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

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 electronwithdrawing 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-CF+3 OMs- with the NR4A1 ligand binding domain, and compound-induced apoptosis of prostate cancer cells was dependent on NR4A1. DIM-Ph-4-CF+3 OMs- showed robust inhibition of LNCaP prostate cancer xenografts with no apparent toxicity. In vitro and in vivo, DIM-Ph-4-CF+3 OMs- activated proapoptotic unfolded protein response (UPR) signaling in prostate cancer cells. Independently of DIM-Ph-4-CF+3 OMs-, the bulk of NR4A1 localized to the cytoplasm in various cancer cell lines, suggesting a cytoplasmic mechanism-of-action of DIMPh- 4-CF+3 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.

Original languageEnglish (US)
Pages (from-to)25057-25074
Number of pages18
JournalOncotarget
Volume9
Issue number38
DOIs
StatePublished - May 18 2018
Externally publishedYes

Keywords

  • Apoptosis
  • Orphan nuclear receptor 4A1
  • Oxidation products
  • Prostate cancer
  • Unfolded protein response

ASJC Scopus subject areas

  • Oncology

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