A Unique Pharmacophore for Activation of the Nuclear Orphan Receptor Nur77 In vivo and In vitro

Abstract

Nur77 is a steroid orphan receptor that plays a critical role in regulating proliferation, differentiation, and apoptosis, including acting as a switch for Bcl-2 function. We previously reported that the octaketide cytosporone B (Csn-B) is a natural agonist for Nur77. In this study, we synthesized a series of Csn-B analogues and performed a structure-activity analysis that suggested criteria for the development of a unique pharmacophore to activate Nur77. The components of the pharmacophore necessary for binding Nur77 included the benzene ring, the phenolic hydroxyl group, and the acyl chain of the Csn-B scaffold, whereas the key feature for activating the biological function of Nur77 was the ester group. Csn-B analogues that bound Nur77 tightly not only stimulated its transactivation activity but also initiated mitochondrial apoptosis by means of novel crosstalk between Nur77 and BRE, an antiapoptotic protein regulated at the transcriptional level. Notably, the derivative n-amyl 2-[3,5-dihydroxy-2-(1-nonanoyl)phenyl]acetate exhibited greater antitumor activity in vivo than its parent compounds, highlighting particular interest in this compound. Our findings describe a pathway for rational design of Csn-B-derived Nur77 agonists as a new class of potent and effective antitumor agents.Cancer Res; 70(9); 3628-37. ©2010 AACR.

Design and characterization of Amoitone B-loaded nanostructured lipid carriers for controlled drug release

“…A series of derivants is synthesized for better activity. Amoitone B (chemical structure shown in Figure 1) is one of the derivants, which has been proved to be the most effective analogue and with the surpassed anticancer activity than its parent compound (Zhan et al, 2008;Liu et al, 2010). It is regarded as a potential anticancer agent due to its powerful functions for Nur77 and outstanding anticancer activity.…”

Erratum: The nuclear receptor TR3 regulates mTORC1 signaling in lung cancer cells expressing wild-type p53

“…This pathway is being extensively exploited for drug development. The importance of TR3 nuclear export has been confirmed in recent studies in liver cancer which show that endogenous suppression of TR3 nuclear export by the chromodomain helicase/adenosine triphosphatase DNA binding protein 1-like oncogene is an important determinant for liver cancer (Chen et al, 2009;Chen et al, 2010). A recent study showed that TR3 knockdown or treatment with DIM-CpPhOH inhibited growth and induced apoptosis in pancreatic cancer cells and downregulated expression of survivin (Lee et al, 2010b).…”

Vitamin K2 as a Chemotherapeutic Agent for Treating Ovarian Cancer

“…This suggests that TR3/Nur77 migrated directly from the cytoplasm to the mitochondria and no translocation from the nucleus to mitochondria occurred. It should be noted that this effect of vitamin K2 on ovarian cancer PA-1 cells is unique and different from that of apoptosis-inducing agents such as etoposide (Li et al, 2000) and cytosporone B (Liu et al, 2010) which cause translocation of TR3/Nur77 from the nuclei to the mitochondria.…”

“…The expression of TR3/Nur77 is rapidly induced during cancer cell apoptosis triggered by various apoptotic agents, such as phorbol ester 12-O-tetradecanoyl phobol-13-acetate (Li et al, 2000), etoposide (Li et al, 2000), cytosporone B (Liu et al, 2010), and the synthetic retinoid 6-[3-(1-admantyl)]-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437, Holmes et al, 2004). TR3/Nur77 translocates from the nucleus to mitochondria in response to these apoptosis inducers, with the exception of CD437 (Li et al, 2000).…”