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Application of 3,4 cleavage cyclic altine triterpenoids in the preparation of autophagy inhibitors and antitumor drugs

An antineoplastic drug, cycloaltin-type technology, applied in the field of medicine, to achieve the diversification of dosage forms and administration methods, wide clinical application prospects, and the effect of inhibiting the growth of tumor cells

Active Publication Date: 2022-07-01
KUNMING INST OF ZOOLOGY CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Schisandra chinensis contains a large number of 3,4-broken ring Altin-type triterpenoids, and there is no report on their autophagy inhibition

Method used

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  • Application of 3,4 cleavage cyclic altine triterpenoids in the preparation of autophagy inhibitors and antitumor drugs
  • Application of 3,4 cleavage cyclic altine triterpenoids in the preparation of autophagy inhibitors and antitumor drugs
  • Application of 3,4 cleavage cyclic altine triterpenoids in the preparation of autophagy inhibitors and antitumor drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] The 3,4-cleavage cyclic Altin-type triterpenoid black schisandrin inhibits the ubiquitination of the autophagy receptor p62.

[0054] (1) Detection of p62 ubiquitination in vitro: ATP, HA-Ub, E1 ubiquitin-activating enzyme UbE1, E2 ubiquitin-conjugating enzyme UbcH5b, E3 ubiquitin ligase HECTD3 and their substrates were sequentially added to the reaction buffer. p62 (with His tag), different concentrations (5 μM, 10 μM, 20 μM) of black schisandrin were added, DMSO was added as a positive control, and ATP was not added as a negative control, and the reaction was performed at 37°C for 40 minutes. After incubation with nickel column overnight, the ubiquitination of p62 was detected by Western Blot after sufficient elution.

[0055] The result is as Figure 1A shown, 20 μM black schisandrin significantly inhibited the ubiquitination of p62 compared to the negative and positive controls.

[0056] (2) Detection of intracellular p62 ubiquitination: p62-Flag, HECTD3 or HECTD3C...

Embodiment 2

[0059] The 3,4-cleavage cyclic altine-type triterpenoid black schisandrin inhibits lapatinib-induced autophagy.

[0060] (1) MDA-MB-468 cells were seeded at a density of 8,000 cells / well in a 24-well culture plate with glass slides in advance. After the cells were completely adherent, the GFP-LC3 plasmid was transfected, and 24 hours later, lapatinib was added respectively. Nitrile (10μM), black schisandrin (20μM) and their combination (10μM lapatinib and 20μM black schisandra) were treated for 4 hours (DMSO was also used as a control group), and fixed with 4% paraformaldehyde for 1 hour , immerse the slides in PBS for 3 times, then seal the slides with DAPI-containing blocking solution, and finally observe the GFP-LC3 fluorescent spots under a fluorescence microscope, and quantitatively calculate the number of GFP-LC3 fluorescent spots.

[0061] The experimental results see Figure 2A and 2B , it can be seen from the figure: the number of fluorescent spots in the lapatinib ...

Embodiment 3

[0065] The 3,4-fragmented cyclic Altin-type triterpenoid black schisandrin inhibits cisplatin-induced autophagy.

[0066] (1) Inoculate MDA-MB-468 cells at a density of 8,000 cells / well in a 24-well culture plate pre-placed with glass slides, and transfect GFP-LC3 plasmid after the cells are completely adherent, and add black schisandrin 16 hours later. (20μM), cisplatin (5μM) and their combination (20μM black schisandrin and 5μM cisplatin) for 4 hours (DMSO was set as a control group), fixed with 4% paraformaldehyde for 1 hour, and immersed in PBS The slides were repeated three times, and then sealed with DAPI-containing blocking solution. Finally, the GFP-LC3 fluorescent spots were observed under a fluorescence microscope, and the number of GFP-LC3 fluorescent spots was quantitatively calculated.

[0067] The experimental results see Figure 3A and 3B , the results showed that the number of fluorescent spots increased significantly in the cisplatin-treated group, indicatin...

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Abstract

The present invention discloses new uses of 3,4-fragmented cyclic altine-type triterpenoids, the compounds are black schisandrin or southern schisandra, including for preparing autophagy inhibitor, preparing for increasing antitumor drug treatment A sensitive drug, the compound can inhibit the ubiquitination modification of autophagy receptor p62, prevent the activation of p62 autophagy receptor function, and can inhibit the protective autophagy of tumor cells induced by anti-tumor drugs, and the present invention also provides An anti-tumor drug composition, including 3,4-fragmented cyclic altine-type triterpenoids and anti-tumor drugs that easily induce tumor cell protective autophagy, can inhibit tumor cell growth and promote tumor cell death, and can be used for Treatment of cancers such as breast cancer.

Description

technical field [0001] The invention belongs to the technical field of medicine; in particular, it relates to the application of a 3,4-fragmented cycloaltin-type triterpenoid in the preparation of autophagy inhibitors and antitumor drugs. Background technique [0002] Autophagy is a highly conserved catabolic process in cells that is mainly divided into four stages: the formation of autophagic vesicle precursors, the formation and extension of autophagosome membranes, lysosomal closure fusion and intravesicular degradation, which function by Degradation of damaged proteins or organelles maintains cellular homeostasis. According to the different ways in which intracellular substrates are transported to the lysosome cavity, mammalian autophagy can be divided into three main ways: macroautophagy, microautophagy and molecular chaperone-mediated autophagy. Macroautophagy. Autophagy can help tumor cells cope with oxidative stress and DNA damage caused by starvation, hypoxia and ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/194A61P35/00
CPCA61K31/194A61P35/00
Inventor 陈策实普诺·白玛丹增孙汉董黄茂波周元飞
Owner KUNMING INST OF ZOOLOGY CHINESE ACAD OF SCI
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