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EGFR-TKIs for overcoming drug resistance of non-small cell lung cancer and combined medication scheme

A technology of drug resistance and regimen, applied in the direction of drug combination, pharmaceutical formula, anti-tumor drugs, etc., can solve the problems that the anti-tumor mechanism has not been fully elucidated

Inactive Publication Date: 2018-05-29
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In recent years, studies have found that statins have an inhibitory effect on tumor cells, but the anti-tumor mechanism has not been fully elucidated

Method used

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  • EGFR-TKIs for overcoming drug resistance of non-small cell lung cancer and combined medication scheme
  • EGFR-TKIs for overcoming drug resistance of non-small cell lung cancer and combined medication scheme
  • EGFR-TKIs for overcoming drug resistance of non-small cell lung cancer and combined medication scheme

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0015] Embodiment 1.MTT experiment

[0016] experimental method:

[0017] PC-9 / GR and H1975 cells were seeded in 96-well cell culture plates. When the cell density reached 80%, a series of doses of MβCD were given to act on the cells for 40-50 minutes, and then discarded, and then different concentrations of gefitinib were added. Act for 48 hours; or give lovastatin, gefitinib and combined administration group, treat for 72 hours; then carefully aspirate the medium, add 150ul of DMEM medium containing 15ul of MTT solution per well, 37°C, 5% CO 2 After culturing in the incubator for 4 hours, take it out, discard it by suction, then add 150ul DMSO, shake it at 37°C, 350rpm, and place it in a microplate reader (measurement wavelength 570nm) for 15min to measure its absorbance. The cell survival rate of the administration group was calculated by the following formula:

[0018] Inhibition rate=(1-(absorbance of treatment group-absorbance of blank group) / (absorbance of control gro...

Embodiment 2

[0019] Embodiment 2.Western Blot experiment

[0020] experimental method:

[0021] PC-9 / GR and H1975 cells were inoculated in the Cell culture dish, and when the cell density reached 80%, MβCD was used to remove intracellular cholesterol or cholesterol was used to restore cholesterol, and then gefitinib was given; or lovastatin, Gefitinib and combined administration group, after treatment for different time; PBS washed cells once, placed on ice plate, scraped the cells with a cell scraper to collect, centrifuged at 8000rpm×1min to obtain cell pellets, each 10μL cell pressure Add 100 μL RIPA cell lysate to the agarose, lyse on ice for 30 min, ultrasonicate 5 times, 2 s each time, and centrifuge at 15,000 rpm×10 min to obtain the supernatant, which is the extracted total protein sample. Protein content was determined by BCA method. The protein sample was added to the loading buffer at a volume ratio of 3:1 and boiled for 5 min. Prepare 8%-12% SDS-PAGE, and separate the sample...

Embodiment 3

[0022] Example 3. Immunofluorescence experiment

[0023] PC-9 / GR and H1975 cells were digested and passaged and inoculated on special confocal glass-bottom culture dishes. After the cells grew to 50% density, they were treated with MβCD, cholesterol or cholesterol-lowering drug lovastatin, and blank control was used to administer the cells After the end, wash once with pre-cooled PBS, fix with 4% paraformaldehyde at 4°C for 20min, add 10μM fluorescently labeled gefitinib backbone for 3h, then incubate with nuclear dye DAPI at room temperature for 25min, wash 4 times with TBST, 5min each time , Zeiss confocal microscope LSM800 took pictures for analysis and exported pictures.

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Abstract

The invention relates to the field of clinical overcoming of drug resistance of tumors and combined medication, in particular to EGFR-TKIs which can overcome the drug resistance of non-small cell lungcancer by lowering cholesterol. Statins can enhance the antitumor efficacy of EGFR-TKIs. The invention discloses the fact that MbetaCD is used for removing cholesterol from human non-small cell lungcancer cell lines PC-9 / GR and H1975 to enhance the efficacy of gefitinib in resisting the non-small cell lung cancer, enhance the inhibition to signal pathways and enhance the affinity of EGFR and EGFR-TKIs. The statins can synergize with EGFR-TKIs in resisting tumors, inhibit the signal pathways and enhance the affinity of EGFR-TKIs and EGFR without toxic doses, and at the same time, the synergistic anti-tumor efficacy of combined use of the statins and EGFR-TKIs is verified on PC-9 and H1975 nude-mouse transplanted tumor models.

Description

technical field [0001] The invention relates to the field of overcoming tumor drug resistance and combination medicine in clinic, and specifically relates to reducing cholesterol to overcome EGFR-TKIs drug resistance of non-small cell lung cancer, and statin drugs can enhance the anti-tumor drug effect of EGFR-TKIs. Background technique [0002] Non-small cell lung cancer (NSCLC) accounts for about 85-90% of lung cancer. 40% to 60% of NSCLC patients have mutations in EGFR, leading to overexpression and promoting tumor growth. In recent years, with the deepening of molecular biology research, targeted molecular drugs epidermal growth factor receptor-tyrosine kinase inhibitors (Epidermal growth factor receptor-tyrosine kinase inhibitors, EGFR-TKIs) have made breakthroughs in the molecular targeted therapy of advanced NSCLC Sexual progression, so that the quality of life of patients has been greatly improved, the representative drugs are gefitinib, erlotinib. EGFR-TKIs have b...

Claims

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Application Information

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IPC IPC(8): A61K31/366A61K31/22A61K31/40A61K31/5377A61K31/517A61P35/00A61P11/00
CPCA61K31/22A61K31/366A61K31/40A61K31/517A61K31/5377A61K2300/00
Inventor 丁选胜陈秋芳潘珍珍
Owner CHINA PHARM UNIV
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