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Application of KMT1A inhibitor in preparation of anticancer drug for bladder cancers

An inhibitor and bladder cancer technology, applied in the field of tumor molecular biology and chemical drugs, can solve the problem of decreased STAT3 protein phosphorylation level, increased GATA3 gene transcription level, bladder cancer stem cell spheroid formation ability and tumor formation ability weakened, etc. question

Inactive Publication Date: 2019-04-12
BEIJING UNIV OF CHEM TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

When the function of KMT1A is lost, the KMT1A-GATA3-STAT3 signaling pathway is inhibited, which increases the transcription level of GATA3 gene; the up-regulation of GATA3 expression further represses the transcription of STAT3, resulting in a decrease in the phosphorylation level of STAT3 protein, and the formation of spheres in bladder cancer stem cells ability and tumorigenicity are markedly impaired

Method used

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  • Application of KMT1A inhibitor in preparation of anticancer drug for bladder cancers
  • Application of KMT1A inhibitor in preparation of anticancer drug for bladder cancers
  • Application of KMT1A inhibitor in preparation of anticancer drug for bladder cancers

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Embodiment 1, cell proliferation experiment

[0032] (1) Bladder cancer cell lines BIU87, T24 were routinely cultured in RPMI 1640 medium with 10% fetal bovine serum.

[0033] (2) Digest BIU87, T24 cells, wash once with 5ml PBS, and count accurately.

[0034] (3) Plate 3000 cells / 100 μl / well in a 96-well plate and culture overnight.

[0035] (4) The next day, after the cells adhered to the wall, replace the culture medium with 5% DMSO, 150 μM AMI-1, 2.5 μM BIX-01294, 50 nM Chaetocin, 2.5 μM DZNeP, 10 μM GSK343 ​​and 2.5 μM UNC0631, and culture for 24 h, 48 h , 72h.

[0036] (5) At each time point, remove the original medium, add 100 μl of serum-free 1640 medium containing CCK8, incubate at 37°C for 2 hours, and measure the absorbance at 450nm (OD 450nm).

[0037] like figure 1 As shown, Chaetocin, a preferred embodiment of the KMT1A inhibitor of the present invention, can specifically inhibit the cell proliferation of bladder cancer cells.

Embodiment 2

[0038] Embodiment two, cell cycle experiment

[0039] (1) The day before, BIU87 and T24 cells were mixed with 4×10 cells per well 5 Cells were seeded in a 6-well plate, and the serum-free medium was replaced in the morning after attachment the next day to synchronize the cell cycle.

[0040](2) After 24 hours, add fresh medium containing 2 μl DMSO to 3 wells, add fresh medium containing 50 nM Chae inhibitor to the other 3 wells, and culture for 24 hours and 48 hours.

[0041] (3) After 24h and 48h, collect the cells by trypsinization, wash twice with PBS, discard the supernatant, add 1ml of 70% pre-cooled ethanol, pipette evenly, and fix at -20°C overnight (>12h).

[0042] (4) Before flow detection, wash with PBS to remove ethanol, centrifuge at 3000rpm for 4min, and wash twice. Resuspend the cells with 0.5ml PBS, add RNaseA to a final concentration of 50μg / ml, and incubate at 37°C for 30min. Add 25 μl PI and mix well, incubate at 37°C for 10 minutes, and measure the period...

Embodiment 3

[0044] Embodiment three, cell apoptosis experiment

[0045] (1) The day before, BIU87 and T24 cells were mixed with 4×10 cells per well 5 The cells were seeded in a 6-well plate, and after adherence the next day, fresh medium containing 2 μl DMSO was added to 3 wells, and fresh medium containing 50 nM Chaetocin inhibitor was added to the other 3 wells, and cultured for 24 h and 48 h.

[0046] (2) After 24h and 48h, suck out the cell culture medium into a suitable centrifuge tube, wash the adherent cells once with PBS, and add an appropriate amount of trypsin cell digestion solution to digest the cells. Incubate at room temperature until the adherent cells can be blown down by gentle pipetting, then aspirate the trypsin cell digestion solution. Overdigestion with trypsin should be avoided.

[0047] (3) Add the cell culture medium collected in step (2), mix slightly, transfer to a centrifuge tube, centrifuge at 1000 g for 5 min, discard the supernatant, collect the cells, gent...

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Abstract

The present invention relates to an application of a KMT1A inhibitor in preparation of an anticancer drug for bladder cancers and discloses that the KMT1A inhibitor can effectively inhibit bladder cancer growth. Compared with normal bladder epithelial cells, KMT1A is specifically highly expressed in bladder cancer cells, so that the KMT1A inhibitor acts on a KMT1A-GATA3-STAT3 signaling pathway bytarget inhibiting KMT1A genes, and enables a transcriptional level of GATA3 gene to be increased; and an up-regulation of the GATA3 further represses STAT3 transcription, leads to a decreased level ofSTAT3 protein phosphorylation, and thus inhibits dry maintenance and tumor formation of bladder cancer stem cells.

Description

technical field [0001] The invention relates to the fields of tumor molecular biology and chemical medicine, and in particular relates to the application of KMT1A inhibitors in the preparation of antitumor drugs. Background technique [0002] The occurrence and development of bladder cancer is a multi-factor and multi-step complex process, but its pathogenesis has not been studied clearly. Currently, non-targeted and non-specific surgical resection combined with intravesical infusion of chemical drugs is used clinically. The overall remission rate of this treatment strategy is only 26%. There is currently no effective strategy for the prevention and targeted therapy of bladder cancer. . [0003] As the best choice for targeted therapy, bladder cancer stem cells have the potential of self-renewal, unlimited proliferation and multi-directional differentiation, and are the root cause of bladder cancer occurrence, development, recurrence and metastasis. But the molecular mecha...

Claims

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Application Information

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IPC IPC(8): A61K45/00A61P35/00
CPCA61K45/00A61P35/00
Inventor 喻长远杨昭成冬晓白素杭钟博张富涵沈宗毅魏振华张琨
Owner BEIJING UNIV OF CHEM TECH
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