Identification of a Raloxifene Analog That Promotes AhR-Mediated Apoptosis in Cancer Cells.

Hyo Jang,Martin Pearce,Bach Nguyen,William Bisson,Siva Kolluri,Robert Tanguay,Edmond O’Donnell,Lisa Truong,Monica Mueller,Nancy Kerkvliet

doi:10.3390/biology6040041

Abstract

We previously reported that raloxifene, an estrogen receptor modulator, is also a ligand for the aryl hydrocarbon receptor (AhR). Raloxifene induces apoptosis in estrogen receptor-negative human cancer cells through the AhR. We performed structure–activity studies with seven raloxifene analogs to better understand the structural requirements of raloxifene for induction of AhR-mediated transcriptional activity and apoptosis. We identified Y134 as a raloxifene analog that activates AhR-mediated transcriptional activity and induces apoptosis in MDA-MB-231 human triple negative breast cancer cells. Suppression of AhR expression strongly reduced apoptosis induced by Y134, indicating the requirement of AhR for Y134-induced apoptosis. Y134 also induced apoptosis in hepatoma cells without having an effect on cell cycle regulation. Toxicity testing on zebrafish embryos revealed that Y134 has a significantly better safety profile than raloxifene. Our studies also identified an analog of raloxifene that acts as a partial antagonist of the AhR, and is capable of inhibiting AhR agonist-induced transcriptional activity. We conclude that Y134 is a promising raloxifene analog for further optimization as an anti-cancer agent targeting the AhR.

Highlights

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that has been well studied in the fields of toxicology, physiology, and pathology [1]
We found that analog E, referred to as Y134, increased AhR
We found that analog E, referred to as Y134, increased AhR activation (Figure 1B)

Summary

Introduction

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that has been well studied in the fields of toxicology, physiology, and pathology [1]. The AhR belongs to the basic helix-loop-helix (bHLH)–Per-Arnt-Sim (PAS) family of proteins, and the bHLH–PAS domain is required for DNA binding and heterodimer formation with other PAS domain proteins such as. Arnt [2,3,4] Members of this family control physiological processes including cancer cell growth and survival, and certain proteins with the bHLH–PAS domain have defined ligand binding pockets that present an opportunity to develop compounds to modulate these desirable biological activities [5]. The AhR has tumor suppressive functions, and can be activated by distinct ligands with diverse underlying mechanisms of action including inhibition of cell cycle progression and cancer cell survival [9,10]. Using small molecule screening approaches, we have previously identified compounds with anti-cancer effects that function through the AhR [11,12,13]

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