Oncotarget

Research Papers:

Oxidized analogs of Di(1H-indol-3-yl)methyl-4-substituted benzenes are NR4A1-dependent UPR inducers with potent and safe anti-cancer activity

Marisa Sanchez, Zebin Xia, Elizabeth Rico-Bautista, Xihua Cao, Michael Cuddy, David J. Castro, Ricardo G. Correa, Liqun Chen, Jinghua Yu, Andrey Bobkov, Vivian Ruvolo, Michael Andreeff, Robert G. Oshima, Shu-Ichi Matsuzawa, John C. Reed, Xiao-Kun Zhang, Donna Hansel, Dieter A. Wolf, _ Marcia I. Dawson

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Oncotarget. 2018; 9:25057-25074. https://doi.org/10.18632/oncotarget.25285

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Abstract

Marisa Sanchez1,*, Zebin Xia1,*, Elizabeth Rico-Bautista1, Xihua Cao1, Michael Cuddy1, David J. Castro1,3, Ricardo G. Correa1, Liqun Chen1, Jinghua Yu1, Andrey Bobkov1, Vivian Ruvolo4, Michael Andreeff4, Robert G. Oshima1, Shu-Ichi Matsuzawa1,5, John C. Reed1,6, Xiao-Kun Zhang1,2, Donna Hansel7, Dieter A. Wolf1,2 and Marcia I. Dawson1

1Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, USA

2School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research and Center for Stress Signaling Networks, Xiamen University, Xiamen, China

3Oregon Health and Science University School of Medicine, Portland, OR, USA

4Section of Molecular Hematology and Therapy, Department of Stem Cell Transplantation and Cellular Therapy, Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, USA

5Present address: Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan

6Present address: Roche, Pharma Research and Early Development, Basel, Switzerland

7Department of Pathology, University of California San Diego, San Diego, CA, USA

*These authors contributed equally to this work

Correspondence to:

Dieter A. Wolf, email: dwolf@sbpdiscovery.org

Keywords: orphan nuclear receptor 4A1; unfolded protein response; apoptosis; prostate cancer; oxidation products

Received: February 04, 2017     Accepted: April 06, 2018     Published: May 18, 2018

ABSTRACT

Di(1H-indol-3-yl)(4-trifluoromethylphenyl)methane (DIM-Ph-4-CF3) is an analog of orphan nuclear receptor 4A1 (NR4A1) ligand cytosporone B. We have synthesized several oxidation products of DIM-Ph-4-CF3, focusing on analogs with electron-withdrawing or donating groups at their phenyl ring 4-positions, and examined their anti-cancer activity and mechanism-of-action. Mesylates (DIM-Ph-4-X+ OMss) having CF3, CO2Me and Cl groups were more effective inhibitors of cancer cell viability than their precursors. 19F NMR spectroscopy and differential scanning calorimetry strongly indicated interactions of DIM-Ph-4-CF3+ OMs with the NR4A1 ligand binding domain, and compound-induced apoptosis of prostate cancer cells was dependent on NR4A1. DIM-Ph-4-CF3+ OMs showed robust inhibition of LNCaP prostate cancer xenografts with no apparent toxicity. In vitro and in vivo, DIM-Ph-4-CF3+ OMs activated proapoptotic unfolded protein response (UPR) signaling in prostate cancer cells. Independently of DIM-Ph-4-CF3+ OMs, the bulk of NR4A1 localized to the cytoplasm in various cancer cell lines, suggesting a cytoplasmic mechanism-of-action of DIM-Ph-4-CF3+ OMs in UPR induction and cell death. In summary, the data suggest that oxidized analogs of DIM-Ph-4-CF3 possess potent and safe anti-cancer activity which is mediated through UPR signaling downstream of NR4A1 binding.


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