Application of canagliflozin in preparation of anti-tumor medicines

An anti-tumor drug and drug technology, applied in anti-tumor drugs, drug combinations, pharmaceutical formulations, etc., can solve the problems of slow progress and retention of small molecule drugs

Active Publication Date: 2019-07-23
INNOVATION INST FOR ARTIFICIAL INTELLIGENCE IN MEDICINE OF ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, most of these compounds are still in the laboratory research stage, so the research on small molecule drugs of PD-1 / PD-L1 is generally progressing slowly

Method used

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  • Application of canagliflozin in preparation of anti-tumor medicines
  • Application of canagliflozin in preparation of anti-tumor medicines
  • Application of canagliflozin in preparation of anti-tumor medicines

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] Canagliflozin significantly down-regulated the PD-L1 protein level after 24 hours of treatment on non-small cell lung cancer H1299 cells and osteosarcoma MG63 cells. Specific steps are as follows:

[0017] Multiple strains of human tumor cells were selected from non-small cell lung cancer H1299 cells and osteosarcoma MG63 cells to inoculate in 6-well plates, 1.0×10 6 Cells / well, 37°C, 5% CO 2 Cultured in the incubator overnight; the next day, canagliflozin (Canagliflozin, 20μM) and γ-interferon (IFNγ, 10ng / ml) were administered for 24 hours, the cells were collected and lysed, the protein was extracted, and the PD- in the cells was detected by Western blotting. For the expression of L1, the inhibitory effect of specific concentrations of canagliflozin on PD-L1 protein in non-small cell lung cancer H1299 cells and osteosarcoma MG63 cells can be found in figure 1 , Canagliflozin can significantly inhibit the total protein expression of PD-L1 in tumor cells.

Embodiment 2

[0019] Canagliflozin significantly down-regulated the level of PD-L1 protein on the cell surface after 24 hours of treatment on non-small cell lung cancer H1299 cells and osteosarcoma MG63 cells. Specific steps are as follows:

[0020] Two lines of human tumor cells, non-small cell lung cancer H1299 cells and osteosarcoma MG63 cells, were selected and inoculated in 6-well plates, 1.0×10 6 Cells / well, 37°C, 5% CO 2 Cultured in the incubator overnight; the next day, canagliflozin (Canagliflozin, 20 μM) and γ-interferon (IFNγ, 10 ng / ml) were administered for 24 hours, and flow cytometry was used to detect the expression of PD-L1 on the cell surface. Inhibitory effect of canagliflozin on PD-L1 protein in non-small cell lung cancer H1299 cells and osteosarcoma MG63 cells figure 2 , Canagliflozin can significantly inhibit the expression of PD-L1 protein on the surface of tumor cells.

Embodiment 3

[0022] Effect of canagliflozin on the stability of PD-L1 protein in non-small cell lung cancer H1299 cells. Specific steps are as follows:

[0023] Non-small cell lung cancer H1299 cells were selected and seeded in 6-well plates, 1.0×10 6 Cells / well, 37°C, 5% CO 2 Incubate overnight in the incubator. The next day, IFNγ (10ng / ml) was administered for 24 hours in advance, and then the protein synthesis inhibitor cycloheximide (CHX, 10μg / mL) or CHX (10μg / mL) + Canagliflozin (20μM) co-administration groups were administered at the same time. At 0h, 2h, 4h, 6h, 8h, and 12h, the cells were collected, and the protein level of PD-L1 in the cells was detected by Western blotting, grayscale analysis was performed, and the stability of the protein was investigated after a graph was drawn. See the specific role image 3 , Canagliflozin can significantly promote the degradation of PD-L1 protein and shorten its protein half-life.

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Abstract

The invention provides application of canagliflozin in preparation of anti-tumor medicines, particularly provides application of canagliflozin in preparation of medicines for treating solid tumors. Researches prove that canagliflozin has a remarkable effect of reducing immune checkpoint protein PD-L1 in multiple tumor cells, and can effectively reinforce the killing effect of a T cell on tumor cells in a T cell and tumor cell co-incubation model, so that the clinical application of chemical drug canagliflozin in tumor immunotherapy can be expanded.

Description

technical field [0001] The invention belongs to the field of pharmacy and relates to the application of canagliflozin in the preparation of antitumor drugs. Background technique [0002] Programmed death-1 (PD-1) and its ligand (Programmed deathligand-1, PD-L1) combine to form an immunosuppressive microenvironment, which plays a key role in tumor immune escape. A monoclonal antibody drug based on blocking PD-1 / PD-L1 binding has been successfully applied in the treatment of clinical hematological tumors and solid tumors, and some patients can even achieve "clinical cure", which is a breakthrough in the field of tumor immunotherapy progress. Although clinical data show that PD-1 / PD-L1 antibody drugs have significant clinical anti-tumor efficacy, PD-1 / PD-L1 monoclonal antibody drugs still face huge challenges: 1) The response rate is low and needs to be further improved. The response rate in solid tumor treatment does not exceed 20%. Some studies believe that one of the reas...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/381A61P35/00
CPCA61K31/381A61P35/00A61K31/7042
Inventor 杨波何俏军丁玲
Owner INNOVATION INST FOR ARTIFICIAL INTELLIGENCE IN MEDICINE OF ZHEJIANG UNIV
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