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Application of Hsp90 inhibitor in preparing tumor multi-drug resistance reversal agents

A multi-drug resistance and inhibitor technology, applied in the field of biomedicine, can solve the problems of limited practical application value, toxic and side effects, and the targeting is easily degraded by DNA enzymes, so as to achieve good application prospects, enhance effect, improve effect of sensitivity

Inactive Publication Date: 2014-05-14
JINAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, its effect is not ideal, and high doses will produce serious side effects, and it cannot specifically act on tumor cells
In addition, for the high expression of multidrug resistance genes in malignant tumors, antisense technology, ribozyme or emerging RNAi technology can be used to inhibit or even completely block harmful genes, but there are still many defects in gene therapy, such as targeted Problems, easy to be degraded by DNA enzymes, high concentration of oligonucleotides will have a toxic effect on cells, and the persistence of therapeutic effects, etc., all limit its practical application value

Method used

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  • Application of Hsp90 inhibitor in preparing tumor multi-drug resistance reversal agents
  • Application of Hsp90 inhibitor in preparing tumor multi-drug resistance reversal agents
  • Application of Hsp90 inhibitor in preparing tumor multi-drug resistance reversal agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] 2-(4-Hydroxycyclohexylamino)-4-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydroindazole))benzamide (AT-760) reverse effect on multidrug resistant tumor cell K562 / ADR:

[0023] K562 / ADR cells were treated with 2×10 5 / mL density was inoculated in 96-well plates, and the cells were treated with different concentrations of compounds in groups. One group was added with 1 μM AT-760 and different concentrations (0, 1, 5, 10, 25, 50 and 100 , 25, 50 and 100 μM) of doxorubicin, placed at 37 ° C, 5% CO 2 Cultivate in the incubator for 48h. After the effect was completed, 20 μL of MTT (5 mg / mL) was added to each well, and the incubation was continued at 37° C. for 4 h, and then 90 μL of supernatant was carefully sucked out from each well. Subsequently, 100 μL of DMSO was added and incubated at 37° C. in the dark for 1 h. Measure the absorbance value of each well at a wavelength of 570nm on a BIO-RAD550 microplate reader (reference wavelength 630nm), calculate the cel...

Embodiment 2

[0026] 2-(4-Hydroxycyclohexylamino)-4-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydroindazole))benzamide Effect of (AT-760) on the accumulation of doxorubicin in multi-drug resistant tumor cells K562 / ADR:

[0027] K562 / ADR cells were treated with 2×10 5 / mL density was seeded in 96-well plates, and different compounds were added to treat the cells. The treatment method was to add 20 μM doxorubicin and different concentrations (0, 0.5, 1, 2 μM) of AT-760 to each group, and after culturing for 4 hours, wash the cells with cold PBS buffer solution (pH 7.4) 3 times to terminate the reaction. Collect the cells, add 0.3M HCl-50% ethanol solution to resuspend the cells, break the cells on an ultrasonic instrument and centrifuge for 15 minutes, take the supernatant and add hydrochloric acid-ethanol solution, and measure the fluorescence value of doxorubicin with a fluorescent microplate reader , the excitation and emission wavelengths are 470 nm and 580 nm, respectively.

...

Embodiment 3

[0030] 2-(4-acetoxycyclohexylamino)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindazole))benzamide ( Reversal effect of BJ-B11) on multidrug resistant tumor cell K562 / ADR:

[0031] K562 / ADR cells were treated with 2×10 5 / mL density was inoculated in 96-well plates, and the cells were treated with different concentrations of compounds in groups. One group was added with 1 μM BJ-B11 and different concentrations (0, 1, 5, 10, 25, 50 and 100 μM) of the chemotherapeutic drug doxorubicin (ADR), and the other group was only added with different concentrations (0, 1, 5, 10 , 25, 50 and 100 μM) of doxorubicin, placed at 37 ° C, 5% CO 2 Cultivate in the incubator for 48h. After the effect was completed, 20 μL of MTT (5 mg / mL) was added to each well, and the incubation was continued at 37° C. for 4 h, after which 90 μL of supernatant was carefully aspirated from each well. Subsequently, 100 μL of DMSO was added and incubated at 37° C. in the dark for 1 h. Measure the absorbance ...

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Abstract

The invention belongs to the field of biomedicine, and particularly relates to an application of an Hsp90 inhibitor in preparing tumor multi-drug resistance reversal agents. The Hsp90 inhibitor is tetrahydroindazolone, and the compound is used as a novel tumor chemotherapeutic sensitizing agent and potentiator, can improve the sensitivity of multi-drug resistance tumor cells to chemotherapeutics, and enhance the effects of antitumor chemotherapeutics.

Description

technical field [0001] The invention belongs to the field of biomedicine, and in particular relates to the application of an Hsp90 inhibitor in the preparation of a tumor multidrug resistance reversal agent. Background technique [0002] Multidrug resistance (MDR) refers to the long-term exposure of tumor cells to a certain chemotherapeutic drug, which not only produces resistance to the chemotherapeutic drug, but also to those cells that have never been exposed, whose structure, function and mechanism of action are irrelevant. Other chemotherapeutic drugs have also developed cross-resistance. The generation of MDR involves multiple mechanisms and is a complex and multifactorial phenomenon, including cell kinetics, pharmacokinetics, and cellular drug resistance mechanisms, involving multiple related or independent pathways, including changes in cellular stress, Such as enhanced DNA damage repair ability or tolerance to adversity, and acquired escape from apoptosis mechanism...

Claims

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Application Information

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IPC IPC(8): A61K31/416A61P35/00
Inventor 刘忠王一飞夏敏王蕊
Owner JINAN UNIVERSITY
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