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Application of substance for inducing IRF8 expression in preparation of medicine for treating disease due to abnormal expression of androgen acceptor

An androgen receptor, substance technology, applied in the field of medicine

Active Publication Date: 2018-06-15
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The purpose of the present invention is to address the current problem of androgen receptor drug resistance, and to provide the application of substances that induce IRF8 expression in the preparation of drugs for the auxiliary treatment of diseases caused by abnormal expression of androgen receptor

Method used

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  • Application of substance for inducing IRF8 expression in preparation of medicine for treating disease due to abnormal expression of androgen acceptor
  • Application of substance for inducing IRF8 expression in preparation of medicine for treating disease due to abnormal expression of androgen acceptor
  • Application of substance for inducing IRF8 expression in preparation of medicine for treating disease due to abnormal expression of androgen acceptor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Example 1 Immunohistochemistry

[0066] Fresh prostate cancer and benign prostatic hyperplasia tissues were collected from Jiangsu Provincial Hospital of Traditional Chinese Medicine. After quick freezing in liquid nitrogen, paraffin sections were prepared. Prostate cancer tissue chips (HPro-Ade180PG-02, 180 points) were purchased from Shanghai Xinchao Company and commissioned for immunohistochemistry Detect the expression of IRF8, and invite senior pathologists to interpret the immunohistochemical results:

[0067] (1) Judgment of staining positive rate: First, observe the tissue point in the entire field of view under a low-magnification microscope, and then select 3 fields of view with different staining intensities for interpretation under a high-power microscope. Randomly record 100 cells in one field of view, and then record the percentage of positive cells in the 100 cells X1%. After looking at the percentages of positive cells in the other two fields of view, X2...

Embodiment 2

[0077] 2.1 DHT can up-regulate the expression of IRF8

[0078]As the ligand of AR, androgen plays a crucial role in the growth and malignant transformation of prostate cancer cells mediated by AR. Abnormal activation of the Androgen-AR signaling pathway is common in the development of prostate cancer. We found that with the increase of the pathological grade of prostate cancer, the expression of IRF8 increased, and the expression of IRF8 was positively correlated with the expression of AR. These studies suggest that there is a link between IRF8 and AR. Studies have shown that a group of ISG proteins in prostate cells can also be regulated by androgen as androgen-stimulated genes. In this example, we detected whether the expression of IRF8 was regulated by the AR signaling pathway. The AR-positive prostate cancer cell line LNCaP was pretreated with 5% carbon-adsorbed serum C-FBS for 24 hrs, and then stimulated with 10 nM DHT for 24 hrs to detect the expression of IRF8 by imm...

Embodiment 3

[0081] Example 3 LNCaP cells knock down IRF8 expression and accelerate cell proliferation

[0082] 3.1 Design and construction of IRF8 knockout cell lines LNCaP-shNC, LNCaP-shRNA1, LNCaP-shRNA2.

[0083] 3.1.1 Design of Oligo

[0084] DNA oligo was designed using Designer3.0 (Genepharma) software, and the primers were synthesized by Shanghai Gemma Pharmaceutical Technology Co., Ltd. The loop structure in the LV3-shRNA template uses TTCAAGAGA to avoid the formation of termination signals. The 5' end of the sense strand contains GATCC, which is complementary to the sticky end formed after BamHI digestion; the 5' end of the antisense strand contains AATTC, which is complementary to the sticky end formed after EcoRI digestion.

[0085] Sense strand: 5'-GATCC-(GN18)-(TTCAAGAGA)-(N18C)-TTTTTTG-3'

[0086] Antisense strand: 3'-G(CN18)-(AAGTTCTCT)-(N18G)-AAAAAACTTAA-5'

[0087] Table 3 Designed DNA Oligo

[0088]

[0089]

[0090] 3.1.2 Annealing of LV3-shDNA template

[0...

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Abstract

The invention discloses an application of a substance for inducing IRF8 expression in preparation of a medicine for treating disease due to abnormal expression of an androgen acceptor. The IRF8 can directly adjust the cell proliferation of prostate cancer and liver cancer, IRF8 expression can adjust the sensitivity of the prostate cancer cell on an AR antagonist Enz, and IRF8 knock-down can tolerate the apoptosis due to prostate cancer cell on Enz. The substance for inducing IRF8 expression such as IFNalpha can up-regulate the IRF8 expression through AR, and participates the adjusting of the prostate cancer cell on the Enz sensitivity. During clinical test, an IFN alpha combined maximum androgen blockout endocrine therapy can enhance the curative effect for the prostate cancer patients. The substance for inducing IRF8 expression can combine with an androgen acceptor antagonist to enhance the of the androgen acceptor antagonist by clinical IRF8 expression low patient, increases the curative effect of the androgen acceptor antagonist, and prolongs the drug-resistant generation.

Description

technical field [0001] The invention belongs to the field of medicine, and relates to the application of substances that induce IRF8 expression in the preparation of medicines for treating diseases caused by abnormal expression of androgen receptors. Background technique [0002] In European and American countries, prostate cancer is the second most common male malignant tumor in terms of incidence and mortality. Although the incidence of prostate cancer in my country is lower than that in western countries, it is increasing significantly with the change of lifestyle and the aging of the population. trend. It is estimated that by 2020, the incidence of prostate cancer will be as high as 40 / 100,000, and the annual new cases will reach 350,000, which is equivalent to the incidence of liver cancer. [0003] The initial prostate cancer is hormone-dependent. At that time, endocrine therapy is sensitive, the symptoms of prostate cancer improve, and the disease process is delayed. ...

Claims

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Application Information

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IPC IPC(8): A61K45/00A61K45/06A61K38/21A61P1/16A61P13/08A61P35/00
CPCA61K38/212A61K45/00A61K45/06A61K2300/00
Inventor 杨勇吴红茜赵志立李岩高晓芳赵伟毛杰
Owner CHINA PHARM UNIV
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