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Use of triptolide in preparing medicament for treating c-KIT tyrosine kinase related tumor

A technology of triptolide and tyrosine kinase, used in antitumor drugs, drug delivery, drug combination and other directions

Inactive Publication Date: 2009-01-28
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these tumors that have been reported are not c-KIT-related tumors, so far there is no literature report that TPL can inhibit the expression of c-KIT and treat c-KIT-related tumors

Method used

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  • Use of triptolide in preparing medicament for treating c-KIT tyrosine kinase related tumor
  • Use of triptolide in preparing medicament for treating c-KIT tyrosine kinase related tumor
  • Use of triptolide in preparing medicament for treating c-KIT tyrosine kinase related tumor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Example 1: The effect of TPL on the expression of oncoprotein c-KIT in c-KIT D816V point mutation cells

[0053] The experiment was carried out using P815 cells of mouse-derived mastocytoma, which carry the c-KIT D814Y mutation (equivalent to the human c-KIT D816V mutation) and are resistant to STI571. P815 is a mouse-derived mast cell tumor carrying the KIT D814Y mutation (equivalent to the human KIT D816V mutation), which is insensitive to STI571. In the experiment, different concentrations of TPL were added to the culture system of P815 cells, and the culture was continued for 24 hours. Cells in the control group or cells treated with different concentrations of drugs were harvested at different times, centrifuged to remove the supernatant, and washed twice with PBS. Cells were suspended in RIPA buffer (1xPBS buffer, 1% NP-40 lysate, 0.5% sodium deoxycholate, 0.1% SDS denaturant) [RIPA needs to be freshly added with 10mM β-glycerophosphate, 1mM sodium orthovanadate,...

Embodiment 2

[0056] Example 2: MTS method to determine the effect of TPL on the proliferation of D816V c-KIT-carrying cells at the nanomolar concentration level

[0057] (1) Experimental materials

[0058] Cell lines: HMC-1.1, HMC-1.2 and P815 cell lines were selected. HMC-1.1 is a human SM cell, which only carries the V560G mutation, and c-KIT is sensitive to STI571, which is used as a control. HMC-1.2 is a human SM cell carrying D816V and V560G mutation c-KIT, which is resistant to STI571. P815 of mouse-derived mast cell tumors carries the KIT D814Y mutation, equivalent to the human c-KIT D816V mutation, and this cell line is resistant to STI571.

[0059] HMC-1.1 and HMC-1.2 were cultured with IMDM (Gibco)+10% fetal bovine serum (Hyclone), and P815 were cultured with DMEM (Gibco)+10% fetal bovine serum (Hyclone).

[0060] Culture medium containing 100u / ml penicillin, 100ug / ml streptomycin, at 37°C, 5% CO 2 Cultured under saturated humidity conditions, the cells used in the experiment...

Embodiment 3

[0069] Example 3: Determination of cell apoptosis by Annexin V / PI double-labeled flow cytometry

[0070] Cell apoptosis was measured by flow cytometry using Annexin V-FITC / PI labeling method. This method has high specificity and high sensitivity, and can distinguish normal cells, early apoptotic cells, late apoptotic cells and necrotic cells.

[0071] According to the kit provided by Sigma-Aldrich Company. Cells in the control group or cells treated with different concentrations of drugs were harvested at different times, centrifuged to remove the supernatant, and washed with 1×binding buffer (10 mM HEPES, [pH 7.4]; 0.15M NaCl; 5mM KCl; 1mM MgCl 2 ; 1.8mM CaCl 2 ) was washed once, and the cells were suspended in 1× binding buffer, and the concentration was adjusted to 2×10 5 / ml. Mix the cell suspension with FTIC-Annexin V, incubate at room temperature for 15 minutes, stain the cells with PI (propidium iodide), and analyze them quickly with a flow cytometer. Experiments w...

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Abstract

The invention relates to a purpose of a medicine which is prepared by triptolide and is used for curing tumor that is relevant to c-KIT tyrosine kinase. The invention verifies that a micromolecule natural product triptolide (TPL) can down-regulate the protein expression of D816V point mutation c-KIT for the first time, inhibit the phosphorylation thereof and induce the cell apoptosis of STI571 resistance c-KIT point mutation (D816). The invention discloses a novel micromolecule stayer of tyrosine kinase, more particularly overcomes the problem that the resistance property of the medicine STI 571 can be inhibited by the first-line tyrosine kinase that is used on the clinic at present. The TPL can be used for developing a novel specific medicine for curing tumors being relevant to c-KIT mutation, such as gastrointestinal stromal tumor, systemic mastocytosis and small cell lung cancer, etc.

Description

technical field [0001] The invention relates to a new application of triptolide, in particular to the application of triptolide in the preparation of medicines for treating tumors related to c-KIT tyrosine kinase. Background technique [0002] Tumor molecular targeted therapy is a treatment method based on the selective killing of tumor cells by chemical or biological means to key molecules closely related to tumor growth. Tyrosine kinases are important targets for tumor molecular targeted therapy. Bcr-Abl and c-KIT are tyrosine kinases. [0003] Bcr-Abl is a fusion protein that causes chronic myelogenous leukemia (CML). The encoded product of c-KIT is a transmembrane receptor protein with tyrosine kinase activity and a molecular weight of 145 kilodaltons. It has five immunoglobulin G-like domains in the extracellular region, so it belongs to Member of the type III tyrosine kinase superfamily. Under physiological conditions, a small amount of c-KIT is expressed in mast c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/365A61K9/00A61P35/00
Inventor 潘景轩曹开源程超靳艳丽
Owner SUN YAT SEN UNIV
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