CN111632146B - Application of OAT inhibitor and oncolytic virus in preparation of antitumor drugs - Google Patents
Application of OAT inhibitor and oncolytic virus in preparation of antitumor drugs Download PDFInfo
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Abstract
本发明首次公开了OAT抑制剂，尤其是Dimesna可以增加溶瘤病毒的抗肿瘤效应，以提高溶瘤病毒作为抗肿瘤药物时的治疗有效性。细胞学实验证明M1病毒和Dimesna联合应用，可显著引起肿瘤细胞的形态学病变，从而显著增强对肿瘤细胞的抑制作用。The present invention discloses for the first time that OAT inhibitors, especially Dimesna, can increase the anti-tumor effect of oncolytic viruses, so as to improve the therapeutic efficacy of oncolytic viruses as anti-tumor drugs. Cytological experiments have shown that the combined application of M1 virus and Dimesna can significantly cause morphological changes in tumor cells, thereby significantly enhancing the inhibitory effect on tumor cells.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to application of an OAT 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 organic anion transporter subfamily 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 the organic anion transporter subfamily in the preparation of an oncolytic virus anti-tumour potentiator or resistance-reversal agent.
The OAT inhibitor is an Organic Anion Transporter (OAT) subfamily, is an important component in a solute transporter 22 (SLC 22) family, and is expressed in various tissues and organs including liver, kidney, brain, placenta and the like. It has received a great deal of attention because it mediates the excretion of many common drugs (antibiotics, antivirals, diuretics, and non-steroidal anti-inflammatory drugs), toxins, and nutrients within the body. Studies have shown that the combined use of OAT inhibitors with cisplatin can reduce nephrotoxicity caused by pathways such as nephrotoxic glutamyl transpeptidase (GGT), Adiponectin (ANP), and cysteine-coupled-beta-lyase (CCBL), and thus play an important role in chemotherapy-induced toxicity.
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 organic anion transporter subfamily inhibitor is a substance that inhibits the activity of an organic anion transporter subfamily protein, or a genetic tool that degrades a substance of an organic anion transporter subfamily, or reduces the expression level of an organic anion transporter subfamily;
preferably, the substance inhibiting the organic anion transporter subfamily is selected from the group consisting of a compound;
or preferably, the genetic tool that reduces the expression level of an organic anion transporter subfamily is a gene silencing, gene editing or gene knock-out tool.
More preferably, according to the use according to the first aspect of the invention, the substance inhibiting the organic anion transporter subfamily is preferably Dimesna or a pharmaceutically acceptable salt, solvate, tautomer, isomer thereof.
Or more preferably, according to the use according to the first aspect of the invention, the gene means for inhibiting the expression level of the subfamily of organic anion transporters 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 invention, there is provided an anti-tumor pharmaceutical composition comprising an organic anion transporter subfamily inhibitor and an oncolytic virus.
According to the pharmaceutical composition of the first aspect of the invention, the organic anion transporter subfamily inhibitor is a substance that inhibits the activity of an organic anion transporter subfamily protein, or a substance that degrades an organic anion transporter subfamily, or a genetic tool that reduces the expression level of an organic anion transporter subfamily;
preferably, the substance inhibiting the organic anion transporter subfamily is selected from the group consisting of a compound;
or preferably, the genetic tool that reduces the expression level of an organic anion transporter subfamily is a gene silencing, gene editing or gene knock-out tool.
More preferably, according to the use according to the first aspect of the invention, the substance inhibiting the organic anion transporter subfamily is preferably Dimesna or a pharmaceutically acceptable salt, solvate, tautomer, isomer thereof.
Or more preferably, according to the use according to the first aspect of the invention, the gene means for inhibiting the expression level of the subfamily of organic anion transporters is siRNA, dsRNA, miRNA, ribozyme or shRNA.
Further, according to the pharmaceutical composition 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 pharmaceutical composition 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.
The invention has the beneficial effects that:
the invention finds that the OAT inhibitor, especially Dimesna 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 the Dimesna can obviously cause morphological lesion of tumor cells, thereby obviously enhancing the inhibiting effect on the tumor cells.
