Application of triptophenolide as androgen receptor antagonist

A technology of androgen receptor and trefenolactone, applied in the field of application of tripterygium twig root extract trefenolactone as an androgen receptor antagonist, can solve the problems of promoting the growth of prostate cancer cells and affecting the curative effect, etc. To achieve the effect of contraceptive effect

Active Publication Date: 2016-04-20
MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the problem of drug resistance developed during treatment seriously affect

Method used

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  • Application of triptophenolide as androgen receptor antagonist
  • Application of triptophenolide as androgen receptor antagonist
  • Application of triptophenolide as androgen receptor antagonist

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Example 1 Tripterygium wilfordii monomer trefenolactone can inhibit the activity of wild-type androgen receptor

[0033] will be 1.4×10 5PC-3 cell suspension per mL was inoculated in a 24-well plate at 500 μL per well. When the cells grew to 80%, each well was co-transfected with 100ngPSA-luc, 20ngAR-WT and 1ngpCMV-Renilla plasmids. 6 hours after transfection, the medium was replaced with phenolred-free RPMI1640 medium containing 10% charcoal-stripped FBS; 24 hours after transfection, one group was added with 1 nM DHT + corresponding concentrations of refenolactone or enzalutamide in each well 1 μL, the other group was added 1 μL of DMSO or corresponding concentrations of rafenolactone or enzalutamide to each well, and continued to culture for 24 hours. Finally, suck off the medium, add 100 μL of 1×PLB to each well to lyse for 20 minutes, collect the cell lysate into a clean EP tube, centrifuge, take 20 μL of the supernatant into a clean white 96-well plate, and follo...

Embodiment 2

[0035] Example 2 Tripterygium wilfordii monomer trefenolactone can inhibit the activity of endogenous androgen receptor

[0036] There may be overexpression of androgen receptor due to exogenous expression, and false positive results may be caused by the plasmid transfection process. Therefore, we carried out the experiment that refenolide inhibits the activity of endogenous androgen receptor. The specific experimental steps refer to Example 1, the difference is that: LNCaP and 22RV1 cells were used for this experiment respectively, co-transfection was 100ngPSA-luc and 1ngpCMV-Renilla plasmid per well, and other operations were the same. Three parallel groups were set up in the experiment, and statistical analysis was carried out, where *P△ P△△ P expressed, and used GraphPadPrism5.0 to draw (see figure 2 ) and statistical analysis.

[0037] Refenolide has a dose-dependent inhibitory effect on the transcriptional activity of endogenous AR in LNCaP and 22RV1, and this inhibit...

Embodiment 3

[0040] Example 3 Refenolactone Can Inhibit the Activity of T877A Mutant Androgen Receptor

[0041] At present, some series of AR mutations have been discovered, including tryptophan (W) → leucine (L) or cysteine ​​(C) at position 741, threonine (T) → alanine at position 877 amino acid (A), 876 phenylalanine (F) → leucine (L). Among them, the W741C mutation is the main cause of bicalutamide resistance, and the T877A mutation is the main cause of flutamide resistance. The specific experimental steps refer to Example 1, the difference is that the AR-WT is replaced by the AR-T877A mutant plasmid during co-transfection, and other operations are the same. Three parallel groups were set up in the experiment, and statistical analysis was carried out, where *P△ P△△ P△△△ P ±s, and use GraphPadPrism5.0 to draw (see image 3 ) and statistical analysis.

[0042] The experimental results showed that refenolide also had a good inhibitory effect on the transcriptional activity of the T877A...

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Abstract

The invention relates to the field of traditional Chinese medicine extract, and particularly discloses application of tripterygium wilfordii root extract triptophenolide (CAS number:74285-86-2) as an androgen receptor antagonist and application of triptophenolide to preparation of drugs for treating androgen disorders and drugs for male contraception. A reliable androgen activity screening method is constructed, the inhibiting effect of various kinds of traditional Chinese medicine extract on androgen receptor activity is tested, and finally it is found that the tripterygium wilfordii root extract triptophenolide is a novel androgen receptor antagonist and can inhibit activity of wild type and mutability androgen receptors. Further, anti-prostrate-cancer activity of triptophenolide is tested, and it is found that triptophenolide has good activity for AR (androgen receptor) positive prostrate cancer cells such as LNCaP and 22 RV1.

Description

technical field [0001] The invention relates to the field of traditional Chinese medicine extracts, in particular to the application of tripterygium twig root extract trefenolactone as an androgen receptor antagonist. Background technique [0002] Androgen, such as androsterone (Testosterone, T), dihydrotestosterone (Dihydrotestosterone, DHT) and adrenal androsterone, is an important class of steroidal sex hormones in the human body. , AR) combine to promote cell differentiation and tissue growth, and participate in many key physiological functions. A certain percentage of androgens are present in both men and women. In the prostate and skin, androsterone T is converted to DHT by 5α-reductase, and compared with T, the affinity of DHT for AR is 3-5 times higher. [0003] AR, a member of the nuclear receptor superfamily, is a ligand-activated transcription factor widely distributed in proliferating and non-proliferating tissues. AR protein has three structural domains: N-te...

Claims

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Application Information

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IPC IPC(8): A61K31/585A61P5/28A61P13/08A61P15/16A61P35/00A61P15/00A61P17/10A61P17/08A61P17/14A61P17/00
CPCA61K31/585
Inventor 周金明何阳李晓宇岑山
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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