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Application of eltrombopag in preparing tumor angiogenesis inhibiting drugs and antitumor drug compositions

An angiogenesis and composition technology, applied in the field of medicine, can solve the problems of unclear mechanism of action, no reports of eltrombopag inhibiting breast cancer angiogenesis, no reports of eltrombopag tumor treatment, etc. Cancer angiogenesis, the effect of treatment for cancer cell growth and metastasis

Inactive Publication Date: 2019-10-15
SHANGHAI UNIV OF T C M
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At the same time, there are also literature reports that Eltrombopag has a certain inhibitory effect on the proliferation of various cancer cell lines (including breast cancer cell lines, lung cancer cell lines, oral cancer cell lines, etc.), but there is no clinical application or animal experiment report. Its specific mechanism of action is still unclear
[0006] According to the search, there are reports about Eltrombopag relieving the symptoms of thrombocytopenia caused by chemotherapy in tumor patients in existing studies, but there is no report on the direct application of Eltrombopag in tumor treatment, and there is no report on Eltrombopag inhibiting breast cancer. Reports on cancer angiogenesis

Method used

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  • Application of eltrombopag in preparing tumor angiogenesis inhibiting drugs and antitumor drug compositions
  • Application of eltrombopag in preparing tumor angiogenesis inhibiting drugs and antitumor drug compositions
  • Application of eltrombopag in preparing tumor angiogenesis inhibiting drugs and antitumor drug compositions

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Example 1. Eltrombopag inhibits the interaction between HuR protein and mRNA in vitro

[0051] Using fluorescence polarization technology to construct HuR protein and ARE VEGF-A The high-throughput screening model of sequence interaction is used for preliminary screening, and the positive compounds obtained by the preliminary screening are verified by gel retardation test. The screened compounds include clinical drugs and their derivatives.

[0052] First, the full-length HuR sequence was cloned into the expression vector pET30a(+), and the constructed HuR expression vector was transformed into E.coli Rosetta (DE3) competent cells, and induced and expressed with 0.2mMIPTG at 16°C for 16-18h, The bacteria were collected for lysis, and the supernatant was collected by centrifugation, and then purified by HisTrap FF prepacked column and Sephacryl S-200 molecular sieve to obtain purified HuR protein. Since the HuR protein is bound to the ARE structure in the 3' end sequen...

Embodiment 2

[0056] Example 2. Eltrombopag inhibits the proliferation of various tumor cell lines.

[0057] In order to study the influence of Eltrombopag on the growth of cancer cells, the present invention uses the MTT method to detect the toxic effects of Eltrombopag on multiple tumor cell lines, figure 2 IC of Eltrombopag acting on various cell lines for 48 hours 50 The results show that Eltrombopag has a certain inhibitory effect on the growth of the tested tumor cell lines, and the inhibitory effect on mouse breast cancer cell 4T1 is the best.

Embodiment 3

[0058] Example 3. Eltrombopag inhibits the mRNA levels of angiogenesis-related genes in 4T1 cells by targeting HuR protein.

[0059] The results of in vitro molecular tests showed that Eltrombopag could inhibit the binding of HuR protein to the terminal sequence of VEGF-A mRNA, and literature studies showed that the mRNA sequence bound by HuR had a high degree of similarity. Therefore, the present invention not only verified the influence of Eltrombopag on VEGF-A mRNA in 4T1 cells, but also explored the influence of Eltrombopag on another angiogenic factor MMP9 mRNA in 4T1 cells, the results are as follows image 3 shown.

[0060] First, 10 μM Eltrombopag treatment of 4T1 cells can significantly reduce the mRNA levels of VEGF-A and MMP9 genes ( image 3 A). Secondly, the mRNA stability experiment showed that Eltrombopag could significantly reduce the stability of VEGF-A and MMP9 gene mRNA in 4T1 cells. The half-life of VEGF-A mRNA decreased from 3.74 hours to 2.50 hours ( i...

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Abstract

The invention belongs to the field of medicine, and particularly relates to application of eltrombopag in preparing tumor angiogenesis inhibiting drugs and antitumor drug compositions. The eltrombopagtargetedly combines with a HuR protein, blocks combination of the HuR protein and angiogenesis-associated factor mRNA and has activities of inhibiting expression and secretion of angiogenesis-associated factors, inhibiting proliferation, migration and blood vessel forming of vascular endothelial cells and inhibiting tumor angiogenesis and tumor cell growth; and meanwhile, the eltrombopag also hasa thrombopoiesis facilitating activity, wherein the thrombopoiesis facilitating activity and the tumor cell growth inhibiting activity supplement each other, so that antitumor treatment is promoted.The eltrombopag can be used for preparing the tumor angiogenesis inhibiting drugs and the antitumor drug compositions. The eltrombopag has a new medical application of serving as a tumor angiogenesisinhibiting drug and thus has important application value and significance.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to the application of Eltrombopag in the preparation of anti-cancer angiogenesis drugs and anti-cancer drug compositions. Background technique [0002] Breast cancer is one of the most common malignant tumors in women. Statistics show that compared with the incidence of other malignant tumors in women, the incidence of breast cancer is as high as 10%, second only to uterine cancer. At present, breast cancer treatment mainly adopts surgical resection, combined with radiotherapy, chemotherapy and hormone therapy, but surgical treatment destroys the body, while chemotherapy, radiotherapy and other treatment options have a huge impact on the patient's physiology and psychology, while the recurrence rate is high and the treatment cost is expensive. Therefore, it is still urgent to find a new treatment for breast cancer. [0003] Studies have shown that tumor growth depends on the gro...

Claims

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Application Information

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IPC IPC(8): A61K31/4152A61K45/06A61P35/00
CPCA61K31/4152A61K45/06A61P35/00
Inventor 张建革朱玉莹林国强
Owner SHANGHAI UNIV OF T C M
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