Application of dnmt1 protein inhibitor in the preparation of drugs for reversing the drug resistance of mtx-resistant tumor cells

A technology of tumor cells and drug-resistant cells, applied in anti-tumor drugs, drug combinations, pharmaceutical formulations, etc., can solve the problems of increasing treatment effect and limited effect, and achieve the effect of reversing tumor resistance and improving efficiency

Active Publication Date: 2022-07-01
HARBIN MEDICAL UNIVERSITY
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AI Technical Summary

Problems solved by technology

Previous studies have shown that HR, NHEJ, and A-EJ multiple repair pathways can promote the formation of double microsomes, so the effect of inhibiting a single repair pathway is limited, and if the repair pathway inhibits multiple downstream pathways during the DNA damage response process, it will increase its therapeutic effect

Method used

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  • Application of dnmt1 protein inhibitor in the preparation of drugs for reversing the drug resistance of mtx-resistant tumor cells
  • Application of dnmt1 protein inhibitor in the preparation of drugs for reversing the drug resistance of mtx-resistant tumor cells
  • Application of dnmt1 protein inhibitor in the preparation of drugs for reversing the drug resistance of mtx-resistant tumor cells

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Embodiment 1

[0055] 1. Cell Culture

[0056] The human colon cancer cell line HT29 was continuously cultured with increasing concentrations of MTX, and a series of HT29MTX-resistant cells were screened out. After each concentration gradient cell was resistant to the corresponding drug concentration, the culture was continued for 5 months until it was stable and resistant. After that, continue the follow-up experiment.

[0057] HT29 parental and drug-resistant cells were cultured in DMEM high-glucose medium containing 15% fetal bovine serum, and the corresponding concentration of MTX was added to the drug-resistant cell line medium. All cells were cultured in 5% CO 2 , in a constant temperature cell incubator at 37°C.

[0058] 2. The expression levels of DDR key proteins in HT29 parental cells and MTX-resistant cells

[0059] Detection of HT29 parental cells and tolerance to MTX by Western Blot was 10 -4 The expression level of DDR pathway protein DNMT1 in DMs-containing HT29 MTX-resistan...

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Abstract

The invention discloses an application of a DNMT1 protein inhibitor in preparing a drug for reversing the drug resistance of MTX drug-resistant tumor cells, and belongs to the technical field of medicine. The invention is aimed at MTX-resistant malignant tumor cells with high amplification of DHFR gene, takes DNMT1 as the target, reduces the amplification degree of DHFR gene, reduces the DMs in cells, and at the same time, interferes with DNMT1 to inhibit the damage response of DNA double-strand breaks Signal, attenuate HR and A-EJ repair effect on DSBs, thereby reversing tumor resistance and improving the efficiency of tumor treatment. The present invention provides a new targeted treatment scheme for the biological treatment of malignant tumors with MTX as the main therapeutic drug and is prone to drug resistance, and reveals the mechanism of DNMT1 in tumor drug-resistant cells participating in the formation of DMs and tumor drug resistance, which is helpful for A more comprehensive analysis of the process of tumor development and drug resistance caused by DSBs will provide a new strategy for reversing tumor drug resistance. In addition, the present invention also has very positive significance for in-depth understanding of the nature of chemotherapy resistance and for finding drug resistance targets for individualized treatment.

Description

technical field [0001] The invention relates to the application of a DNMT1 protein inhibitor in the preparation of a drug for reversing the drug resistance of tumor cells to MTX, in particular to the application of a DNMT1 protein inhibitor in the preparation of a DNMT1 protein inhibitor by reducing the cell's ability to repair DNA double-strand break damage, down-regulating DHFR gene amplification, and then The invention relates to the application of the medicine for reversing the resistance of tumor cells to MTX, belonging to the technical field of medicine. Background technique [0002] Methotrexate (MTX), as an antimetabolite antitumor drug, is widely used in the treatment of acute lymphoblastic leukemia, lymphoma, choriocarcinoma, breast cancer, head and neck cancer, bladder cancer and lung cancer. treat. MTX can competitively inhibit the activity of dihydrofolate reductase (DHFR), impair the synthesis of dihydrofolate to tetrahydrofolate, lead to the inhibition of DNA...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K45/00A61K48/00A61K31/7088A61P35/00
CPCA61K45/00A61K48/005A61K31/7088A61P35/00
Inventor 孟祥宁张慧姝孟庆欣崔晓波朱静白静高淑英冀国华冯犇韩江邢若男任万奎
Owner HARBIN MEDICAL UNIVERSITY
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