阅读说明：本技术 富马酸二甲酯dmf在调节肿瘤代谢、抑制肿瘤生长方面的应用 (Application of dimethyl fumarate DMF in regulating tumor metabolism and inhibiting tumor growth ) 是由 殷雷 雷骏 方嘉凌 杨怡 李永征 于 2020-01-02 设计创作，主要内容包括：本发明属于生物技术及医学领域,具体涉及富马酸二甲酯DMF在调节肿瘤代谢、抑制肿瘤生长方面的应用。本发明首次发现小分子抑制剂DMF调控肿瘤代谢从而抑制肿瘤生长方面的应用；DMF可以在体外抑制多种肿瘤细胞的增殖并降低肿瘤细胞代谢,在体内对肿瘤的发生发展具有一定的抑制作用；通过抑制肿瘤代谢,改善肿瘤酸性微环境降低对T细胞功能的抑制,提高T细胞反应性,增强免疫治疗的效率,为肿瘤治疗提供新靶点和新思路。(The invention belongs to the field of biotechnology and medicine, and particularly relates to application of dimethyl fumarate DMF in regulation of tumor metabolism and inhibition of tumor growth. The invention discovers the application of a small molecular inhibitor DMF in the aspect of regulating and controlling tumor metabolism so as to inhibit tumor growth for the first time; DMF can inhibit the proliferation of various tumor cells in vitro and reduce the metabolism of the tumor cells, and has certain inhibiting effect on the generation and development of tumors in vivo; by inhibiting tumor metabolism, the tumor acidic microenvironment is improved, the inhibition of T cell functions is reduced, the T cell reactivity is improved, the immunotherapy efficiency is enhanced, and a new target and a new thought are provided for tumor therapy.)

1. Application of dimethyl fumarate DMF in preparation of medicines for regulating and controlling tumor metabolism is provided.

2. Application of dimethyl fumarate DMF in preparation of medicines for inhibiting tumor growth is provided.

3. Use of dimethyl fumarate DMF in the preparation of a medicament for increasing T cell reactivity.

4. Application of dimethyl fumarate DMF in preparation of medicines for enhancing tumor immunotherapy efficiency.

5. Application of dimethyl fumarate DMF in preparation of medicines for reducing side effects of IL-2 in treating tumors.

6. Application of dimethyl fumarate DMF and IL-2 pharmaceutical composition in preparation of drugs for inhibiting tumor growth.

Technical Field

The invention belongs to the field of biotechnology and medicine, and particularly relates to application of dimethyl fumarate DMF in regulation of tumor metabolism and inhibition of tumor growth.

Background

The metabolism isThe basic feature of the life activities of the body is the most important way for the cells to obtain energy. In the process of tumor development, energy metabolism is often disordered, which changes the Tumor Microenvironment (TME) and helps tumor cells to survive, transfer and escape in immunity. Studies have demonstrated that in some tumors, glycolysis is the predominant mode of energy metabolism, as the tumor is in a hypoxic microenvironment. In the last 30 th century, doctor OttoWarburg discovered in O₂Under sufficient conditions, tumor cells still rely on aerobic glycolytic energy production. Such tumor cells do not utilize mitochondrial oxidative phosphorylation energy even under aerobic conditions, and the phenomenon of utilizing glycolytic energy production is called Warburg effect (Warburg effect) or aerobic glycolysis. Many tumor cells produce lactate and ATP by enhancing the glycolytic pathway to consume glucose, studies have shown that: in the mouse kidney cancer model, tumor metabolic activity and activation are negatively correlated with infiltration of T cells; in melanoma and non-small cell lung cancer patients, tumor metabolic activity is enhanced, resulting in poor infiltration of T cells. Furthermore, tumor aerobic glycolysis stimulates the expression of granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage colony-stimulating factor (GM-CSF), recruits myeloid-derived suppressor cells (MDSCs) into TEM, and inhibits the ability of immune cells to respond to tumors.

