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Drug for treating cancer

A drug and cancer technology, applied in the field of drugs, can solve problems such as affecting the activation of RARβ2 gene, and achieve the effects of inhibiting proliferation, improving sensitivity, and promoting apoptosis

Active Publication Date: 2020-09-22
SOUTH CHINA UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Recently, it has been reported that CARM1 / PRMT4-mediated methylation of R469 affects the binding of HSP70 and TFIIH, thereby affecting the activation of RARβ2 gene

Method used

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  • Drug for treating cancer
  • Drug for treating cancer
  • Drug for treating cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Example 1: An experiment on transplanted tumors of pancreatic ductal adenocarcinoma (pancreatic cancer) in mice.

[0054] In a xenograft tumor model, mouse pancreatic ductal adenocarcinoma (pancreatic cancer) cells (1×10 6 ) was resuspended in 0.1 mL of Hank's buffer without calcium and magnesium, and injected subcutaneously into the flank of nude mice. Tumor length and width were measured with calipers twice a week. PRMT1 inhibitor DB75 was intraperitoneally injected into mice twice a week for 3 weeks. The low dose is 5mg / kg and the high dose is 20mg / kg. The vehicle solution was used as a control. Tumor-bearing mice were euthanized on the verge of death or at designated time points after inoculation, and the tumors were excised and weighed. Tumor volume (mm 3 ) calculation formula is: short diameter 2×long diameter / 2.

[0055] See the experimental results Figure 1-A , Figure 1-B . Figure 1-A , describing a pancreatic ductal adenocarcinoma (pancreatic carcinom...

Embodiment 2

[0056] Example 2: Migration and invasion experiments of human pancreatic ductal carcinoma cells.

[0057] The day before transfection, 5×10 5 MDA28 and PANC-1 cells were seeded on 6-well plates in 1.5 mL of cell culture medium containing 10% FBS. Choose the number of cells for initial seeding that will bring the cells to 70-90% confluency within 24 hours. Add 100 pmol siRNA (or 2 μg DNA) to 250 μl Opti-MEM, mix gently; mix lipofectamin2000 reagent, dilute 5 μl lipofectamin2000 with 250 μl Opti-MEM, mix gently, and place at room temperature for 5 minutes; dilute the diluted siRNA\DNA Mix with lipofectamin2000; mix gently, and place at room temperature for 20 minutes to form siRNA / lipofectamin (or DNA / lipofectamin) complexes. Add 500 μl of siRNA / lipofectamin (or DNA / lipofectamin) complex to the corresponding wells of the culture plate containing cells and medium, and gently shake the cell culture plate back and forth. In MDA28 cells, siPRMT1 was transferred, and siCtrl was us...

Embodiment 3

[0060] Example 3: Immunoprecipitation experiment

[0061]Using the transfection method described in Example 2, the PRMT overexpression plasmid was transfected in mouse pancreatic ductal carcinoma cells, and pcDNA3.1 was used as a negative control. After 36 hours of transfection, the culture medium was poured out, and the bottle was buckled upside down. Absorb the culture medium on the absorbent paper. Add 1ml of 4°C pre-cooled PBS (0.01M pH7.2-7.3) to each well of cells. Cells were lysed with the addition of protease inhibitor PierceIP lysis buffer (Thermo Fisher Scientific). Cell lysates were incubated with HSP70 antibody overnight (12 hours) at 4°C on a rotator. Protein A / G + agarose (Santa Cruz) was then added for further incubation at 4°C for 2 hours. Following 4 washes with PBST plus protease inhibitors followed by 2×SDS-PAGE and boiling for 5 minutes, protein complexes were released from the agarose. The protein concentration of the whole cell lysate was determined b...

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Abstract

The invention discloses a drug for treating a cancer. It is found that expression of PRMT1 is obviously increased in cancer tissues relative to normal tissues and is directly related to the malignantdegree and worse prognosis of tumors, and the research on PRMT1-mediated HSP70 methylation, the influence of the PRMT1-mediated HSP70 methylation on the cancer cell treatment effect and a fundamentalmechanism of the PRMT1-mediated HSP70 methylation is developed. The invention finds that overexpression of the PRMT1 increases arginine methylation of HSP70. The methylation of the HSP70 is to protectcancer cells from apoptosis caused by emergency pressure and treatment of various cells by enhancing the combination of AU-rich elements in the HSP70 and BCL-2 mRNA 3'-UTR, increasing the stability of BCL-2 mRNA and correspondingly increasing the expression of a BCL-2 protein. The drug provided by the invention seals an arginine methylation site of a heat shock protein through an antibody and a small molecular inhibitor, so that the survivability of cancer cells can be reduced, and the treatment effect can be improved.

Description

technical field [0001] The invention relates to the technical field of medicines, in particular to a medicine for treating cancer. Background technique [0002] Intrinsic and acquired resistance or tolerance of malignancies to treatment modalities is a key challenge in clinical practice, resulting in the minimal impact of existing treatment strategies on overall survival. Altered balance of pro-apoptotic and anti-apoptotic signaling in cancer cells is associated with therapeutic resistance, cancer progression and metastasis, which are major causes of cancer-related death. [0003] 70kDa heat shock proteins (HSP70s) are an evolutionarily conserved protein family and are ATP-dependent molecular chaperones. HSP70 is encoded by the HSPA gene family, and there are 13 HSP70 family members in mammals. HSP70, the main member of this family, plays a key role in promoting cell survival under various stress conditions, including cytotoxic chemotherapy. HSP70 is a classic protein cha...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395A61K45/06A61P35/00
CPCA61K39/3955A61K45/06A61P35/00C07K16/18
Inventor 谢克平
Owner SOUTH CHINA UNIV OF TECH
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