CN111658766A

CN111658766A - Application of GSK3 beta and agonist thereof in treatment and rehabilitation of epithelial-derived malignant tumor

Info

Publication number: CN111658766A
Application number: CN202010642170.5A
Authority: CN
Inventors: 陈长宏
Original assignee: Individual
Current assignee: Individual
Priority date: 2020-07-06
Filing date: 2020-07-06
Publication date: 2020-09-15

Abstract

The invention discloses an application of GSK3 beta and an agonist thereof in the treatment and rehabilitation of epithelial malignant tumors, which can reduce the anti-apoptosis threshold level of tumor cells, interfere the proliferation and metabolism process of the tumor cells, slow down the growth speed of the tumors, promote the differentiation of the tumor cells and reduce the recurrence of the tumors by activating GSK3 beta, can improve the killing effect of various existing tumor treatment methods on the tumors by reducing the overall anti-apoptosis level of the tumors and up-regulate the overall anti-tumor capability of organisms, promote the rehabilitation of patients, and is one of the most fundamental means for improving the overall anti-tumor capability of the tumor patients, improving the survival time and the survival quality of the patients and reducing the recurrence and metastasis of the tumors.

Description

Application of GSK3 beta and agonist thereof in treatment and rehabilitation of epithelial-derived malignant tumor

Technical Field

The invention relates to the technical field of clinical tumor treatment, in particular to application of GSK3 beta and an agonist thereof in treatment and rehabilitation of epithelial-derived malignant tumor.

Background

The recurrence and metastasis of malignant tumors are the most problematic problems faced by clinical tumor therapy. Surgery, chemotherapy and radiotherapy are currently the most common means of tumor treatment.

The operation treatment is the first choice treatment means for most of early and middle stage tumors in clinic, and can play a radical treatment effect on part of early stage tumors which are not subjected to distant metastasis, while the early stage metastasis problem of the tumors becomes an important factor for restricting the operation effect on middle and late stage tumors and part of early stage tumors with high malignancy degree. Chemotherapy is a systemic treatment that works on both primary and metastatic tumors. The chemotherapy drugs can be used alone, or several chemotherapy drugs can be combined or sequentially used, or combined with other treatment means such as surgery, radiotherapy and the like. Conventional chemotherapy aims to suppress proliferation of tumor cells and promote death of tumor cells. The chemotherapy of regular and pedicure course can effectively eliminate the tumor cells which are sensitive to the chemotherapy in part of tumor patients. However, increasing the dose of the chemotherapeutic drug or prolonging the chemotherapeutic time for insensitive (such as cell proliferation cycle G0, tumor cells in partial G1 stage, and tumor stem cells) or resistant tumor cells does not allow the patient to benefit further, and the toxic and side effects of the chemotherapeutic drug are gradually increased. Radiotherapy has a good killing effect on part of radiotherapy-sensitive tumor cells, particularly proliferation cells, but the radiation characteristic of radiotherapy determines that the radiotherapy is mainly adopted in a local treatment mode, and the radical removal of tumors is difficult to achieve in principle by the radiotherapy with a tolerant dose, so that the recurrence of the tumors cannot be avoided under most conditions.

In recent years, new therapeutic means such as targeted therapy and immunotherapy are being applied to clinical application, and new hopes are brought to tumor treatment. The targeting and immunotherapy are mainly applied to patients with corresponding gene mutation or high expression of immune related markers, and the treatment effect of part of patients is obvious. However, the cost of targeting and immunotherapy is high and the highly heterogeneous tumor tissue is also constantly placing changing demands on targeted drugs or immunotherapy. The drug resistance of tumor tissues to targeting or immunotherapy is improved due to continuous adaptive mutation of tumors under the same target, and the proliferation progress of heterogeneous tumor subgroups with different genotypes or epigenotypes needs to be continuously developed and applied aiming at different related abnormal proliferation targets or immune targets. Clinical studies with targeted therapy and immunotherapy have shown that for most of the enrolled cases, targeted and immunotherapy under the current conditions does not completely prevent the recurrence of the tumor.

The method searches a new target for treating the malignant tumor, improves the treatment effect of the malignant tumor, prolongs the overall survival time of a tumor patient, and is an urgent subject in the field of tumor research.