TME is the cellular environment in which tumors exist, including peripheral blood vessels, extracellular matrix (ECM), other non-malignant cells, and signaling molecules 3, 4. The preparation is characterized by low oxygen, low pH, low sugar and the like. The tumor microenvironment contains a large amount of growth factors, cell chemotactic factors and immunoinflammatory response molecules generated by various proteolytic enzymes, and the characteristics of the growth factors, the cell chemotactic factors and the immunoinflammatory response molecules are favorable for the proliferation, invasion, adhesion and angiogenesis of tumors and the resistance to radiotherapy and chemotherapy, and promote the survival, proliferation and metastasis of the tumors. The tumor microenvironment is closely related to the behaviors of tumor growth, metastasis, immune escape and the like, and the microenvironment characteristics of weak acid, hypoxia, immunosuppression and the like of the tumor are also an important reason for the tolerance of clinical antitumor treatment. Research shows that tumor aerobic glycolysis has certain influence on the treatment of tumors, such as: aerobic glycolysis of tumors causes therapeutic resistance to chemotherapy and radiotherapy, among other things. Thus, TME is considered to be one of the biggest obstacles to successful treatment of tumors. Effective treatment of tumors requires overcoming the obstacles of TME.

In addition to tumor cells, tumors also have a variety of non-cancerous cells, including fibroblasts, vascular endothelial cells, and immune cells, including T cells, macrophages, and neutrophils, which function differently. Initial T cell dependent oxidative phosphorylation maintains energy requirements; when naive T cells are stimulated with antigen, they proliferate and differentiate to form effector T cells. The rapid replication of T cells and secretion of cytokines increases the demand for bioenergy and anabolism. To address these needs, activated T cells have increased glucose and amino acid uptake and utilization by enhancing pathways such as glycolysis, glutamine breakdown, and branched chain amino acid catabolism. Glucose is a key substrate for T cells and M1-type macrophages, and its role in tumor development relies on aerobic glycolysis to maintain activation and effector function. Nutrition and O in the tumor microenvironment₂The activity of HIF-1 α increases, promotes glycolysis, inhibits the increase in the concentration of metabolites and leads to acidification of the local environment, lactic acid is further secreted out of the tumor cell to trigger the acidic microenvironment of the tumor, further impairing T cell function, the Warburg effect is a metabolic mode characteristic of tumors that exhibit high levels of aerobic glycolysis, rapidly depletes the glucose in the surrounding environmentAnd little, ultimately resulting in the conversion of effector T cells into null cells.

Disclosure of Invention

Aiming at the defects of the prior art, the invention aims to provide the application of dimethyl fumarate DMF in the aspects of regulating tumor metabolism and inhibiting tumor growth.

In order to achieve the purpose of the invention, the technical scheme adopted by the invention is as follows:

application of dimethyl fumarate DMF in preparation of medicines for regulating and controlling tumor metabolism is provided.

Application of dimethyl fumarate DMF in preparation of medicines for inhibiting tumor growth is provided.

Use of dimethyl fumarate DMF in the preparation of a medicament for increasing T cell reactivity.

Application of dimethyl fumarate DMF in preparation of medicines for enhancing tumor immunotherapy efficiency.

Application of dimethyl fumarate DMF in preparation of medicines for reducing side effects of IL-2 in treating tumors.

Application of dimethyl fumarate DMF and IL-2 pharmaceutical composition in preparation of drugs for inhibiting tumor growth.

The invention has the beneficial effects that: the invention discovers the application of a small molecular inhibitor DMF in regulating and controlling tumor metabolism so as to inhibit the growth of tumors for the first time; DMF can inhibit the proliferation of various tumor cells in vitro and reduce the metabolism of the tumor cells, and has certain inhibiting effect on the generation and development of tumors in vivo; by inhibiting tumor metabolism, the tumor acidic microenvironment is improved, the inhibition of T cell functions is reduced, the T cell reactivity is improved, the immunotherapy efficiency is enhanced, and a new target and a new thought are provided for tumor therapy.

Drawings

FIG. 1 shows the inhibition of the proliferation of various tumor cells by DMF in example 1.

FIG. 2 is a graph showing the use of DMF to regulate the metabolic processes of various tumor cells in example 2.

FIG. 3 is the inhibition of tumor growth in tumor-bearing mice by DMF as in example 3.

FIG. 4 is a graph of example 4 showing the use of bioinformatics to analyze GAPDH expression differences in tumor tissue specimens and negative correlation with patient prognosis.

FIG. 5 is a graph showing the improvement of proliferation and normal function of immune-related cells after improving tumor microenvironment using DMF in example 5.

FIG. 6 is a structural mechanism of inhibition of GAPDH enzyme activity by DMF in example 6, which is analyzed by structural biology techniques.

FIG. 7 is a graph showing that DMF can be used to reduce side effects of IL-2 treatment on tumors in example 7.

FIG. 8 is a graph of the inhibition of tumor growth in tumor-bearing mice using DMF in combination with IL-2 therapy in example 8.

Detailed Description

In order to better understand the present invention, the following examples are further provided to illustrate the present invention, but the present invention is not limited to the following examples.