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Application of MSH2 inhibitor in preparation of drug for reversing drug resistance of MTX drug-resistant tumor cells

A tumor cell, MSH2 technology, applied in the field of medicine, can solve problems such as reduced NHEJ repair activity and impaired protein expression

Active Publication Date: 2019-02-01
HARBIN MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Deletion of MLH1 and MSH6 will lead to impaired expression of RAD50 and MRE11 proteins, resulting in reduced NHEJ repair activity, indicating that MLH1 and MSH6 play an important role in NHEJ repair

Method used

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  • Application of MSH2 inhibitor in preparation of drug for reversing drug resistance of MTX drug-resistant tumor cells
  • Application of MSH2 inhibitor in preparation of drug for reversing drug resistance of MTX drug-resistant tumor cells
  • Application of MSH2 inhibitor in preparation of drug for reversing drug resistance of MTX drug-resistant tumor cells

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Embodiment 1

[0061] 1. Cell Culture

[0062] The present invention selects the degree of tolerance to MTX as 10 -4 mol / L human colon cancer cell HT29 drug-resistant cells containing DMs were used as research objects. HT29 parental and drug-resistant cells were cultured in DMEM high-glucose medium containing 15% fetal bovine serum, and all cells were cultured in 5% CO 2 , 37 ℃ constant temperature cell culture incubator.

[0063] 2. Expression analysis of key MMR proteins

[0064] Western Blot method was used to detect the expression levels of MMR key proteins MSH2, MSH3, MSH6 and MLH1 in HT29 parents and DMs-containing HT29MTX drug-resistant cells.

[0065] (1) Extraction of total cell protein

[0066] Place the cell culture flask on ice, wash the cells with pre-cooled PBS 3 times, and aspirate the residual PBS. Add an appropriate amount of cell lysate (the volume ratio of protease inhibitor: phosphatase inhibitor: RIPA buffer is 1:1:10), scrape the cells with a cell scraper and colle...

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Abstract

The invention discloses an application of a MSH2 inhibitor in preparation of a drug for reversing drug resistance of MTX drug-resistant tumor cells, which belongs to the technical filed of medicine. The application is directed to MTX-resistant and highly amplified DHFR gene malignant tumor cells, MSH2 is taken as a target point, the repair of DSBs is inhibited, and the formation of DMs and HSRs isreduced; at the same time, the formation of micro-bud / micronucleus containing the DHFR amplified gene is increased, so that the dose of the DHFR gene in the cells is reduced, the resistance capability of cells to MTX is reduced, the drug resistance of the MTX drug-resistant tumor cells is reversed, and the treatment efficiency of tumors can be improved. The MTX is used as a main therapeutic drug,a new targeted treatment scheme is provided for the biotherapy of the malignant tumor which is easy to generate drug resistance, and provides a scientific basis for effectively resisting the MTX drugresistance. In addition, the application is also very positive meaning for understanding the nature of chemotherapy resistance and finding drug-resistant targets for individualized treatment.

Description

technical field [0001] The present invention relates to the application of using MSH2 as a target to inhibit gene amplification and reverse the drug resistance of MTX drug-resistant tumor cells, and particularly relates to the preparation of MSH2 inhibitors by inhibiting the repair of DSBs, down-regulating DHFR gene amplification and then reversing the drug resistance of tumor cells to MTX The application in the medicine, the invention belongs to the technical field of medicine. Background technique [0002] Methotrexate (Methotrexate, MTX) is an antimetabolite antineoplastic drug and one of the most widely used chemotherapeutic drugs. MTX is a competitive inhibitor of dihydrofolate reductase (DHFR), which inhibits DNA synthesis and cell proliferation by blocking folate metabolism. At present, MTX combination chemotherapy is used for a variety of tumors such as breast cancer, bladder cancer, head and neck cancer, osteosarcoma, choriocarcinoma and leukemia, and is also used ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61K31/7088A61P35/00
CPCA61K31/7088A61K45/00A61P35/00
Inventor 孟祥宁刘鹏冀国华朱静崔晓波孙文靖张春玉金焰王旭孟庆欣柏小青曲亚楠
Owner HARBIN MEDICAL UNIVERSITY
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