The inventor combines Dimesna and M1 viruses to act on a human hepatocellular carcinoma Hep3B strain, and unexpectedly discovers that when the Dimesna and M1 viruses are combined to be used, 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 present invention, when M1 virus (MOI ═ 0.001) was used alone to treat hepatoma cells, the survival rate of tumor cells was 71.3%, whereas when 25 μ M Dimesna was used in combination with M1 virus of the same MOI, the survival rate of tumor cells decreased significantly to 45.7%. Compared with the anti-tumor effect of the M1 virus alone, the tumor dissolving effect is obviously improved when the Dimesna and the M1 are used together.
The invention finds that the combined application of Dimesna and oncolytic virus to treat tumor cells has a remarkably better tumor cell killing effect than that of Dimesna with the same concentration, for example, when the tumor cells are treated by Dimesna with 25 mu M, the survival rate of the tumor cells is still as high as 97.8 percent, and when the Dimesna with 25 mu M is combined with M1 virus, the survival rate of the tumor cells is greatly reduced to 45.7 percent. It can be seen that the greatly enhanced oncolytic effect of Dimesna in combination with M1 is due to the synergistic mechanism between Dimesna and M1 virus, and not simply by the anti-tumor mechanism of Dimesna.
The combined use of the OAT inhibitor (such as Dimesna) and the alphavirus discovered by the invention not only enhances the oncolytic effect, but also has higher safety without influencing normal cells by the medicament per se, and simultaneously realizes two benefits, which are hard to obtain and have important and positive significance for the health of tumor patients.
Drawings
FIG. 1 Effect of Dimesna in combination with M1 virus treatment 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 1 combination treatment of Dimesna with M1 virus significantly reduced the 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 this example, the OAT inhibitor is Dimesna, which has the formula shown in formula 1:
formula 1: dimesna.
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, cells were completely attached, and the experiment was divided into a control group, a Dimesna-only group, an M1-infected group, and a Dimesna/M1 combination group. The dosages used were: m1 virus (MOI ═ 0.001) infected cells; dimesna was 25. 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, treatment with M1 virus (MOI ═ 0.001) alone had a small inhibitory effect on tumor cell Hep3B, with tumor cell survival reaching 71.3%, and tumor cell survival in the 25 μ M Dimesna-treated group was still as high as 97.8%, however, when the same 25 μ M Dimesna was used in combination with M1 virus (MOI ═ 0.001) (Dimesna + M1), tumor cell survival was greatly reduced to 45.7%, indicating that Dimesna significantly enhanced the oncolytic effect of M1 virus.
Example 2
A pharmaceutical composition for treating a tumor comprising an organic anion transporter subfamily inhibitor and an oncolytic virus.
It may also be a pharmaceutical kit for the treatment of tumors comprising an OAT inhibitor or a derivative thereof or a combination thereof, and an oncolytic virus. A pharmaceutical package differs from a composition in that the OAT inhibitor is not in the form of an oncolytic virus but is packaged separately (e.g., in pills, or capsules, or tablets or ampoules, containing the OAT inhibitor; another pills, or capsules, or tablets or ampoules, containing the oncolytic virus).
The oncolytic virus, the OAT inhibitor, and the combination of the oncolytic virus and the OAT inhibitor 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 contain separately packaged OAT inhibitors, as well as separately packaged oncolytic viruses. Administration of the OAT inhibitor, and the oncolytic virus in the pharmaceutical kit, may be simultaneous administration or administration in any order, e.g. administration of the OAT inhibitor before the oncolytic virus, or administration of the OAT inhibitor after the oncolytic virus, or both. In various embodiments, the patient may be a mammal. The mammal may be a human.
The OAT inhibitor includes, but is not limited to, compounds such as Dimesna (formula 1) which inhibit OAT activity. Or for tools for suppressing expression of OAT genes, including but not limited to, tool approaches for gene interference, gene silencing, and gene editing or knockout. As an embodiment of this embodiment, the OAT inhibitor is selected from Dimesna.
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, the Dimesna provided by the present invention 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 (4)
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