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Application of acyl-coenzyme A: cholesterol acyltransferase-2 (ACAT2) inhibitor in liver cancer growth inhibition

A cholesterol acyl and acyl coenzyme technology, applied in the fields of biomedicine and pharmacy, can solve the problems of unsuccessful liver cancer intervention and unclear molecular mechanism of liver cancer.

Active Publication Date: 2014-01-29
CENT FOR EXCELLENCE IN MOLECULAR CELL SCI CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Based on long-term epidemiological investigations, although it is relatively clear that chronic hepatitis infection, excessive alcohol intake, and aflatoxin from food sources may cause liver cancer, the specific molecular mechanism of liver cancer development is still unclear , and interventions against liver cancer have not been successful

Method used

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  • Application of acyl-coenzyme A: cholesterol acyltransferase-2 (ACAT2) inhibitor in liver cancer growth inhibition
  • Application of acyl-coenzyme A: cholesterol acyltransferase-2 (ACAT2) inhibitor in liver cancer growth inhibition
  • Application of acyl-coenzyme A: cholesterol acyltransferase-2 (ACAT2) inhibitor in liver cancer growth inhibition

Examples

Experimental program
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Effect test

Embodiment 1

[0136] High expression of ACAT2 in human liver cancer tissues is associated with accumulation of cholesterol metabolites

[0137] In this example, the inventors used 19 pairs of cancer tissues and paracancerous tissues of liver cancer patients to first detect the mRNA level of ACAT2 gene and perform statistical analysis.

[0138] The results showed that, compared with the adjacent tissue cells, the mRNA level of ACAT2 gene in liver cancer tissue cells was significantly increased ( figure 1 A). Next, the levels of cholesterol metabolites in liver cancer and adjacent tissue cells were detected. The results showed that the levels of cholesterol metabolites in 6 pairs of liver cancer tissues were significantly higher than those in adjacent tissues ( figure 1 B).

[0139] The above results indicated that the high expression of ACAT2 gene in liver cancer tissues was related to the accumulation of cholesterol metabolites.

Embodiment 2

[0141] ACAT2 is involved in the secretion and efflux of cholesterol metabolites in hepatocellular carcinoma cells

[0142] In order to study the role of ACAT2 in the metabolism of cholesterol metabolites in liver cancer cells, the inventors detected intracellular and secreted cholesterol metabolites (27- and 24-hydroxycholesterol) in the liver cancer cell line Huh7 under the condition of exogenously delivering high amounts of cholesterol metabolites (27- and 24-hydroxycholesterol). Extracellular cholesterol metabolite content. After the lipoprotein secreted by Huh7 cells was separated by FPLC, the content of cholesterol metabolites was detected by GC-MS.

[0143] The results showed that the liver cancer cells Huh7 could secrete three kinds of lipoproteins (named VLDLI, VLDLII and HDL in turn), and the determination of the total cholesterol content showed that the cholesterol was mainly distributed in the VLDLII component ( figure 2 A); Furthermore, the treatment of ACAT2 inh...

Embodiment 3

[0146] Combination of ACAT2 inhibitors and cholesterol metabolites can inhibit the growth of liver cancer cells

[0147] In this example, the inventors studied the role of ACAT2 inhibitors in inhibiting the growth of liver cancer cells.

[0148] The results of growth experiments showed that ACAT2 inhibitor had little effect on the growth of Huh7 cells under the condition of no exogenous delivery of cholesterol metabolites; while under the condition of exogenous delivery of mixture of cholesterol metabolites 27- and 24-hydroxycholesterol, with With the increase of its concentration (2× to 4×), cholesterol metabolites significantly inhibited the growth of Huh7 cells, and the combination with ACAT2 inhibitors significantly increased the inhibitory effect of cholesterol metabolites on the growth of Huh7 cells ( image 3 A).

[0149] Analysis of the content of cholesterol metabolites in Huh7 cells showed that under the condition of exogenous delivery of a mixture of cholesterol me...

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Abstract

The invention relates to application of an acyl-coenzyme A: cholesterol acyltransferase-2 (ACAT2) inhibitor in liver cancer growth inhibition. Concretely, the inhibition of the activity of the ACAT2 can effectively inhibit the growth of human liver cancer cells and transplanted tumors respectively in cellular and animal levels, and the inhibitory effect is generated through accumulating intracellular cholesterol metabolites by blocking the secretion and excretion of ACAT2-mediated cholesterol metabolites. The accumulation of the cholesterol metabolites has effects on promoting the apoptosis of liver cancer cells and inhibiting the growth of liver cancer; the excretion of the cholesterol metabolites can remove the inhibitory effect.

Description

technical field [0001] The invention belongs to the fields of biomedicine and pharmacy, and particularly relates to the application of an acyl-CoA:cholesterol acyltransferase-2 inhibitor in inhibiting the growth of liver cancer. Background technique [0002] The liver is the center of cholesterol metabolism in the body and plays a vital role in maintaining the balance of cholesterol metabolism in the body. The liver can produce a large amount of cholesterol through de novo synthesis; extrahepatic tissues must transport harmful excess cholesterol metabolites and cholesterol to the liver for metabolism through the cholesterol reverse transport (RCT, Reverse Cholesterol Transportation) pathway, degrade them into bile acids, and assemble lipoproteins Wait. The liver can also assemble esterified neutral cholesteryl esters into lipoproteins and secrete them into the blood to provide sufficient cholesterol for the life activities of extrahepatic tissues. [0003] The level of int...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61K31/4433A61P35/00C12Q1/02C12N5/09
Inventor 李伯良鲁明胡西旵李琴熊缨杨新颖宋保亮胡光晶许佳佳赵晓楠
Owner CENT FOR EXCELLENCE IN MOLECULAR CELL SCI CHINESE ACAD OF SCI
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