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Application of trametinib in preparing medicine for reversing multi-medicine resistance of tumors

A multi-drug resistance and drug technology, applied in the direction of antineoplastic drugs, drug combinations, pharmaceutical formulations, etc., can solve the problem of low toxicity, unstudied reversal of tumor multi-drug resistance of trametinib, and no bright future and other issues to achieve the effect of restoring sensitivity

Active Publication Date: 2015-03-25
JINAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Compared with the first-generation reversal agent, the second-generation reversal agent has stronger activity and lower toxicity. It also has the effect of reversing MDR in vivo, but there is no bright prospect in clinical application
[0006] Trametinib is a small-molecule inhibitor of the kinases MEK1 and MEK2, which was approved by the US FDA in 2013 for the treatment of melanoma, as a single-drug oral tablet, suitable for carrying the proto-oncogene BRAF V600E or V600K mutation The treatment of adult patients with surgically unresectable melanoma or metastatic melanoma has been widely used clinically, but the effect of trametinib on reversing tumor multidrug resistance has not been studied in the prior art

Method used

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  • Application of trametinib in preparing medicine for reversing multi-medicine resistance of tumors
  • Application of trametinib in preparing medicine for reversing multi-medicine resistance of tumors
  • Application of trametinib in preparing medicine for reversing multi-medicine resistance of tumors

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Experimental program
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Effect test

Embodiment 1

[0036] (a) Trametinib can significantly restore the sensitivity of drug-resistant cells to the anticancer drug vincristine

[0037] Parental cells (KB) and P-gp high-expressing cells (KB V200 ) in a 96-well plate (5000 cells / well), after 4 hours the cells were completely adhered to the wall, vincristine was added to the corresponding wells in a concentration gradient, and the difference in the volume of the drug was filled with phosphate buffered saline (PBS), 72 After 1 hour, add 10 μL of 0.5 mg / ml thiazolium blue (MTT) to each well, incubate at 37°C for 4 hours, absorb the culture medium, and add 50 μL of dimethyl sulfoxide (DMSO) to each well to dissolve the crystals after drying. Measure the OD value at 570nm of the standard instrument; after combining different concentrations (1 μM, 3 μM and 10 μM) of trametinib with gradient concentrations of vincristine, repeat the above process, and set the combination of 10 μM verapamil and vincristine For comparison, calculate the IC5...

Embodiment 2

[0052] Trametinib can significantly restore the sensitivity of drug-resistant cells to the anticancer drug doxorubicin

[0053] Parental cells (KB) and P-gp high-expressing cells (KB V200 ) in a 96-well plate (5000 cells / well). After 4 hours of complete cell attachment, add doxorubicin to the corresponding wells in different concentration gradients. The difference in the volume of the drug was filled with phosphate buffered saline (PBS). 72 After 1 hour, add 10 μL of 0.5 mg / ml thiazolium blue (MTT) to each well, incubate at 37°C for 4 hours, absorb the culture medium, and add 50 μL of dimethyl sulfoxide (DMSO) to each well to dissolve the crystals after drying. Measure the OD value at 570nm of the standard instrument; after combining different concentrations (1 μM, 3 μM and 10 μM) of trametinib with gradient concentrations of doxorubicin, repeat the above process, and set the combination of 10 μM verapamil and doxorubicin For comparison, the IC50 of each group was calculated,...

Embodiment 3

[0059] Effect of trametinib on ATP hydrolase activity of P-gp

[0060] The transport of P-gp is driven by the hydrolysis of ATP. The interaction between the reversal agent and P-gp will affect the activity of ATP hydrolase, and the P-gp assay system (Promega, CAT: V3601) is used for detection. P-gp is first incubated with the substrate, and then a certain amount of ATP is added and then terminated. The ATP hydrolysis reaction of P-gp, the remaining ATP not metabolized by the hydrolase is detected by the luciferase reaction system. Compared with the no-substrate group, the greater the weakening of the fluorescence signal, the more ATP was consumed by P-gp, so the greater the signal decrease, the higher the P-gp activity; conversely, the increase of the signal indicated that the ATP hydrolysis activity was inhibited. In this experiment, different concentrations of trametinib were used as the substrate experimental group, and the experimental steps were as follows:

[0061] (1)...

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Abstract

The invention belongs to the technical field of medicine application, and discloses an application of trametinib in preparing a medicine for reversing multi-medicine resistance of tumors. Trametinib can be used for significantly reversing the multi-medicine resistance of the tumors mediated by membrane transport protein to ensure that the sensitivity of P-glycoprotein high expression cells to anti-cancer medicines can be restored. According to the medicine for reversing the multi-medicine resistance of the tumors, disclosed by the invention, trametinib and the anti-cancer medicines can be combined to ensure that the effects of treating and controlling resistant tumors can be achieved by restoring the sensitivity of resistant cells to the anti-cancer medicines.

Description

technical field [0001] The invention belongs to the technical field of drug application, and in particular relates to an application of trametinib in the preparation of drugs for reversing tumor multidrug resistance. Background technique [0002] Malignant tumors are one of the key diseases in my country. A major disadvantage in the process of cancer treatment is that tumor cells develop primary or induced drug resistance to conventional anticancer chemotherapy drugs, which leads to clinical chemotherapy failure. Long-term exposure of tumor cells to a certain chemotherapeutic drug during chemotherapy will not only produce resistance to this drug, but also produce cross-resistance to other chemotherapeutic drugs with different structures and functions. This phenomenon is called Multidrug resistance (MDR). Therefore, the expression of tumor drug resistance genes and the study of reversing MDR have become urgent problems to be solved in tumor therapy. The occurrence of MDR i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/519A61K31/704A61P35/00A61K31/475
CPCA61K31/136A61K31/337A61K31/4745A61K31/475A61K31/519A61K31/704A61K31/7048A61K2300/00
Inventor 石智邱建阁梅晓龙张文姬覃武明
Owner JINAN UNIVERSITY
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