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Application of CDK2 antagonist as differentiation therapy drug sensitizer

A technology for treating drugs and antagonists, applied in the field of biopharmaceuticals, can solve problems such as increasing the sensitivity of differentiation inducers, and achieve the effects of increasing sensitivity, reducing dosage and improving quality of life

Inactive Publication Date: 2013-11-27
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Studies have shown that the main mechanism by which small molecule inhibitors of CDK2 are used in anti-tumor therapy is that they can induce apoptosis and exert curative effect. However, whether small molecule inhibitors of CDK2 can increase the sensitivity of differentiation inducers, especially whether retinoids can promote Drugs can induce differentiation of leukemia cells, thereby improving the prognosis of leukemia patients and solving related drug resistance problems have not yet been reported.

Method used

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  • Application of CDK2 antagonist as differentiation therapy drug sensitizer
  • Application of CDK2 antagonist as differentiation therapy drug sensitizer
  • Application of CDK2 antagonist as differentiation therapy drug sensitizer

Examples

Experimental program
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Effect test

Embodiment 1

[0030] Human leukemia cell line NB4 (gifted by Dr. Lingtao Wu, University of Southern California) or U937 (purchased from the Cell Bank of the Chinese Academy of Sciences) via the differentiation therapy drug ATRA (30ng / ml acts on NB4, 300ng / ml acts on U937, purchased from Sigma-aldrich company), TPA (10ng / ml acts on NB4 and U937, purchased from Sigma-aldrich), AM80 (3.5ng / ml acts on NB4, 35ng / ml acts on U937, gift from Dr. Lingtao Wu, University of Southern California), Dasatinib (DASA, 2.53 / ml acts on NB4, 5.06 / ml acted on U937 (purchased from Sprycel Company) for 72 hours, the cells were collected, and the cells were lysed with cell lysate to extract protein, and then Western blot was performed with CDK2 antibody (purchased from Santa Cruz Company). It was found that all differentiation-inducing drugs can significantly promote the decrease of CDK2 protein expression level, see figure 1 .

Embodiment 2

[0032] The siRNA targeting CDK2 (SEQ ID NO:1) and the negative control were introduced into NB4 cells by electroporation, then 30ng / ml ATRA was added to continue the effect, and the cells were harvested after 72 hours, and the cells were lysed with cell lysate to extract protein , and then Western blot was performed with CDK2 antibody (purchased from Santa Cruz Company). It was found that the above-mentioned CDK2 siRNA can effectively inhibit the protein expression of CDK2, and compared with the single use group, the combination group of siRNA and ATRA also has a significant inhibitory effect. See results figure 2 .

Embodiment 3

[0034] The siRNA targeting CDK2 (SEQ ID NO:1) and the negative control were introduced into NB4 cells by electroporation, and then 30ng / ml ATRA was added to continue to act. After 24, 48, 72 and 120 hours, hemocytometers were used to respectively The number of cells in each group was counted. The results showed that both the above-mentioned CDK2 siRNA and ATRA could effectively inhibit the proliferation of NB4 cells, and compared with the single-use group, the inhibitory effect of the siRNA and ATRA combined group on cell proliferation was more obvious. See results image 3 .

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Abstract

The invention provides application of a CDK2 antagonist in preparation of sensitization drugs of induction differentiation therapy drugs. The CDK2 antagonist inhibits CDK2 gene transcription and / or translation and / or kinase activity, and is siRNA and small molecule chemical inhibitor specific to CDK2. Studies show that the CDK2 antagonist has an induction differentiation effect on leukemia cells, at the same time also promotes the induction differentiation effect of retinoic acid drugs on leukemia cells, and promotes the proliferation inhibition ability on leukemia cells, expression of cell surface differentiation specific antigen CD11b, enhancement of NBT reduction ability and increase of segmented cell number. The CDK2 antagonist involved in the invention is in favor of improving the sensitivity of tumor cells to differentiation therapy drugs, strengthening the differentiation therapy effects, reducing chemotherapy drug dosage, alleviating the toxic and side effects of chemotherapy drugs on human normal cells, and improving the quality of life of tumor patients, thus having good application prospects in the therapy field of leukemia and other tumors.

Description

technical field [0001] The invention belongs to the field of biopharmaceuticals, and relates to the use of CDK2 antagonists to improve the sensitivity of tumor differentiation therapy drugs for clinical tumor treatment. Background technique [0002] Differentiation induction therapy is an important field of tumor chemotherapy. It uses chemical drugs to induce tumor cell differentiation and reverse its proliferation, invasion, metastasis and other malignant phenotypes, making it become normal or close to normal cells, so as to achieve the purpose of treating tumors. Retinoids are the most widely studied and clinically used differentiation inducers, among which all-trans retinoid acid (ATRA) is the first differentiation-inducing drug successfully applied in the treatment of leukemia, which can specifically induce Acute promyelocytic leukemia (APL) cells mature. In 1988, Shanghai Ruijin Hospital took the lead in using ATRA to treat 24 cases of APL, and 23 cases a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61K48/00A61K31/4178A61P35/00A61K31/203
Inventor 应美丹何俏军杨波邵雪晶齐晓甜
Owner ZHEJIANG UNIV
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