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Application of MLL-menin inhibitor composition in preparation of anti-hepatoma drug

A technology of inhibitors and compositions, applied in anti-tumor drugs, drug combinations, pharmaceutical formulations, etc., can solve problems such as unsatisfactory curative effect of hepatocellular carcinoma, and achieve the effects of enhancing binding effect, reducing expression level, and increasing sensitivity

Active Publication Date: 2021-12-10
中国医学科学院肿瘤医院深圳医院
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Paclitaxel mainly affects the spindle formation of cancer cells during mitosis by binding to tubulin, thereby inhibiting the division and proliferation of cancer cells. It is mainly suitable for the treatment of ovarian cancer and breast cancer in clinical practice, but it has no effect on hepatocellular carcinoma. ideal

Method used

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  • Application of MLL-menin inhibitor composition in preparation of anti-hepatoma drug
  • Application of MLL-menin inhibitor composition in preparation of anti-hepatoma drug
  • Application of MLL-menin inhibitor composition in preparation of anti-hepatoma drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] The present invention finds that the MLL-menin inhibitor MI-2 composition can down-regulate the protein level of CYP1B1 in the hepatocellular carcinoma cell lines Huh7 and Li-7.

[0026] Reagents and materials:

[0027] The liver cancer cell lines HuH-7 and Li-7 were purchased from the Shanghai Cell Bank of the Chinese Academy of Sciences. HuH7 was cultured in DMEM medium (CORNING, product number 10-013-CV) containing 10% GBICO fetal bovine serum, Li-7 was cultured in RPMI-1640 medium (CORNING, product number 10-013-CV, adding Sodium Pyruvate 0.11 g / L), and containing 10% fetal bovine serum; culture conditions are 37 ℃, 5% CO2. MI-2 was purchased from TargetMol (Cat. No. T2649).

[0028] experimental method:

[0029] Treat Huh7 and Li-7 cells with DMSO (dimethyl sulfoxide) and MI-2 (10 μmol / L, 25 μmol / L, 50 μmol / L) respectively, extract cell sample protein, pre-cool RIPA lysate on ice, and use immediately Before adding protease inhibitor PMSF at a final concentratio...

Embodiment 2

[0033] The present invention found that the combination drug MI-2 and paclitaxel can synergistically enhance the toxicity of paclitaxel to hepatocellular carcinoma cell lines.

[0034] Reagents and materials:

[0035] Paclitaxel was purchased from Aladdin (Product No. P106869), and other reagent materials were the same as in Example 1.

[0036] experimental method:

[0037] Preparation of MI-2, paclitaxel stock solution and working solution:

[0038] Using DMSO as solvent, dilute MI-2 to 500x stock solution, paclitaxel to 1000x stock solution, and store at -20°C.

[0039] The working solution is prepared immediately before use, and 10 μL working solution / 100 μL culture system / well is added to each well when dosing:

[0040] MI-2 working solution: 2μL stock solution + 98μL medium → 100μL working solution (10x)

[0041] Paclitaxel working solution: 1 μL stock solution + 99 μL medium → 100 μL working solution (10x)

[0042] Cell culture and dosing:

[0043]HuH7 (5000cells / w...

Embodiment 3

[0058] The present invention finds that the combined drug MI-2 and paclitaxel can promote microscopic protein aggregation and increase the toxicity of paclitaxel in the mouse model.

[0059] Reagents and materials:

[0060] Female Balb / C nude mice were purchased from Shanghai Experimental Animal Research Center and bred in the Experimental Animal Center of Zhejiang University. All the other reagent materials are the same as in Example 1.

[0061] experimental method:

[0062] A mouse model of hepatocellular carcinoma was constructed, and Balb / C nude mice aged 4 to 6 weeks were used as experimental objects, and divided into four groups: solvent control group, MI-2 group, paclitaxel group and paclitaxel and MI-2 combined group, divided into 5 groups Only. Will 1x10 7 A large number of Li-7 or Huh7 cells were inoculated in the axilla of nude mice. For PDX models, the tumor tissues of hepatocellular carcinoma patients with the size of mung beans were inoculated in the axilla o...

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Abstract

The invention provides an application of an MLL-menin inhibitor composition in preparation of an anti-liver cancer drug. The composition is composed of an MLL-menin inhibitor and paclitaxel. According to the composition, H3K4me3 catalyzed by MLL is inhibited, so that the expression quantity of CYP1B1 is reduced, the binding effect of the paclitaxel on tubulin is enhanced, the sensitivity of an in-vitro hepatocellular carcinoma cell line and an in-vivo hepatocellular carcinoma mouse on the paclitaxel is synergistically increased, after the hepatocellular carcinoma which is highly resistant to the paclitaxel and is ineffective by singly using an epigenetic drug MLL-menin inhibitor is treated by the composition, the chemotherapy curative effect is obviously improved. The composition provides a novel chemotherapeutic drug for paclitaxel-resistant hepatocellular carcinoma treatment.

Description

technical field [0001] The invention belongs to the field of medicine, and relates to the application of an MLL-menin inhibitor composition in the preparation of anti-liver cancer drugs. The MLL-menin inhibitor is used to down-regulate the expression of CYP1B1 protein, and is applied to improve the sensitivity of hepatocellular carcinoma to paclitaxel . Background technique [0002] The global mortality rate of liver cancer ranks third in cancer-related mortality. As a high-incidence region of liver cancer, my country accounts for more than half of the world's new cases and deaths each year. Primary liver cancer mainly includes hepatocellular carcinoma, intrahepatic cholangiocarcinoma and other rare subtypes, among which hepatocellular carcinoma accounts for about 70%-85% of primary liver cancer. At present, the clinical treatment of liver cancer is facing problems such as poor curative effect, easy drug resistance, and high recurrence rate. The five-year survival rate of p...

Claims

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Application Information

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IPC IPC(8): A61K45/06A61K31/519A61K31/337A61P1/16A61P35/00
CPCA61K45/06A61K31/519A61K31/337A61P1/16A61P35/00A61K2300/00
Inventor 郑小丽曾苏吴式琇王绿化汪佳琪余露山
Owner 中国医学科学院肿瘤医院深圳医院
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