Application of natural micromolecule HEC-23 to preparation of medicine for promoting lysosome mediated cell death

A technology of small molecular compounds and lysosomes, applied in the field of chemical biology, can solve the problems of lack of apoptosis mechanism and tumor drug resistance, and achieve the effect of reducing the dose of chemotherapy drugs, reducing the dose of cisplatin, and improving the effect of chemotherapy

Inactive Publication Date: 2018-09-04
FUDAN UNIV +2
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In addition, there is a lack of apoptosis mechanism in tumor cells (such as caspase mutation inactivation), and clinical tumor

Method used

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  • Application of natural micromolecule HEC-23 to preparation of medicine for promoting lysosome mediated cell death
  • Application of natural micromolecule HEC-23 to preparation of medicine for promoting lysosome mediated cell death
  • Application of natural micromolecule HEC-23 to preparation of medicine for promoting lysosome mediated cell death

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Example 1: HEC-23 induces cell death of human cervical cancer cell line (HeLa)

[0043] Adding 10 μM HEC-23 to cultured human HeLa cells for 3 hours, it was found that HEC-23 specifically increased LAMP-1-positive lysosomes, but did not significantly affect Rab5-positive early endosomes and Rab7-positive endosomes. Late endosomes, such as attached figure 1 shown.

Embodiment 2

[0045] HeLa cells were transfected with mCherry-LAMP1 plasmid to specifically mark lysosomes, treated with 10 μM HEC-23 for 3 hours, then added 1 μM lysosome acidified fluorescent probe LysoSensor and stained for 30 minutes. Later, it was found that the LysoSensor staining in the enlarged lysosomes of HEC-23 was significantly reduced, indicating that the enlarged lysosomes could not be acidified normally, as shown in the attached figure 2 shown.

Embodiment 3

[0047] BODIPY pepstatin A can specifically bind to the activated lysosomal hydrolase cathepsin D, indicating the maturation of lysosomes. After HeLa cells were treated with 10 μM HEC-23 for 3 hours, BODIPY pepstatin A staining was added for 30 minutes, and the staining of BODIPYpepstatin A in the enlarged lysosomes of HEC-23 was significantly reduced, indicating that the enlarged lysosomes could not mature. image 3 shown.

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Abstract

The invention provides a method for constructing a chemical biological screening system. The method comprises the following steps: cultivating caenorhabditis elegans by using a 24-pore plate; settingdifferent experimental groups; wrapping the 24-pore plate with tin foil paper to keep away from light and prevent irradiation; putting into a shaking table and performing cultivation; after 48 or 72 hours, putting the cultivated caenorhabditis elegans into a glass slide, putting under a microscope and observing the change of the stable state of a lysosomal membrane in macrophage in the body cavityof the caenorhabditis elegans. The invention further provides a natural micromolecular compound as well as application thereof to preparation of a medicine for promoting lysosome mediated necrocytosis disease, wherein the natural micromolecular compound can promote lysosome mediated necrocytosis and is screened out according to the method for constructing the chemical biological screening system.

Description

technical field [0001] The present invention relates to the field of chemical biology, in particular to the field of biomedicine, in particular to a chemical biology screening system, and the use of a natural small molecular compound HEC-23 and its analogues for promoting lysosome-mediated cell necrosis. Background technique [0002] Lysosome is an acidic organelle (pH 4.5-5.0) with a single-membrane structure in the cell, and is an important place for intracellular material degradation and metabolic regulation. Lysosomal dysfunction leads to a variety of major human diseases, including lysosomal storage disorders (Lysosomal Storage Disorders, LSD), neurodegenerative diseases, metabolic diseases and tumors. The integrity of lysosomal membrane not only affects the function of lysosomal membrane proteins such as proton pump v-ATPase, but also plays an important role in maintaining the localization of hydrolases and the transport of substrates after degradation. Therefore, rev...

Claims

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Application Information

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IPC IPC(8): A61K49/00A61K33/24A61K31/55A61P35/00A61P35/02A01K67/033G01N33/50
CPCA01K67/033A61K31/55A61K33/24A61K49/0008A61P35/00A61P35/02G01N33/5055A61K2300/00Y02A50/30
Inventor 李洋张于郝小江杨崇林
Owner FUDAN UNIV
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