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Application of dopamine receptor antagonist chlorprothixene in treatment of acute myeloid leukemia

A receptor antagonism, acute myeloid technology, used in the field of biomedicine to achieve good safety effects

Active Publication Date: 2019-12-20
SHANGHAI JIAO TONG UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Different fusion proteins can jointly regulate the expression of downstream target genes. Although there are many subtypes of AML, the molecular mechanisms regulated by different fusion proteins may be the same

Method used

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  • Application of dopamine receptor antagonist chlorprothixene in treatment of acute myeloid leukemia
  • Application of dopamine receptor antagonist chlorprothixene in treatment of acute myeloid leukemia
  • Application of dopamine receptor antagonist chlorprothixene in treatment of acute myeloid leukemia

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0103] Example 1, the role of the target genes co-regulated by the three fusion proteins PML-RARA, AML1-ETO and CBFb-MYH11 in AML disease

[0104] Download three sets of ChIP-seq data about fusion proteins PML-RARA, AML1-ETO and CBFb-MYH11 on the public database GEO, the three sets of data are GSE18886, GSE23730 and GSE46044 respectively. The first is to analyze and control the quality of Raw reads to remove low-quality reads and various contaminated fragments. The software used is FastQC; the second is to locate peaks. For different data quality, choose a relatively appropriate mapping method. Different numbers of mismatches are allowed to get the data. Based on these sequences mapped to the genome and their abundance, find statistically significant site peaks. The software used is MACS 2.0 to obtain site peaks. The nearest RefSeq gene for each peak is identified as a cancer fusion protein The target gene of is displayed with IGV software for each peak value obtained.

[01...

Embodiment 2

[0111] Example 2, Telden is identified as a potential drug for the treatment of AML by means of computational bioinformatics

[0112] First, the 594 target genes regulated by the three fusion proteins PML-RARA, AML1-ETO and CBFb-MYH11 were named gene set set1, and the modulated gene set caused by adding all-trans retinoic acid to NB4 cells was named For gene set set2, both gene sets set1 and set2 were considered as potential therapeutic targets. The overlap between potential therapeutic targets and differential gene sets of each drug was then counted to determine meaningful drugs for AML treatment. Use the cMAP database to mine potential drugs that have an impact on AML, such as Figure 7 As shown, the modulated gene sets caused by drug treatment in the cMAP database are represented by T1, T2, T3...Tn respectively. The method of cumulative hypergeometric test enrichment analysis was used to screen the important drugs that could induce the differential expression of Set1. Fi...

Embodiment 3

[0114] Example 3, cell viability detection, cell morphology detection and upper flow cytometry detection of cell cycle

[0115] Four cell lines were selected, namely NB4, KasuMi-1, K562 and U937. NB4, KasuMi-1, K562 and U937 are suspension human acute leukemia cell lines. In RPMI-1640 medium, the growth density of cells is maintained at 1x105 to 5x105 cells / ml. In order to prevent the cells from being polluted, 2 mM L-glutamine, 100 U / ml penicillin and 100 μg / ml streptomycin were added to the culture medium, and they were routinely cultured at 37°C in an incubator under 5% CO2 saturated humidity conditions.

[0116] The cck8 kit was used to detect the cell viability of NB4, KasuMi-1, K562 and U937 under different concentration gradients. Inoculate the cell suspension (100 μl / well) in a 96-well plate, the number of inoculated cells is about 5x103, and place the culture plate in an incubator at 37°C and 5% CO2 for 24 hours. Set up different drug concentration treatments, the T...

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Abstract

The invention discloses an application of a dopamine receptor antagonist chlorprothixene in treatment of acute myeloid leukemia, develops a new application of the dopamine receptor antagonist chlorprothixene as a drug, also provides a new way for treating acute myeloid leukemia, and uses the action mechanism between different fusion proteins and the existing APL theoretical model as support. Related in-vitro cell experiments and in-vivo animal experiments prove that: the chlorprothixene can induce cell apoptosis and autophagy pathways to promote death of AML cells, and can induce the decreaseof the expression quantity of fusion proteins PML-RARA and AML1-ETO, so that the chlorprothixene is a potential drug for inducing AML cell death, and provides a new visual angle for exploring alternative strategies of various AML subtype treatments.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to the application of dopamine receptor antagonist Telden in the treatment of acute myeloid leukemia. Background technique [0002] Acute myeloid leukemia (AML) is a malignant clonal blood system disease that is extremely harmful to human health. The main feature of AML is the uncontrolled proliferation and accumulation of myeloblasts in bone marrow and peripheral blood. Causes myeloid cell differentiation blockage, hematopoietic insufficiency (granulocytopenia, thrombocytopenia, or anemia), with or without leukocytosis. In addition, AML has the lowest survival rate of all types of leukemia. AML is rare in children but relatively common in adults over the age of 65. The incidence rate in developed countries is higher than that in developing countries, and in western countries is higher than in eastern countries. The incidence rate in the world is 2.25 / 100,000 population, and the inciden...

Claims

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Application Information

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IPC IPC(8): A61K31/382A61P35/02
CPCA61K31/382A61P35/02
Inventor 魏冬青杜玉昕
Owner SHANGHAI JIAO TONG UNIV
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