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Application of ritonavir as estrogen receptor modulator

A technology of estrogen receptor and ritonavir, which is applied in the field of medicine, can solve the problems of drug resistance and unsatisfactory effect, and achieve obvious curative effect

Inactive Publication Date: 2014-05-28
WUHAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, in many patients, the effect of these drugs is not satisfactory, that is, drug resistance and recurrence occur. Carlos Caldas, a researcher at the University of Cambridge in the United Kingdom, said that about one-third of breast cancer patients are indifferent to him. Drugs such as xifen are resistant, and 50% of patients relapse (Bertone et al., Lancet, (2005), 365:101-102), so more estrogen receptor modulators need to be discovered for different drug-resistant patients to choose , improve the therapeutic effect and prolong the life of patients

Method used

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  • Application of ritonavir as estrogen receptor modulator
  • Application of ritonavir as estrogen receptor modulator
  • Application of ritonavir as estrogen receptor modulator

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] [Example 1] The inhibitory effect of ritonavir on tumor cells is partially dependent on estrogen receptor

[0048] Breast cancer cells MDA-MB-231 and MCF-7 cells were purchased from the Shanghai Cell Bank of the Chinese Academy of Sciences. MCF-7 is an estrogen receptor-positive cell, and MDA-MB-231 is an estrogen receptor-negative cell. MDA-MB-231 cells were cultured in RPMI-1640 (HyClone, Logan, UT, USA) with 10% fetal bovine serum (FBS) (HyClone, Logan, UT, USA) and 100 U / mL penicillin and 100 μg / mL Streptomycin, cultured at 37°C and 5% carbon dioxide. MCF-7 cells were cultured in MEM medium containing 10% FBS, 100 U / mL penicillin and 100 μg / mL streptomycin. 12 hours before administration, change to phenol red-free-MEM medium (Wuhan Boster Bioengineering Co., Ltd.) containing 10% fetal bovine serum (FBS) (HyClone, Logan, UT, USA) to exclude the effect of phenol red on estrogen Stimulation of receptors interferes.

[0049] MCF-7 and MDA-MB-231 cells in the logarit...

Embodiment 2

[0050] [Example 2] Ritonavir down-regulates the protein expression level of estrogen receptor of α subtype

[0051] The effect of ritonavir on the expression level of estrogen receptor protein was studied by western blotting. After MCF-7 cells were treated with 15 μM ritonavir for 24 hours, 200 μL of frozen lysate (containing 150 mM sodium chloride, 1% Triton X-100 and 50 mM Tris-hydrochloric acid, pH 8.0) was added. Cells were cultured in parallel after adding ritonavir-free solvent in MEM without phenol red as a blank control. Sonicate the lysate (pulse 3 with intervals of 5 seconds), add electrophoresis sample buffer at a ratio of 1:1, boil at 100 °C for 5 minutes, centrifuge at 12,000 g for 2 minutes, collect supernatant, 12% sodium lauryl sulfate polypropylene Amide gel electrophoresis (SDS-PAGE) separation. The protein was transferred from the gel to a nitrocellulose membrane, and the membrane was washed with Tris and Tween 20 buffer (TBST). The membrane was incubated...

Embodiment 3

[0052] [Example 3] Real-time fluorescence quantitative PCR analysis to study the impact of ritonavir on the level of estrogen receptor mRNA

[0053] MCF-7 cells were treated with 15 μM RTV (ritonavir) for 24 hours, the total RNA in the cells was extracted with TRIzol reagent (Invitrogen, USA), and the recovered RNA was quantitatively detected by measuring the ratio of optical density at 280 nm to 260 nm. 1‰ sulfoxide treatment group was used as blank control. Four micrograms of RNA were used for cDNA synthesis using the First Strand Synthesis Kit (RT Kit) (Fermentas, LTU). The specific primer sequence is as follows: Forward primer of human α subtype estrogen receptor 5′-CCACCAACCAGTGCACC-

[0054] ATT-3' (SEQ ID NO.1), reverse primer 5'-GGTCTTTTTCGTATCCCACCCTTTC-3'

[0055] (SEQ ID NO.2), the amplified product is 108 bp; the forward primer of human GAPDH 5′-ACCCACTCCT-

[0056] CCACCTTTG-3' (SEQ ID NO.3), reverse primer 5'-CTCTTGTGCTCTTGCTGGG

[0057] -3' (SEQ ID NO.4), th...

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Abstract

The invention discloses novel applications of ritonavir, and metabolite thereof and / or a metabolite derivative and / or a structural analogue of ritonavir as an estrogen receptor modulator. An inhibition effect of ritonavir to tumor cells is partially depended on an estrogen receptor. Ritonavir down-regulates protein expression level and gene transcription level of an alpha subtype estrogen receptor of the tumor cells; ritonavir inhibits F promoter activity of the alpha subtype estrogen receptor; interactive experiments of rotonavir and the alpha subtype estrogen receptor-ligandb inding domain demonstrate that ritonavir is a selective antagonist of the alpha subtype estrogen receptor, belongs to the estrogen receptor modulator, and can bind the estrogen receptor and modulate transcription and expression level of the estrogen receptor, thereby generating effects of inhibiting growth of the tumor cells and increasing cell mortality rate. Reposition of conventional drugs can reduce risks and reduce research cost. The drug is expected to be used for preparing tumor-treating drugs for drug resistance and chemotherapy resistance of conventional antitumor drugs.

Description

[0001] technical field [0002] The present invention relates to the field of medicine, more specifically to ritonavir, ritonavir metabolites and / or ritonavir metabolite derivatives and / or ritonavir structural analogues as estrogen receptor regulators new uses of agents. Background technique [0003] Ritonavir (RTV) is an orally effective inhibitor of human immunodeficiency virus-1 (HIV-1) and human immunodeficiency virus-2 (HIV-2) aspartic proteases, blocking the enzyme to promote the formation of morphological The polyprotein required for biologically mature HIV particles keeps HIV particles in an immature state, thereby slowing down the spread of HIV in cells to prevent new rounds of infection and delay the development of the disease. [0004] In recent years, it has been reported that ritonavir can inhibit lung cancer and ovarian cancer (Sato et al., Int J Oncol, (2012), 41(1):46-52; Kraus et al., Blood Cancer Journal, (2013), 3, e103; Anjaiah et al., J Thorac Oncol, (...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/426A61K31/427A61P35/00A61P5/30
Inventor 项瑾杨芳魏蕾郑忠亮张京伟王莹胡鹏超苏可
Owner WUHAN UNIV
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