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Application of OPAGANIB in preparation of medicine for treating regorafenib-tolerant liver cancer

A technology for regorafenib resistance and treatment of liver cancer, which can be used in tumor therapy, especially in the field of reversal therapy of tumor resistance, and can solve problems such as unclear process and mechanism.

Active Publication Date: 2020-08-21
NANJING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The acquired resistance of liver cancer to regorafenib is also a research proposition that has just emerged, and its process and mechanism are still unclear. Therefore, whether inhibiting SphK2 can reverse the acquired resistance of liver cancer to regorafenib is still controversial

Method used

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  • Application of OPAGANIB in preparation of medicine for treating regorafenib-tolerant liver cancer
  • Application of OPAGANIB in preparation of medicine for treating regorafenib-tolerant liver cancer
  • Application of OPAGANIB in preparation of medicine for treating regorafenib-tolerant liver cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Example 1 Successful Construction of Liver Cancer Regorafenib Acquired Drug-Resistant Cells

[0043] We detected the sensitivity of five strains of HCC cells BEL-7402, HuH-7, PLC / PRF / 5, SMMC-7721, and MHCC-97H to regorafenib by CCK-8 experiment, and calculated the corresponding Regorafenib IC 50 value. It can be found that the IC of regorafenib of SMMC-7721 and MHCC-97H 50 It was at a lower level in the five cell lines (Table 1), which proved that the two cell lines were relatively sensitive to regorafenib. Therefore, we selected these two lines of cells to construct regorafenib acquired drug-resistant HCC cell lines by increasing the concentration gradient method. After regorafenib continuously stimulated SMMC-7721 and MHCC-97H for six months, we tested the sensitivity of these two cell lines to regorafenib again and found that the IC of the two cell lines regorafenib 50 The value was significantly increased, and the drug resistance index RI was 3.133 (97H-R / 97H), ...

Embodiment 2

[0048] Example 2 The expression level of SphK2 is related to the acquired drug resistance of regorafenib

[0049] In order to verify whether SphKs is involved in the regulation of acquired drug resistance to regorafenib in HCC, we first compared the differences in the protein expression levels of SphK1 and SphK2 between drug-resistant cells and non-resistant maternal cells. The results of Western blot experiments showed that there was no significant difference in the expression of SphK1 protein between MHCC97H and 97H-R, SMMC-7721 and 7721-R, while the expression level of SphK2 was significantly increased in drug-resistant cells 97H-R and 7721-R ( figure 2 .A-B), indicating that SphK2, but not SphK1, may mediate acquired resistance to regorafenib in HCC. In addition, we also found that in five HCC cell lines BEL-7402, HuH-7, PLC / PRF / 5, SMMC-7721, and MHCC97H, the higher the gray value of the Western blot band of SphK2, the corresponding regorafenib IC 50 The value is also h...

Embodiment 3

[0050] Example 3 Overexpression of SphK2 reduces the sensitivity of HCC cells to regorafenib

[0051] In view of the fact that reducing the expression level of SphK2 protein can increase the sensitivity of drug-resistant cells to regorafenib, we further tested whether increasing the expression level of SphK2 protein can reduce the sensitivity of non-drug-resistant cells to regorafenib, and positively verified the role of SphK2 in Important role in acquired resistance to regorafenib in HCC.

[0052] We used lentiviral transfection technology to increase the protein expression level of SphK2 in non-drug-resistant HCC cells MHCC97H and SMMC-7721, and verified it by Western blot experiments. The results showed that the overexpression of SphK2 in non-drug-resistant HCC cells was successful ( image 3 .A). After stimulating HCC cells successfully overexpressing SphK2 and control HCC cells with different concentrations of regorafenib for 48 h, CCK-8 detection found that the viabilit...

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Abstract

The invention relates to the field of treatment of drug-resistant tumors, in particular to an application of a small molecular compound in preparation of a drug for treating regorafenib-tolerant livercancer. The invention discloses a SphK2 inhibitor OPAGANIB capable of reversing the drug resistance of liver cancer to regorafenib. On the basis of a regorafenib liver cancer drug-resistant cell strain and an in-vivo liver cancer drug-resistant model, it is found that the sensitivity of the OPAGANIB treated drug-resistant cell strain to regorafenib is remarkably improved; and after overexpressionof SphK2, the sensitivity of the drug-resistant cell strain to regorafenib is significantly reduced, the results show that the sensitivity of liver cancer cells to regorafenib can be effectively improved by inhibiting the activity of SphK2, so that the problem of drug resistance of liver cancer to regorafenib can be solved. According to the invention, the activity of SphK2 is inhibited by using OPAGANIB, so that the drug resistance of liver cancer to regorafenib is reversed.

Description

technical field [0001] The present invention relates to the field of tumor treatment, especially the reversal treatment of tumor drug resistance, and specifically refers to the application of small molecular compound OPAGANIB in the preparation of drugs for treating regorafenib-resistant liver cancer. Background technique [0002] Hepatocellular carcinoma (HCC) is a major disease that threatens the lives and health of our people. Regorafenib is the standard second-line drug for the treatment of advanced HCC, and it can be used in the treatment of first-line drug Sorafenib (Sorafenib). After that, it continued to take effect, and showed good anti-HCC effects in both in vivo and in vitro studies. However, the occurrence of acquired drug resistance not only limits the long-term benefit of HCC patients from regorafenib treatment, but also exacerbates the disease and accelerates the course of the disease; Optional medicines. Therefore, it is of great clinical significance to se...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/166A61P35/00
CPCA61K31/166A61P35/00
Inventor 江春平吴俊华石维维王忠夏刘淑雯马丁胡丽丽张姗张广曹胤
Owner NANJING UNIV
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