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Application of proteasome inhibitor in anti-cancer drugs

A proteasome inhibitor and anticancer drug technology, applied in the application field of proteasome inhibitors in anticancer drugs, can solve the problems such as the advent of immunotherapy programs, and achieve the effects of weakening the therapeutic effect, increasing infiltration, and improving the microenvironment

Inactive Publication Date: 2020-12-01
JINAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Some cytokines and compounds such as IL-23, polyporus polysaccharide and the recently discovered Nodal inhibitor have been proven to promote the transformation of TAM from M2 type to M1 type to achieve anti-tumor effects, but there is still no TAM as a target. Point-of-care immunotherapy program comes out

Method used

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  • Application of proteasome inhibitor in anti-cancer drugs
  • Application of proteasome inhibitor in anti-cancer drugs
  • Application of proteasome inhibitor in anti-cancer drugs

Examples

Experimental program
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Effect test

Embodiment 1

[0034] Proteasome inhibitors (Carfilzomib, Bortezomib, MLN9708, MG132) promote the expression of M1 macrophage markers while inhibiting the expression of M2 macrophage markers

[0035] 1. Experimental method

[0036] (1) Preparation of mouse bone marrow-differentiated macrophages: Take adult mice about 8 weeks old, kill them by cervical dislocation, soak them in 75% ethanol for 2 minutes, take them out, dissect and separate the mice For the legs, the coat and most of the muscles were removed, and then soaked in 75% ethanol for 10 minutes, then the leg bones were taken out, placed in PBS, and washed 2-3 times with PBS to remove residual ethanol. Use scissors and tweezers to separate the femur and tibia, and then peel off the articular cartilage at one end of the femur and tibia to expose the cross section, and cut the other end with scissors. Use a 10ml syringe to draw the PBS containing 1% serum and 1% penicillin-streptomycin mixture prepared in advance, wash the bone marrow ...

Embodiment 2

[0045] Proteasome inhibitor drugs Carfilzomib, Bortezomib and MLN9708 promote the phagocytosis of tumor cell L1210 by primary macrophage BMDM

[0046] 1. Experimental method:

[0047] (1) Induce BMDM differentiation: Inoculate 1×10 per well in a 12-well plate 5 Each BMDM was divided into five groups on the next day for different drug treatments, namely mock (blank group), IL-4 (20ng / ml), Carfilzomib (1μM), Bortezomib (1μM), MLN9708 (1μM) were pretreated for 1 hour and then Add IL-4 (20ng / ml) treatment group.

[0048] (2) Co-incubation of macrophages and tumor cells: After 12 hours of drug treatment, macrophages were replaced with serum-free medium, starved for 2-3 hours, and 4×10 5 Mouse leukemia cells (L1210-GFP) expressing GFP green fluorescent protein were incubated for 2 hours.

[0049] (3) Observation record: wash away the suspended L1210-GFP cells, observe the phagocytosis of target cells by macrophages under a fluorescence microscope, and take pictures for statistics...

Embodiment 3

[0053] Carfilzomib inhibits the growth of subcutaneous xenografts of mouse melanoma cell B16

[0054] 1. Experimental method

[0055] (1) The prepared mouse melanoma cell B16 was mixed with 100 μL of PBS and Matrigel (Matrigel) (1:1) containing 1×10^6 cells, and the tumor cell gel mixture was implanted into The flanks of 6-week-old BALB / c nude mice were injected with the mixture in a volume of 100 μl per implantation point.

[0056] (2) When the tumor volume reaches 80mm 3 When left or right, the mice were randomly divided into groups, one group was a normal saline control group (control group, tail vein injection, administered once every 2-3 days, 100 μl / time), and one group was a Carfilzomib treatment group (tail vein injection, Administration once every 2-3 days, each administration dose is 2mg / kg, 100μl / time), and the two groups of mice were administered synchronously.

[0057] (3) After 2 weeks of treatment, the mice were sacrificed, the tumors were dissected, and the ...

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Abstract

The invention discloses an application of a proteasome inhibitor in anti-cancer drugs. The proteasome inhibitor comprises Carfilzomib (carfilzomib), Bortezomib (bortezomib), MLN9708 (ixazomib), MG132and the like. The targeted cancer is a cancer in which macrophage polarization participates, i.e., a tumor in which the macrophage type is mainly M2 type in a tumor microenvironment, including a solidtumor and a hematologic tumor, and also including an in-situ cancer and a transplanted cancer. It is found through a large amount of creative work that the proteasome inhibitor converts M2 type TAM in the tumor immune microenvironment into M1 type TAM, thereby improving the tumor microenvironment, promoting the phagocytic effect of macrophages on tumor cells and increasing infiltration of immunecells on tumors to inhibit tumor growth.

Description

technical field [0001] The invention belongs to the field of biomedicine, and in particular relates to the application of proteasome inhibitors in anticancer drugs. Background technique [0002] Cancer immunotherapy is an emerging and most promising treatment method after surgery, radiotherapy and chemotherapy, and targeted therapy, and it is also the focus and hotspot in the field of cancer research. However, most patients in clinical cases are still insensitive to immunotherapy, which has been proved to be inseparable from immune tolerance mediated by tumor microenvironment (TME). Targeting TME to relieve immunosuppression is beneficial to restore and rebuild the normal anti-tumor immune defense ability of the human body, and enhance the efficacy of immunotherapy. [0003] Tumor associated macrophages (tumor associated macrophage, TAM) is an important part of TME, which plays an important role in the occurrence, development, invasion and metastasis of tumors. According t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61K38/08A61P35/00
CPCA61K38/08A61K45/00A61P35/00
Inventor 陈良周倩
Owner JINAN UNIVERSITY
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