Application of homoharringtonine-type compounds in antitumor drug preparation

A technology for homoharringtonine and harringtonine, which is applied in the fields of medicine and medicinal chemistry, and can solve the selection and application of clinical indications of hindering compounds, homoharringtonine and harringtonine target molecules and their target molecules. Molecular mechanism ominous and other issues

Inactive Publication Date: 2016-01-06
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, so far, the exact target molecules of homoharringtonine and harringtonine and their molecular mechanisms are still unknown, seriously hindering the selection and application of these compounds for clinical indications

Method used

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  • Application of homoharringtonine-type compounds in antitumor drug preparation
  • Application of homoharringtonine-type compounds in antitumor drug preparation
  • Application of homoharringtonine-type compounds in antitumor drug preparation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Example 1: Identification of the target molecule p-eIF4E for the antitumor effect of homoharringtonine

[0019](1) Biotin-labeled homoharringtonine and 1ml human leukemia THP-1 cell protein solution were incubated overnight at 4°C in a 1.5ml EP centrifuge tube to allow biotin-labeled homoharringtonine to interact with the protein Fully combined; (2) add an appropriate amount of avidin magnetic beads and incubate at room temperature for 1 hour, so that the protein specifically bound to homoharringtonine can be captured on the surface of avidin magnetic beads by biotin; (3) in the magnetic field Wash off the unbound protein with buffer on the rack; (4) add protein lysate and boil in a water bath for 5 minutes to lyse the protein specifically bound to homoharringtonine from the surface of the magnetic beads; (5) The lysed protein was separated by SDS-PAGE protein electrophoresis, and the protein band was stained with Coomassie brilliant blue; (6) The stained protein band...

Embodiment 2

[0020] Example 2: Expression of phosphorylated eIF4E (p-eIF4E) in different tumor cell lines, primary tumor cell samples and normal cells

[0021] (1) Experimental materials

[0022] Leukemia cell lines: KG-1a, KG-1, Kasumi, HL-60, U937, NB4, THP-1. Primary leukemia cell samples were from different types of AML, and normal blood cell samples were from volunteers.

[0023] (2) The experimental method adopts conventional immunoblotting technique.

[0024] The cellular proteins of leukemia cells and normal blood cell samples were extracted according to conventional methods, separated by SDS-PAGE protein electrophoresis, and then transferred to NC membranes, and the experimental steps of primary antibody and secondary antibody incubation, color development, and exposure were performed according to conventional methods. β-actin was used as an internal reference. The result is as figure 2 It shows that p-eIF4E is highly expressed in leukemia cell lines (A) and some primary le...

Embodiment 3

[0025] Example 3: Harringtonine and homoharringtonine inhibit the expression of p-eIF4E in human THP-1 leukemia cells

[0026] (1) Experimental materials

[0027] Leukemia cell line: human THP-1 leukemia cell line (acute myeloid leukemia-M5, AML-M5).

[0028] Reagents: harringtonine, homoharringtonine

[0029] (2) Experimental method

[0030] Well-grown leukemia cells were inoculated into the wells of a 6-well cell culture plate at a density of 1×10 6 / ml. The culture medium was 1640 cell culture medium containing 10% fetal bovine serum. Add different concentrations of harringtonine and homoharringtonine, mix well, and place in carbon dioxide (5% CO 2 ) cell incubator 37 oC Incubate for 48 hours. Then the cellular protein was extracted, and the expression level of p-eIF4E was detected by immunoblotting.

[0031] (3) Experimental results

[0032] See the experimental results image 3 . Harringtonine (HT) and homoharringtonine (HHT) down-regulated p-eIF4E levels in ...

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Abstract

The invention provides application of homoharringtonine-type compounds in antitumor drug preparation, especially aiming at p-eIF4E expressed positive tumors. Phosphorylated eIF4E(p-eIF4E), which is separated and identified from tumor cells by biotin-labeled HHT (homoharringtonine), is one of important anti-tumor target molecules of the homoharringtonine-type compounds; studies show that the p-eIF4E is in an extremely high expression state in some tumors, and the homoharringtonine-type compounds have remarkable inhibition effect on the p-eIF4E expressed positive tumors. The homoharringtonine-type compounds can be applied to preparation of drugs for treating the p-eIF4E expressed positive tumors.

Description

technical field [0001] The invention belongs to the field of medicine and medicinal chemistry, and relates to antitumor compounds and corresponding target molecules, in particular to the use of homoharringtonine compounds in treating phosphorylated eIF4E (p-eIF4E) positive tumors. Background technique [0002] Homoharringtonine (Homoharringtonine, HHT) is derived from the three-pointed taxa plant three-pointed taxa ( Cephalotaxusharringtonia ) alkaloids extracted and isolated from plants of the same genus. This genus contains a variety of alkaloids, such as homoharringtonine (HHT), harringtonine (HT), isoharringtonine and deoxyharringtonine, Some of these alkaloids such as harringtonine and homoharringtonine not only have similar structures, but also have significant anticancer activity and immunosuppressive activity, and have been widely used in the treatment of various malignant tumors such as leukemia (SmithCRJr, et al. .ThegenusCephalotaxus:sourceofhomoharringtonineand...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/55A61P35/00A61P35/02
Inventor 徐荣臻黄文栋干小仙古莹周虹陆新良
Owner ZHEJIANG UNIV
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