Oxidized analogs of Di(1H-indol-3-yl)methyl-4-substituted benzenes are NR4A1-dependent UPR inducers with potent and safe anti-cancer activity
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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
Dieter A. Wolf, email: [email protected]
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
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+ OMs–s) 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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