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Application of acetaldehyde dehydrogenase 2 as drug target for treating tumor cells with anthracycline type chemotherapy drugs

A technology of acetaldehyde dehydrogenase and chemotherapeutic drugs, applied in the fields of biotechnology and medicine, can solve the problems of increasing the risk of multiple cancers, and achieve the effects of increasing the killing effect and wide application prospect.

Inactive Publication Date: 2014-05-14
RUIJIN HOSPITAL AFFILIATED TO SHANGHAI JIAO TONG UNIV SCHOOL OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there are few studies on the relationship between aldehyde dehydrogenase 2 and cancer, and most of them focus on statistics. There are many statistical data showing that people who carry ALDH2 mutation genotypes drink a lot of alcohol will significantly increase the risk of various cancers , including liver cancer, esophageal cancer, etc.

Method used

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  • Application of acetaldehyde dehydrogenase 2 as drug target for treating tumor cells with anthracycline type chemotherapy drugs
  • Application of acetaldehyde dehydrogenase 2 as drug target for treating tumor cells with anthracycline type chemotherapy drugs
  • Application of acetaldehyde dehydrogenase 2 as drug target for treating tumor cells with anthracycline type chemotherapy drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1: Anthracycline chemotherapy drugs specifically kill VHL-deficient renal clear cell carcinoma cell lines.

[0032] Based on the deletion of VHL-expressing renal clear cell carcinoma cell line RCC4 cells, we transfected VHL to construct a VHL-expressing cell line RCC4-VHL, and transfected empty RCC4 cells, such as figure 1 As shown, RCC4 cells under normoxic (N) and hypoxic (H) treatment conditions, due to the absence of VHL, HIF1-expressed continuously; while RCC4-VHL cells, due to the expression of VHL, HIF1- only accumulated under hypoxic conditions . Using RCC4 and RCC4-VHL cells as models, we tested the cell growth inhibition rate of commonly used chemotherapeutic drugs and some potential anti-tumor drugs CCK-8. We found that anthracycline chemotherapy drugs (in the red box) specifically inhibited the growth of RCC4, but had little effect on RCC4-VHL ( figure 2 A). We further verified with different concentrations and times, and found that there were su...

Embodiment 2

[0033] Example 2: Through proteomics and large-scale screening methods, it was found that VHL may cause differences in the sensitivity of cells to DOX by regulating aldehyde dehydrogenase 2.

[0034] Example 1 suggested that the genes affecting the sensitivity of anthracyclines in renal cancer cells are HIF-1-independent, so we treated RCC4 and RCC4-VHL cells with normoxia and hypoxia, respectively, and used quantitative proteomics based on SILAC A method to find proteins that are only regulated by VHL but not regulated by HIF-1 ( image 3 A), a total of 129.

[0035] In order to further find out those proteins that affect doxorubicin sensitivity, we established a nematode drug screening model, the screening process is as follows image 3 B, first we verified whether our screening model was available, we knocked out VHL in nematodes, and the number of nematodes died after being treated with DOX was significantly more than that of the control group ( Figure 4 A, Figure 4 C...

Embodiment 3

[0036] Example 3: VHL can transcriptionally regulate aldehyde dehydrogenase 2.

[0037] like image 3 As shown, we found that aldehyde dehydrogenase 2 (ALDH2) was significantly regulated by VHL, while HIF-1 did not affect its expression. At the same time, we verified the results of proteomics. We treated RCC4 and RCC4-VHL cells under normoxia and hypoxia respectively, and detected the protein of acetaldehyde dehydrogenase 2 by WB ( Figure 5 A) and mRNA expression ( Figure 5 B), The protein and mRNA levels of aldehyde dehydrogenase 2 are only regulated by VHL, but not by HIF-1 and hypoxia. Further, we knocked out VHL in RCC4-VHL cells ( Figure 5 C), overexpression of VHL in 786-0 cells ( Figure 5 D), knocking out VHL in CAKI-1 cells ( Figure 5 E), it was found that VHL always positively regulates the mRNA of ALDH2 from the transcriptional level. In addition, we wanted to know whether this regulation is unique to renal clear cell carcinoma, so we selected a liver canc...

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Abstract

The invention discloses an application of acetaldehyde dehydrogenase 2 as a drug target for treating tumor cells with anthracycline type chemotherapy drugs. Drug screening shows that the anthracycline type chemotherapy drugs can specifically kill renal clear cell cancer cells with VHL deletion or mutation and has small toxicity to normal cells, thus providing an effective choice for chemotherapy of renal cancer and overcoming the disadvantage that the renal cancer is only treated through operations in clinical at present. Further study shows the sensitivity of the acetaldehyde dehydrogenase 2 mediated anthracycline type chemotherapy drugs to tumor cells, thus remaindering the application of the acetaldehyde dehydrogenase 2 as the drug target for treating tumor cells with the anthracycline type chemotherapy drugs. Deletion or mutation of the acetaldehyde dehydrogenase 2 exists in 40% of populations in Asia, so that the application of the acetaldehyde dehydrogenase 2 has a broader application prospect. For patients without the deletion or the mutation of the acetaldehyde dehydrogenase 2, killing effects on tumor cells can be significantly enhanced through combination of the anthracycline type chemotherapy drugs and an inhibitor of the acetaldehyde dehydrogenase 2.

Description

technical field [0001] The invention relates to the fields of biotechnology and medicine, in particular to the application of acetaldehyde dehydrogenase 2 as a drug target when anthracycline chemotherapy drugs treat tumor cells. Background technique [0002] Tumor is currently one of the biggest killers that endanger human health. At present, the main treatment methods for clinical tumors are surgical resection and radiotherapy and chemotherapy. Chemotherapy uses chemical drugs to kill tumor cells, inhibit the growth and reproduction of tumor cells, and promote the differentiation of tumor cells. A treatment method, it is a systemic treatment that has a therapeutic effect on primary lesions, metastatic lesions, and subclinical metastatic lesions. However, chemotherapy can kill tumor cells while killing normal cells and immune cells. It can also cause side effects such as gastrointestinal dysfunction and bone marrow suppression, which greatly reduces the quality of life of pa...

Claims

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Application Information

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IPC IPC(8): A61K31/704A61K45/00A61P35/00
Inventor 王立顺陈国强高耀辉李彩霞
Owner RUIJIN HOSPITAL AFFILIATED TO SHANGHAI JIAO TONG UNIV SCHOOL OF MEDICINE
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