当前位置： SCI文献检索 > BIOCHEMICAL PHARMACOLOGY期刊下所有文献 > TRC4, an improved triptolide derivative, specifically targets to truncated form of retinoid X receptor-alpha in cancer cells.

TRC4, an improved triptolide derivative, specifically targets to truncated form of retinoid X receptor-alpha in cancer cells.

Abstract：

:The nuclear retinoid X receptor-α (RXRα) plays critical roles in cell homeostasis and in many physiological processes mainly through its transcriptional function. However, an N-terminal truncated form of RXRα, tRXRα, was frequently described in various cancer cells and tumor tissues, thus representing a new promising drug target. We recently demonstrated that triptolide (TR01) could target to the oncogenic activity of tRXRα. To improve its tumor selectivity, we developed several TR01 derivatives by introducing different amine ester groups on C-14-hydroxyl site. Interestingly, C-14 modification could differently affect the expression of tRXRα without interfering the level of its full length RXRα. Among the derivatives, TRC4 could strongly reduce tRXRα expression, while TRC5-7 increased it. The capability of inhibiting tRXRα expression was shown to be closely associated with its inactivation of AKT and induction of apoptosis in various cancer cells. Conversely, treatment of cancer cells with the tRXRα-stabilizing compounds TRC5-7 resulted in enhanced AKT activity and apoptosis-resistance. However, although TR01 could strongly reduce tRXRα expression and AKT activity, it also strongly inhibited the expression and transcriptional activity of RXRα in normal cells. Importantly, the tRXRα-selective TRC4 that did not significantly inhibit RXRα transcriptional function retained the most potency of the anticancer effect of TR01 and had no significant effect on the viability of normal cells. In conclusion, our results demonstrated that tRXRα-selective TRC4 will have potential clinical application in terms of drug target and side effects. Our findings will offer new strategies to develop improved triptolide analogs for cancer therapy.

journal_name

Biochem Pharmacol

journal_title

Biochemical pharmacology

authors

Wang PY,Zeng WJ,Liu J,Wu YL,Ma Y,Zeng Z,Pang JY,Zhang XK,Yan X,Wong AST,Zeng JZ

doi

10.1016/j.bcp.2016.10.014

subject

Has Abstract

pub_date

2017-01-15 00:00:00

pages

19-28

eissn

0006-2952

issn

1873-2968

pii

S0006-2952(16)30383-5

journal_volume

124

pub_type

杂志文章

在线工具

TRC4, an improved triptolide derivative, specifically targets to truncated form of retinoid X receptor-alpha in cancer cells.