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New application of glycolytic inhibitor

An inhibitor and glycolysis technology, applied in the field of glycolysis inhibitors, can solve the problems of many adverse reactions and recurrence of rapamycin, and achieve the effects of less toxic and side effects and good curative effect

Inactive Publication Date: 2011-10-26
THE INST OF BASIC MEDICAL SCI OF CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In the actual application process, rapamycin is used as an immunosuppressant. In the process of treating tumors caused by mTOR activation, such as pulmonary lymphangioleiomyomatosis and tuberous sclerosis caused by TSC mutation, rapamycin There are many adverse reactions of glucocorticoids, and there will be relapses to varying degrees after drug withdrawal, so it has become an important reason for restricting its use.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1 : Relationship between mTOR signaling pathway and glycolysis

[0029] In order to clarify the relationship between the mTOR signaling pathway and glycolysis, we first collected PTEN, TSC1, and TSC2 that were cultured normally and cultured with mTOR signaling pathway inhibitor rapamycin (Rapamycin, purchased from sigma, product number R0395). Gene knockout mouse embryonic fibroblasts (see, Kwiatkowski, D.J., et al., A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6kinase activity in Tsc1null cells. Hum Mol Genet, 2002.11 (5): p.525-34; Zhang, H., et al., Loss of Tsc1 / Tsc2 activates mTOR and disrupts PI3K-Aktsignaling through downregulation of PDGFR. J Clin Invest, 2003.112(8): p.1223-33 .) (MEF, Pten- / -, Tsc1- / -, Tsc2- / -) and the supernatant of the corresponding wild-type cells (wt), then use the lactate analyzer (BIOSEN C line, Clinic) of EKF-diagnostic company Glucose and lactate levels in the cultur...

Embodiment 2

[0030] Example 2: Glycolysis Inhibitors Can Block the Proliferation of mTOR-Activated Cells

[0031] Since mTOR overactivation can lead to upregulation of glycolysis levels, we infer that the mechanism of mTOR activation tumorigenesis may be achieved by enhancing cellular glycolysis, so the application of glycolysis inhibitors may hinder the proliferation of mTOR activated cells. Will grow well 3-5 x 10 3 Tsc2- / -MEF cells were inoculated in four 96-well plates, and after the cells adhered to the wall, 20 μM 3-BrPA (3-bromopyruvate) was added to treat them for 24 hours, 48 ​​hours and 72 hours, and the cell proliferation was detected by MTT method, 3 cells in each group Duplicate holes, with no drug group as the control, such as image 3 As shown, the growth of Tsc2- / -MEF cells supplemented with 3-BrPA was significantly inhibited compared with that of Tsc2- / -MEF cells without 3-BrPA. In addition, we will 3×10 3 ~5×10 3 Wt and Tsc2- / -MEF cells (Tsc2 gene knockout mouse emb...

Embodiment 3

[0032] Example 3: Glycolysis inhibitors can be used in the treatment of tumors caused by mTOR overactivation

[0033] In order to further study that glycolysis inhibitors can be used in the treatment of tumors caused by overactivation of mTOR, we used a nude mouse model of tumor formation for in vivo experiments of drug treatment. First, the PTEN-deficient human prostate cancer cell line PC3 cells (purchased from ATCC) were injected with 1×10 6 Inoculate subcutaneously in nude mice aged 4-6 weeks, when the tumor volume is 60-100mm 3 The nude mice were divided into four groups, and 3-BrPA (6mg / kg) and Rapamycin (0.02mg / kg) were used for monotherapy and combination therapy respectively, twice a week. The result is as Image 6 As shown, the combined application of small doses of the two drugs can significantly inhibit the growth of tumors, and also produce a synergistic effect in vivo. It provides a theoretical basis for the combination of glycolysis inhibitors and rapamycin...

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Abstract

The invention provides a new application of a glycolytic inhibitor. Based on the increased glycolytic level in a rapamycin target protein highly-activated cell, and the significantly inhibited growth of a mTOR activated cell due to the application of a glycolytic inhibitor, the invention provides an application of the glycolytic inhibitor in preparing medicaments for treating mammal tumors or diseases caused by activation of mammal target protein and an upstream pathway thereof. The glycolytic inhibitor can specifically inhibit the glycolytic pathway, can pertinently treat tumors caused by mTOR activation, and has less toxic side effects, so better curative effect can be achieved.

Description

technical field [0001] The present invention relates to a new use of glycolysis inhibitors. Specifically, the present invention relates to a new application of glycolysis inhibitors in the treatment of mammalian tumors or other diseases caused by abnormal activation of mammalian target protein of rapamycin and its upstream pathway. Background technique [0002] Abnormal glucose metabolism is an important feature of tumor cells. Most normal cells obtain energy through the aerobic oxidation of sugar in the presence of oxygen, and metabolize through glycolysis only in the absence of oxygen. On the other hand, tumor cells mainly rely on glycolysis to metabolize glucose regardless of the presence or absence of oxygen, accompanied by the production of a large amount of lactic acid, which is called aerobic glycolysis. This phenomenon was first discovered by Otto Warburg, also known as the Warburg effect (see, Warburg, O., On the origin of cancer cells. Science, 1956.123 (3191): p....

Claims

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Application Information

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IPC IPC(8): A61K45/00A61K45/06A61K31/436A61P35/00A61P35/02A61P17/00A61P27/02A61P13/12A61P9/00
Inventor 张宏冰孙倩
Owner THE INST OF BASIC MEDICAL SCI OF CHINESE ACAD OF MEDICAL SCI
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