Among the many targets for tumor research, glycogen synthase Kinase-3 β (glycogen synthase Kinase-3 β, GSK3 β) is receiving increasing attention from researchers. GSK3 β is a highly conserved serine/threonine protein kinase widely present in almost all eukaryotes, and was originally discovered as a regulator of glycogen metabolism. Numerous studies have been conducted to confirm whether GSK3 β is also a downstream critical regulation switch for various signal pathways. These pathways include: RAS/MAPK/ERK, P38MAPK, JNK, PI3K/AKT, Wnt/beta-Catenin, PKC, PKA, NF-kB, Receptor Tyrosine Kinases (RTK), Notch, Hedgehog, G protein-coupled receptors (GPCR) and other signal pathways. GSK3 β participates in a wide range of signaling cascades, involving cell metabolism, cell cycle regulation, proliferation, differentiation, motility, substance transport, biorhythm control, apoptosis, etc.

GSK3 β was also found to be involved in the metastatic process of tumor cells. Epithelial-mesenchymal Transition (EMT) is considered to be a key element in the development of metastasis of tumor cells. The tumor cells with EMT transformation are transformed from epithelial cell characteristics to mesenchymal cell characteristics, and the enhancement of cell movement and migration capacity is accompanied, so that a foundation is provided for invasion and metastasis of tumors. GSK3 β plays an important role in EMT by modulating Wnt, Hedgehog and Snail pathways.

The effects of GSK3 β include: GSK3 β is a key regulatory node for cell death, cell differentiation or proliferation, and is one of the most central substances for healthy survival and function development around parenchymal cells during the evolution of a living body. The GSK3 beta can play its role in regulating cell metabolism direction, regulating the switch of cell survival adaptive pathway, regulating biological rhythm, regulating cell movement and substance transport. GSK3 β is also a precise regulator in the dose-response system of living organisms, plays a central role in regulation in the processes of channel selection, opening degree of different channels, channel compensation, etc., and is also the most important determinant of adaptive capacity of tissue cells.

GSK3 β also plays an extremely important role in the development and progression of tumor cells. Inhibition of GSK3 β activity is a prerequisite for activation of multiple proliferation pathways, anti-apoptosis and adaptive survival of tumor cells. In view of the important role of GSK3 β in tumor development and progression, tumor therapy targeting GSK3 β is expected to be high.

Disclosure of Invention

In view of the above situation, the present invention provides a GSK3 β and its agonist for use in the treatment and rehabilitation of epithelial malignant tumors by activating GSK3 β to reduce the anti-apoptotic threshold level of tumor cells, interfere with the proliferative metabolic process of tumor cells, slow down the growth rate of tumors, promote the differentiation of tumor cells, and reduce the recurrence of tumors.

In order to achieve the purpose, the invention adopts the following technical scheme:

GSK3 beta and application of an agonist thereof in treatment and rehabilitation of epithelial-derived malignant tumors, wherein the application utilizes the GSK3 beta or GSK3 beta agonist to promote apoptosis of tumor cells, slow proliferation of the tumor cells, and enhance killing effect on the tumors by combining with conventional tumor treatment means.

Further, the GSK3 beta comprises virus or non-virus expression vector of artificially synthesized GSK3 beta protein or active polypeptide, GSK3 beta complete gene sequence, cDNA or ORF, and the GSK3 beta agonist comprises GSK3 beta active binding protein, GSK3 beta activator protein and activator thereof, and inhibitor or antagonist of GSK3 beta inhibitory protein.

Further, the conventional tumor treatment means includes chemotherapy, radiotherapy, targeted therapy, interventional therapy, cold/heat ablation therapy, biological therapy.

Further, the GSK3 β or GSK3 β agonist is used prior to, during or after administration of a chemotherapy, targeted therapy, interventional therapy, cold/heat ablation therapy, biological therapy session.

Further, the main therapeutic drugs used in the therapeutic means include, but are not limited to, alkylating agents, hormones, antimetabolites, antibiotics, antitumor plants, platins, protein inhibitors, enzyme preparations, methylation drugs, antitumor targeting drugs, monoclonal antibodies for tumor therapy, immunomodulatory and therapeutic drugs.

Has the advantages that:

the application of GSK3 beta and the agonist thereof in the treatment and rehabilitation of epithelial malignant tumors provided by the invention has the following beneficial effects:

the GSK3 beta and GSK3 beta agonists are used in the treatment scheme of the epithelial malignant tumor, can improve the killing effect of various existing tumor treatment methods on the tumor and promote the recovery of a patient by reducing the integral anti-apoptosis level of the tumor and increasing the integral anti-tumor capability of an organism, and is one of the most fundamental means for improving the integral anti-tumor capability of the tumor patient, improving and improving the survival time and the survival quality of the patient and reducing the tumor recurrence and metastasis.

Drawings

FIG. 1 is a flow chart of the treatment of the present invention.

Detailed Description

The invention is further described below with reference to the accompanying drawings.

