Effects and application of artemisinin and its derivative in inhibition of platelet-derived growth factor receptor A

A technology of artemisinin derivatives and growth factor receptors, which is applied in the field of biomedicine and can solve the problems of unclear targets, related signaling pathways and mechanism of action

Active Publication Date: 2013-08-21
SHANGHAI INST OF BIOLOGICAL SCI CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] With the continuous deepening of research on the activity of artemisinin and its derivatives, it has been found that this kind of compound has inhibitory effect on the growth of various tumor cells and good therapeutic effect. However, its specific action targets and related signaling pathways and mechanism of action is unclear

Method used

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  • Effects and application of artemisinin and its derivative in inhibition of platelet-derived growth factor receptor A
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  • Effects and application of artemisinin and its derivative in inhibition of platelet-derived growth factor receptor A

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Experimental program
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Effect test

Embodiment 1

[0112] Artemisinin and its derivatives directly bind to PDGFRα, inhibit its phosphorylation activity, and promote its degradation

[0113] Using PDGFRα in vitro kinase experiments, surface plasmon resonance, computer-aided isotype modeling and reverse docking experiments and other advanced biological techniques and methods such as molecular pharmacology and biophysics, it is confirmed that artemisinin derivatives can directly bind to PDGFRα, inhibit The receptor tyrosine kinase activity of PDGFRα. At the same time, studies have found that dihydroartemisinin can inhibit the protein stability of PDGFRα in PDGFRα-positive cells and promote its ubiquitin-dependent degradation process.

[0114] figure 1 It shows that artemisinin and its derivatives can directly bind to PDGFRα, PDGFRα is the direct target of artemisinin and its derivatives, and can inhibit its phosphorylation activity and promote its degradation. In vitro kinase experiments showed that artemisinin and its derivativ...

Embodiment 2

[0116] Artemisinin and its derivatives inhibit the growth and metastasis of PDGFRα-positive tumor cells

[0117] The orthotopic ovarian cancer xenograft model in nude mice was used to study the anti-ovarian cancer activity of dihydroartemisinin in animals. The luciferase-labeled human ovarian cancer cells A2780 were injected into the peritoneal cavity of Balb-c nude mice to establish an orthotopic model of ovarian cancer in nude mice, and then treated with dihydroartemisinin: control group (normal saline), low-dose group ( DHA 10mg / kg). The high-dose group (DHA 25mg / kg) was treated five times a week, with a two-day break, for a total of 6 weeks of treatment. During the period, an in vivo imaging system was used to observe the growth and metastasis of ovarian cancer in mice.

[0118] Through a series of studies at the cell level and animal level, it has been shown that artemisinin derivatives can effectively inhibit the growth, migration and invasion of PDGFRα-positive tumor ...

Embodiment 3

[0123] Sensitization of artemisinin and its derivatives with first-line chemotherapeutics

[0124] Artemisinin and dihydroartemisinin alone in vitro can significantly inhibit the growth, proliferation, migration and invasion of ovarian cancer and liver cancer cells. In this example, whether it has a chemosensitizing effect was tested. Artemisinin and dihydroartemisinin combined with gemcitabine respectively acted on human liver cancer cells HepG2 and Hep3B, and combined with carboplatin on ovarian cancer A2780 and OVCAR3 To observe the inhibitory effect of combined drugs on cell growth. result( Figure 5 )As follows:

[0125] HepG2 and Hep3B cells were treated with 10 μmol / L artemisinin or dihydroartemisinin alone or combined with 10 μg / L gemcitabine for 48 hours, and quantitative detection of cell apoptosis was carried out according to the above method. Specifically, gemcitabine alone acts on HepG2, and Hep3B cells show a certain apoptosis-promoting effect ( Figure 5 a),...

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Abstract

The invention relates to effects and application of artemisinin and its derivative in inhibition of platelet-derived growth factor receptor A. Particularly, artemisinin and its derivative directly act on a molecular target platelet-derived growth factor receptor A (PDGFR alpha) of a tumor and combines with PDGFR alpha on a cell membrane to inhibit activation of tyrosine kinase at the intracellular domain of PDGFR alpha, inhibit protein stability of PDGFR alpha, and promote a ubiquitin-dependent proteasome mediated degradation process. The artemisinin and its derivative has dose-dependent cell growth inhibition and migration invasion inhibition effects on PDGFR alpha highly expressed tumor cells, and also can inhibit activation of signaling pathways PI3K/AKT and MAPK/ERK.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular, the invention relates to the effect of artemisinin and its derivatives in inhibiting platelet-derived growth factor receptor A and their application. Background technique [0002] Artemisia annua, also known as Artemisia anaua L., belongs to the Asteraceae family and is an annual herb. Artemisinin is a sesquiterpene lactone antimalarial drug extracted by Chinese pharmaceutical workers from the traditional Chinese medicine Artemisia annua in the early 1970s. In view of the common problem of resistance to traditional quinine drugs, artemisinin and its derivatives have replaced them and become the mainstream anti-malarial drugs in the world. There is an endoperoxide bridge on the macrocycle of artemisinin, under the catalysis of ferrous ion or heme, it will release a carbon-centered free radical. Proteins and nucleic acids in cells die after being alkylated by these free radicals. Plasmo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/366A61K31/357A61P35/00A61P9/10A61P9/12A61P11/00A61P1/16A61P17/00A61P13/12A61P9/00A61K31/7068A61K31/282
Inventor 王慧李晓光陈培战
Owner SHANGHAI INST OF BIOLOGICAL SCI CHINESE ACAD OF SCI
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