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Applications of dopamine I receptor agonists in preparing tumor treatment medicines

A receptor agonist and tumor treatment technology, applied in the field of biomedicine, can solve the problems of accelerating cells, cell necrosis, death, etc., and achieve the effect of inhibiting growth

Inactive Publication Date: 2017-07-07
RUIJIN HOSPITAL AFFILIATED TO SHANGHAI JIAO TONG UNIV SCHOOL OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Reactive oxygen species (reactive oxygen species, ROS) is a kind of toxic substances that damage cells. Recent studies have found that ROS, as a signaling molecule, participates in multiple physiological processes such as cell proliferation, differentiation and apoptosis; ROS, especially mitochondrial sources Sexual ROS, as a signaling molecule, participates in the regulation of autophagy, leading to cell survival or death in different environments; the increase of ROS can lead to the opening of mitochondrial membrane permeability transport pore (MPT), and the opening of MPT causes mitochondrial transmembrane potential (Δψm) decreases, cytochrome C is released, and then activates a series of caspase enzymes to induce apoptosis; excessive ROS in cells induces apoptosis, and a large amount of ROS will cause cell necrosis, of course, in the same tissue Necrosis and apoptosis can also occur at the same time, and the shift from apoptosis to necrosis is determined by the content of ROS in tumor cells; it has been reported in the literature that chronic stimulation of D1 receptors, such as SKF38393, can lead to an increase in neuronal NOS, Thus accelerating cell death; however, the research mechanism of tumor cell death due to the increase of ROS caused by DRD5 activation has not been reported; whether SKF83959 has the effect of inhibiting tumor growth has not been reported yet

Method used

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  • Applications of dopamine I receptor agonists in preparing tumor treatment medicines
  • Applications of dopamine I receptor agonists in preparing tumor treatment medicines
  • Applications of dopamine I receptor agonists in preparing tumor treatment medicines

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] Example 1 SFK83959 inhibits cell line growth experiment

[0018] Experimental Materials:

[0019] Rat pituitary tumor cell lines GH3 and MMQ (purchased from ATCC), and human primary pituitary adenoma cells (removed from surgery and placed in culture medium directly for culture) were incubated at 37°C and 5% CO 2 Under normal conditions, the culture medium is DMEM / F12 (Gibco) containing 2.5% fetal bovine serum (Gibco) plus 12.5% ​​horse serum. N2A cells and other malignant tumor cells (U87, U66, U251, SCG7901, SW480, hepG2) (Chinese Academy of Sciences) at 37 ° C, 5% CO 2 Under conventional conditions, the culture medium is DMEM (Gibco) medium containing 10% fetal bovine serum (Gibco). Dopamine type 1 receptor agonists SKF83959 and SKF38393 were purchased from Tocris (UK), the mother solution 50mM was prepared from DMSO (sigma), and the MTS assay reagent for cell viability was purchased from Promega (USA).

[0020] experimental method:

[0021] 1. MTS assay to detect...

example 2

[0039] Example 2. Nude mice xenograft tumor model experiment

[0040] Experimental Materials:

[0041] Nude mice were purchased from SLAC (Shanghai), and the rest were the same as in Example 1.

[0042] experimental method:

[0043] 1) Select 4-week-old nude mice;

[0044] 2) Collect the logarithmically grown tumor cells, use 10 ml of serum-free medium, centrifuge at 1000 rpm for 3 minutes, wash continuously for 3 times, and finally resuspend the tumor cells with serum-free medium, and adjust the density to 1×10 7 Cells / ml, each nude mouse was inoculated with 100ul (i.e. 1×10 6 tumor cells), the tumor can be palpable in the armpit of nude mice in about 4 days;

[0045] 3) When the tumor volume grows to about 100mm 3 Timely divided into DMSO and SKF83959 groups, given SKF83959 (1mg / kg) intraperitoneal injection, each nude mouse body weight is about 20g, each nude mouse intraperitoneal injection amount is 1μl of SKF83959 (50mM)+99μl normal saline, administered once a day, ...

Embodiment 3

[0047] Example 3, SKF83959 induces autophagy by inhibiting the mTOR pathway

[0048] Experimental Materials:

[0049] RIPA Lysis Solution, PMSF, Loading Buffer (5×), BCA Protein Quantification Kit, and DAPI were purchased from Beyontien Biotechnology Research Institute (Jiangsu); Protease Inhibitor Cocktail was purchased from Merck (Germany). BSA was purchased from sigma (9048-46-8). PBS, 0.5% Trypsin-EDTA were purchased from Gibco. Antibody: Antibody LC3(sigma L7543), Antibody GAPDH(Huaan ARH4156), Antibody PARP(CST#9542), Antibody p-4EBP1(CST#2855), Antibody p-mTOR(CST#5536), Anti-rabbit IgG(CST 14708), Anti-rabbit IgG-Peroxidase antibody (sigma A0545); strong chemiluminescence kit was purchased from Bio-rad company.

[0050] experimental method:

[0051] 1) GH3 cells were suspended in conventional medium, and the cell density was adjusted to 4×10 5 The cells / well were inoculated in 6-well culture plates and adhered overnight, each well contained 2ml of culture medium, ...

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Abstract

The invention belongs to the technical field of biological medicines, relates to novel medicinal applications of dopamine I receptor agonists, and in particular relates to novel applications of the dopamine I receptor agonists in preparing tumor treatment medicines. The dopamine I receptor agonists comprise DRD1 and DRD5 agonists, and are selected from SKF83959 or SKF38393 compounds. The cell culture and drug intervention experiments prove that the dopamine receptor agonist SKF83959 can inhibit the mTOR pathway for inducing autophagy, and increase ROS for prompting the cell death from the in-vitro and in-vivo levels, so that the growth of benign or malignant tumor can be inhibited. The dopamine I receptor agonists SKF83959 and SKF38393 can be used for preparing the medicines for treating tumors, wherein the tumors comprise the benign tumour including pituitary adenoma and the malignant tumors including malignant glioma, colon cancer, liver cancer, stomach cancer and the like.

Description

technical field [0001] The invention belongs to the technical field of biomedicine and relates to a new medicinal application of a dopamine type 1 receptor agonist, in particular to a new application of a dopamine type 1 receptor agonist in preparing tumor treatment drugs. Background technique [0002] According to the information released by the National Bureau of Statistics, the annual incidence of malignant tumors in my country is 3.5 million people. For this huge population, even if they receive comprehensive treatment of surgery + radiotherapy and chemotherapy, the disability rate and mortality rate are extremely high. It endangers the life and quality of life of patients; on the other hand, it also brings great economic pressure and pressure on medical resources to the country and patients' families. For example, the clinical practice shows that the malignant glioma of the brain has an average survival rate of 14.6 months after the current internationally recommended st...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61K31/55A61P35/00
CPCA61K31/55A61K45/00
Inventor 吴哲褒冷志根林绍坚吴泽睿赵卫国
Owner RUIJIN HOSPITAL AFFILIATED TO SHANGHAI JIAO TONG UNIV SCHOOL OF MEDICINE
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