The GSK3 beta and the application of the agonist thereof in the treatment and rehabilitation of epithelial-derived malignant tumors provided by the invention utilize GSK3 beta or GSK3 beta agonists to promote the apoptosis of tumor cells and slow down the proliferation of the tumor cells, and the killing effect on tumors is enhanced by combining with conventional tumor treatment means.

The GSK3 beta comprises virus or non-virus expression vector of artificially synthesized GSK3 beta protein or active polypeptide, GSK3 beta complete gene sequence, cDNA or ORF, and the GSK3 beta excitant comprises GSK3 beta active binding protein, GSK3 beta activator protein and activator thereof, and inhibitor or antagonist of GSK3 beta inhibitory protein.

The conventional tumor treatment means comprises chemotherapy, radiotherapy, targeted therapy, intervention therapy, cold/heat ablation therapy and biological therapy, and the GSK3 beta or GSK3 beta agonist is used before, during or after the chemotherapy, the targeted therapy, the intervention therapy, the cold/heat ablation therapy and the biological therapy. The tumor treatment means can be used singly or in combination of several means or sequentially.

The main therapeutic drugs used in the treatment means include but are not limited to alkylating agents used for tumor therapy (such as cyclophosphamide, ifosfamide, chlorambucil, carmustine, melphalan, malignane, etc.); metabolites (e.g., methotrexate, cytarabine, fludarabine, gemcitabine, fluorouracil, hydroxyurea, etc.); antineoplastic antibiotics (including adriamycin, daunorubicin, pingyangmycin, actinomycete D, doxorubicin and epirubicin); antineoplastic plant medicine (such as vinblastine (vincristine, vindesine), homotricuspid ester, and taxus); hormones (e.g., prednisone, dexamethasone, diethylstilbestrol, megestrol, testosterone propionate, tamoxifen, aminoglutethimide, letrozole, flutamide, etc.); platinum compounds (such as cisplatin, carboplatin, oxaliplatin, etc.); enzyme preparations (e.g., asparaginase); protein inhibitor drugs (such as bortezomib); methylated drugs (e.g., decitabine, azacitidine); targeted therapeutic drugs (such as anti-angiogenesis drugs and tyrosine kinase inhibitors); drugs of monoclonal antibodies (e.g., rituximab, herceptin, etc.) for tumor therapy; immune regulation and treatment (such as thymosin, interferon, cell factor, PD-1 monoclonal antibody, PD-L1 monoclonal antibody, CTLA-4 monoclonal antibody), the drug treatment comprises single drug administration or combination of several drugs or sequential drug administration of several drugs.

The limitation of the protection scope of the present invention is understood by those skilled in the art, and various modifications or changes which can be made by those skilled in the art without inventive efforts based on the technical solution of the present invention are still within the protection scope of the present invention.

Claims

The application of GSK3 beta and an agonist thereof in the treatment and rehabilitation of epithelial-derived malignant tumors is characterized in that the GSK3 beta or GSK3 beta agonist is used for promoting the apoptosis of tumor cells and slowing the proliferation of the tumor cells, and the killing effect on the tumors is enhanced by combining with a conventional tumor treatment means.
2. The use of GSK3 β and agonists thereof for the treatment and rehabilitation of epithelial-derived malignancies as claimed in claim 1, wherein GSK3 β comprises a viral or non-viral expression vector artificially synthesized to GSK3 β protein or active polypeptide, GSK3 β complete gene sequence, cDNA or ORF, and the GSK3 β agonists include GSK3 β active binding proteins, GSK3 β activator proteins and activators thereof, inhibitors or antagonists of GSK3 β inhibitor proteins.
3. The use of GSK3 β and agonists thereof in the treatment and rehabilitation of malignant tumors of epithelial origin as claimed in claim 1, wherein said conventional tumor treatment modalities include chemotherapy, radiation therapy, targeted therapy, interventional therapy, cold/heat ablation therapy, biological therapy.
4. The use of GSK3 β and agonists thereof for the treatment and rehabilitation of malignancies of epithelial origin as claimed in claims 2 or 3, wherein the GSK3 β or GSK3 β agonists are used before, during or after the course of chemotherapy, targeted therapy, interventional therapy, cold/heat ablation therapy, biological therapy.
5. The use of GSK3 β and agonists thereof for the treatment and rehabilitation of malignant tumors of epithelial origin according to claim 4, wherein the main therapeutic drugs used in said treatment modalities include, but are not limited to, alkylating agents, hormones, antimetabolites, antibiotics, antineoplastic plants, platins, protein inhibitors, enzymes, methylating agents, antineoplastic targeting drugs, monoclonal antibodies for tumor therapy, immunomodulating and therapeutic drugs.