TRC4, an improved triptolide derivative, specifically targets to truncated form of retinoid X receptor-alpha in cancer cells.
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.
State Key Laboratory of Cellular Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.
Pei-Yu
PY
Wang
State Key Laboratory of Cellular Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.
Wen-Jun
WJ
Zeng
State Key Laboratory of Cellular Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.
Jie
J
Liu
State Key Laboratory of Cellular Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.
Yun-Long
YL
Wu
State Key Laboratory of Cellular Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.
Yinghui
Y
Ma
State Key Laboratory of Cellular Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.
Zhiping
Z
Zeng
School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, China. Electronic address: cespjy@mail.sysu.edu.cn.
Ji-Yan
JY
Pang
State Key Laboratory of Cellular Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.
Xiao-Kun
XK
Zhang
College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, China.
Xiaomei
X
Yan
School of Biological Sciences, University of Hong Kong, Pokfulam Road, Hong Kong.
Alice Sze Tsai
AST
Wong
State Key Laboratory of Cellular Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China. Electronic address: jzzeng@xmu.edu.cn.
Jin-Zhang
JZ
Zeng
D015153:Blotting, Western; D045744:Cell Line, Tumor; D004224:Diterpenes / Q000494:pharmacology*; D004852:Epoxy Compounds / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008856:Microscopy, Fluorescence; D010616:Phenanthrenes / Q000494:pharmacology*; D047490:Retinoid X Receptor alpha / Q000187:drug effects* / Q000235:genetics; D015533:Transcriptional Activation
D004224:Diterpenes; D004852:Epoxy Compounds; D010616:Phenanthrenes; D047490:Retinoid X Receptor alpha; C001899:triptolide
AKT; Cancer; Derivatives; Triptolide; Truncated retinoic X receptor-alpha