating enzyme E2 inhibitor is administered after the oncolytic virus, or both. In various embodiments, the patient may be a mammal. The mammal may be a human.
The ubiquitin conjugating enzyme E2 inhibitor includes but is not limited to Bay11-7082 (formula 1) which is a compound inhibiting the activity of ubiquitin conjugating enzyme E2. Or for inhibiting the gene expression of ubiquitin-conjugating enzyme E2, including but not limited to gene interference, gene silencing, gene editing or knocking-out and other tool means. As a preferred embodiment of the present invention, the inhibitor of ubiquitin conjugating enzyme E2 is selected from Bay 11-7082.
The oncolytic virus is selected from one or more of alphavirus, adenovirus, vaccinia virus, measles virus, vesicular stomatitis virus and herpes simplex virus; wherein the alphavirus is selected from the group consisting of M1 virus and Getavirus. In a preferred embodiment, the oncolytic virus is at least one selected from the group consisting of M1 virus and togavirus.
The oncolytic virus is selected from one or more of alphavirus, adenovirus, vaccinia virus, measles virus, vesicular stomatitis virus and herpes simplex virus; wherein the alphavirus is selected from the group consisting of M1 virus and Getavirus. In a preferred embodiment, the oncolytic virus is at least one selected from the group consisting of M1 virus and togavirus. The M1 virus belongs to a Getta similar virus, and the homology of the two viruses is as high as 97.8%.
Preferably, the oncolytic virus adopted is the M1 virus with the preservation number of CCTCC V201423.
Preferably, the tumor is a solid tumor or a hematological tumor. The solid tumor is liver cancer, colorectal cancer, bladder cancer, breast cancer, cervical cancer, prostate cancer, glioma, melanoma, pancreatic cancer, nasopharyngeal carcinoma, lung cancer, or gastric cancer. In a preferred embodiment, the tumor is an oncolytic virus insensitive tumor. In a more preferred embodiment, the tumor is a tumor that is not susceptible to M1 oncolytic virus.
As an alternative embodiment, Bay11-7082 may be an injection, tablet, capsule, patch, kit, or the like. As a preferred embodiment, the potentiating agent is an injection; preferably, intravenous injection may be used.
The embodiments described above are merely illustrative examples, which are described in more detail and specific, but should not be construed as limiting the scope of the invention. It should be noted that, for those skilled in the art, various changes and modifications, substitutions, combinations and simplifications may be made without departing from the spirit of the invention, and all such changes and modifications should be considered as equivalent replacements.
Claims (10)
1. Application of ubiquitin-conjugating enzyme E2 inhibitor in preparing oncolytic virus anti-tumor synergist or drug resistance reversal agent.
2. The use according to claim 1, wherein the oncolytic virus is selected from one or more of an alphavirus, an adenovirus, a vaccinia virus, a measles virus, a vesicular stomatitis virus, and a herpes simplex virus; preferably, the alphavirus is at least one selected from the group consisting of M1 virus and togavirus.
3. The use according to claim 1, wherein the inhibitor of ubiquitin conjugated enzyme E2 is a substance inhibiting the activity of ubiquitin conjugated enzyme E2, or a substance degrading ubiquitin conjugated enzyme E2, or a gene means reducing the expression level of ubiquitin conjugated enzyme E2; preferably, said substance inhibiting the activity of ubiquitin conjugating enzyme E2 is selected from the group consisting of compounds; the gene tool for reducing the expression level of ubiquitin-conjugated enzyme E2 is a tool for gene silencing, gene editing or gene knockout.
4. Use according to claim 2, characterized in that the substance inhibiting the activity of ubiquitin conjugating enzyme E2 is preferably Bay11-7082 or a pharmaceutically acceptable salt, solvate, tautomer, isomer thereof.
5. The use of claim 1, wherein the tumor comprises a solid tumor or a hematological tumor; preferably, the solid tumor is liver cancer, colorectal cancer, bladder cancer, breast cancer, cervical cancer, prostate cancer, glioma, melanoma, pancreatic cancer, nasopharyngeal cancer, lung cancer, or gastric cancer.
6. An anti-tumor pharmaceutical composition comprises ubiquitin conjugating enzyme E2 inhibitor and oncolytic virus.
7. The pharmaceutical composition of claim 7, wherein the inhibitor of ubiquitin conjugated enzyme E2 is a substance inhibiting the activity of ubiquitin conjugated enzyme E2, or a substance degrading ubiquitin conjugated enzyme E2, or a gene tool reducing the expression level of ubiquitin conjugated enzyme E2; preferably, said substance inhibiting the activity of ubiquitin conjugating enzyme E2 is selected from the group consisting of compounds; the gene tool for reducing the expression level of ubiquitin-conjugated enzyme E2 is a tool for gene silencing, gene editing or gene knockout.
8. The pharmaceutical composition of claim 7, wherein the oncolytic virus is selected from one or more of an alphavirus, an adenovirus, a vaccinia virus, a measles virus, a vesicular stomatitis virus, and a herpes simplex virus; preferably, the alphavirus is at least one selected from the group consisting of M1 virus and togavirus.
9. The pharmaceutical composition of claim 7, wherein the tumor comprises a solid tumor or a hematological tumor; preferably, the solid tumor is liver cancer, colorectal cancer, bladder cancer, breast cancer, cervical cancer, prostate cancer, glioma, melanoma, pancreatic cancer, nasopharyngeal cancer, lung cancer, or gastric cancer.
10. The pharmaceutical composition of claim 6, in a dosage form selected from the group consisting of: injections, tablets, capsules, kits or patches; preferably, the dosage form is selected from injections.
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| CN113209303A (en) * | 2021-05-18 | 2021-08-06 | 上海交通大学医学院 | WWP1 degradation oncoprotein MUC1 through lysosome pathway to inhibit tumor and application thereof |
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| CN113209303A (en) * | 2021-05-18 | 2021-08-06 | 上海交通大学医学院 | WWP1 degradation oncoprotein MUC1 through lysosome pathway to inhibit tumor and application thereof |
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