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Application of triptolide, triptolide derivant and triptolide analogue in preparation of antitumor drugs

A technology of triptolide, an anti-tumor drug, applied in the field of triptolide, which can solve the problems of unclear mechanism of anti-tumor effect, no target, modification and optimization, etc.

Inactive Publication Date: 2012-08-15
XIAMEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although it is widely used in the treatment of rheumatoid arthritis, lupus erythematosus, psoriasis and recently for anti-tumor diseases, the mechanism of anti-tumor effects of tripterygium wilfordii and its derivatives is still unclear, and has not been found. A clear target, so it is difficult to effectively modify and optimize the structure, which is the main reason restricting its further development as an anticancer drug

Method used

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  • Application of triptolide, triptolide derivant and triptolide analogue in preparation of antitumor drugs
  • Application of triptolide, triptolide derivant and triptolide analogue in preparation of antitumor drugs
  • Application of triptolide, triptolide derivant and triptolide analogue in preparation of antitumor drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Example 1. The anticancer activity of triptolide is closely related to the expression of tRXRα in cells

[0027]In many different cancer cells, we found that triptolide and its analogs are a strong inducer of cancer cell apoptosis. Through reporter gene analysis, we found that triptolide and triptolide and other triptolide compounds have Inhibiting the agonistic effect of 9-cis-RA on RXRα indicates that this kind of compound may regulate the activity of RXRα. Since tRXRα is abundantly expressed in cancer cells in many tumors, in order to study whether the apoptotic effect of triptolide is related to the expression of tRXRα in cells, we selected a variety of different cancer cells, including liver cancer 7703 cells, breast cancer cells MCF-7 cells, colon cancer SW480 cells and cervical cancer Hela cells were analyzed by Western blotting to analyze the expression of tRXRα in cancer cells, and to analyze its relationship with triptolide-induced PARP cleavage.

[0028] The...

Embodiment 2

[0035] Example 2: Intracellular transfection of tRXRα can enhance the apoptosis-inducing effect of triptolide

[0036] tRXRα is a truncated protein due to the cleavage of the N-terminus. Judging from the molecular weight, the cleavage site is near the 80 amino acids of the N-terminus (Zhou, H. et al, 2010), and a mutation of 80aa missing the N-terminus was constructed The expression vector pCMV-Myc-RXRα / Δ80 was transfected into HEK293T and SW480 cells that did not express tRXRα, and MCF-7 cells that expressed higher levels, to study whether the effect of triptolide was due to the expression of tRXRα in cells increase and enhance.

[0037] The cells were cultured in a 6-well tissue culture plate at 37°C and 5% carbon dioxide incubator. After 24 hours, the constructed pCMV-Myc-RXRα / Δ80 was transfected into SW480 by liposome 2000, and the cells were cultured for 24 hours. Treat with 50nM triptolide in serum-free DMEM for 9h. Cells were collected and lysed on ice for 30 min with...

Embodiment 3

[0039] Example 3. The apoptosis-inducing effect of triptolide on cancer cells was significantly weakened by siRNA interference with the expression of tRXRα in cancer cells.

[0040] In order to further study whether the apoptosis-inducing effect of triptolide is mediated by intracellular tRXRα, we synthesized a variety of siRNAs that can interfere with the expression of intracellular tRXRα (Zhou, H. et al, 2010), and transfected them into In cervical cancer cell HeLa and breast cancer cell MCF-7, which highly express tRXRα, the cells were treated with triptolide to analyze whether the apoptosis-inducing effect of triptolide was affected.

[0041] The cells were cultured in a 6-well tissue culture plate at 37°C and 5% carbon dioxide incubator. After 24 hours, the synthetic siRNA was transfected into the cells through liposomes. DMEM treatment for 12h. Cells were collected and lysed on ice for 30 min with improved RIPA lysis buffer (50 mM Tris-HCl, pH 7.4; 150 mM NaCl; 5 mM EDT...

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Abstract

Application of triptolide, triptolide derivant and triptolide analogue in preparation of antitumor drugs relates to triptolide. A method for utilizing tRXRZ (truncated retinoid X receptor) alpha as a target spot to screen the triptolide, the triptolide derivant and the triptolide analogue which is tripdiolide includes a following step of acting the triptolide into a tumor cell line containing the tRXR alpha so as to obtain the triptolide, the triptolide derivant and the triptolide analogue which are screened by utilizing the tRXR alpha as the acting target spot. After the triptolide, the triptolide derivant and the triptolide analogue which are screened by utilizing the tRXR alpha as the acting target spot act to the tumor cell line, the tRXR alpha can be targeted, mutual actions of the tRXR alpha and p85 can be inhibited, then AKT (threonine kinase) activation induced by TNF (tumor necrosis factor) alpha can be inhibited, a caspase 8 apoptosis signal channel induced by the TNF alpha can be activated, and cancer cell apoptosis can be induced.

Description

technical field [0001] The invention relates to triptolide, in particular to a method for screening and optimizing triptolide and its analogues by taking tRXRα as an action target. Background technique [0002] Nuclear receptors (nuclear receptors, NR) are a family of transcription factor supergenes that are activated by lipophilic small molecule ligands in cells, and retinol X receptors (RXR) are a core member of the nuclear receptor superfamily , it has three different subtypes of α, β and γ, among which, RXRα is highly expressed in most cells, and its unique role is that it can form homodimers or form heterodimers with RAR Retinoids mediate the biological effects of retinoids, and can also participate in the expression of other nuclear receptors, such as PPAR, VDR, LXR, PXR, TR3 and COUP-TF, by about 1 / 3 in the form of heterodimers The functional regulation of the family members of the family leads to different biological effects (Germain, P. et al. 2006; Zeng, J. Z. et ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12Q1/02A61K31/585A61P35/00
Inventor 曾锦章张晓坤陆娜刘金星
Owner XIAMEN UNIV
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