Application of sorafenib in the preparation of drugs for reversing tumor multidrug resistance

A multi-drug resistance and drug resistance technology, which can be used in anti-tumor drugs, drug combinations, active ingredients of heterocyclic compounds, etc. Significant degradative effect

Inactive Publication Date: 2011-12-14
INST OF BASIC MEDICAL SCI ACAD OF MILITARY MEDICAL SCI OF PLA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

②Inhibitors of other targets, such as the selective inhibitor of BCR-ABL tyrosine kinase imatinib (STI571) and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor Gefitinib, these reversal agents are basically It is a new use of old medicine, and it has highly targeted therapeutic functions. When it is used as a reversal agent, its original therapeutic functions will inevitably bring serious toxic and side effects
Therefore, the actual dosage in clinical research is very low, and the blood concentration of patients is far lower than the concentration of optimal activity used in in vitro research.
③ BCRP-specific inhibitors, currently there are few reports in the literature, such as mycotoxin C (FTC) and its derivatives, 6-prenylchrysin and poplaraxanthin
However, whether it has an inhibitory effect on BCRP-mediated multidrug resistance is still unknown

Method used

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  • Application of sorafenib in the preparation of drugs for reversing tumor multidrug resistance
  • Application of sorafenib in the preparation of drugs for reversing tumor multidrug resistance
  • Application of sorafenib in the preparation of drugs for reversing tumor multidrug resistance

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1 Effect of sorafenib on the accumulation of BCRP substrate mitoxantrone in BCRP highly expressed drug-resistant cells

[0035] Harvest the resistant strain HEK293 / BCRP with high expression of BCRP and the parental HEK293 / VEC respectively, add BCRP substrate fluorescent dye MX in the presence or absence of sorafenib (sorafenib concentration is 2.5 μM), 37°C After incubation for one hour, FACS was used to detect the change of fluorescence intensity in the cells. Reversal factor = GMean of treatment group / GMean of DMSO group.

[0036] The results showed that sorafenib could significantly increase the accumulation of mitoxantrone in HEK293 / BCRP in a dose-dependent manner, but had no effect on parental cells ( Figure 1-2 ). However, taking a similar method, sorafenib has no similar effect in K562 / A02 cells with high expression of Pgp. This indicated that Sorafenib could specifically block the efflux of BCRP to its substrate.

Embodiment 2

[0037] Example 2 Effect of Sorafenib on the expression level of BCRP in BCRP highly expressed drug-resistant cells

[0038] Sorafenib was stimulated at 0.625 μM, 1.25 μM, 2.5 μM for 72 h or 2.5 μM for 24 h, 48 h, and 72 h on HEK293 / BCRP cells, and Weston Blot technique was used to detect the expression of BCRP.

[0039] The results showed that Sorafenib could significantly, dose- and time-dependently reduce the protein expression level of BCRP ( image 3 ). Taking a similar approach, it was found that Sorafenib could not cause the degradation of Pgp. At the same time, it was detected that the selected reversal concentration had no effect on the phosphorylation levels of AKT and ERK.

Embodiment 3

[0040] Example 3 Sorafenib specifically reverses BCRP-mediated multidrug resistance in vitro

[0041] HEK293 / BCRP cells highly expressing BCRP were suspended in 10% FBS / DMEM and seeded in 96-well microplates (40000 cells / 160 μl / well), and cultured at 5% CO2 and 37°C for 24 hours. Add 20 μl of Sorafenib solution to the final concentration of 0.625 μM, 1.25 μM, 2.5 μM (IC 10 non-toxic dose), 5% CO2, 37 ° C incubation for 2h, add mitoxantrone solution 20μl to a final concentration of 100nM (IC 10 The non-toxic dose within 100 g), the cell viability was determined by the MTS method after 72 hours of culture.

[0042] The results showed that the survival rate of drug-resistant cells decreased significantly after the non-toxic dose of sorafenib and mitoxantrone acted together, and the same experiment did not have this effect on sensitive cells HEK293 / VEC, indicating that sorafenib can specifically Reversal of HEK293 / BCRP resistance to mitoxantrone ( Figure 4 ). Using a similar me...

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Abstract

The invention belongs to the production technology for antitumor drugs, and discloses uses of sorafenib and sorafenib salts in preparing drugs for reversing BCRP protein-mediated multidrug resistance of tumors. According to the present invention, the sorafenib and the sorafenib salts are combined with antitumor drugs, such that the sensitivity of multidrug resistant tumor cells to the antitumor drugs are recovered; the prepared drugs are applicable for providing combination chemotherapy for the clinical chemotherapy resistant patients or preventing the drug resistance of the tumor cells from generation.

Description

technical field [0001] The invention belongs to the technical field of preparation of antitumor drugs, and in particular relates to the application of sorafenib and its salts in the preparation of drugs for reversing BCRP protein-mediated tumor drug resistance. Background technique [0002] Malignant tumors are one of the key diseases in my country. A major disadvantage in the process of tumor treatment is that tumor cells develop primary or induced resistance to anticancer drugs, which leads to failure of clinical chemotherapy. According to statistics, more than 90% of cancer patients died of drug resistance to varying degrees. The main phenotype of tumor cell drug resistance is multidrug resistance (MDR), that is, after patients receive chemotherapy drugs, they develop resistance to the original drug and cross-resistance to other anticancer drugs with different structures and mechanisms of action. Drugs, resulting in reduced or ineffective clinical efficacy. Therefore, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/44A61P35/00
Inventor 彭晖魏寅祥赵青任志广冯健男林周黎燕沈倍奋
Owner INST OF BASIC MEDICAL SCI ACAD OF MILITARY MEDICAL SCI OF PLA
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