1,1-Bis(3'-indolyl)-1-(p-chlorophenyl)methane activates the orphan nuclear receptor Nurr1 and inhibits bladder cancer growth.

Abstract

Nurr1 is an orphan nuclear receptor and a member of the nerve growth factor I-B subfamily of transcription factors with no known endogenous ligand or stimulator. We show, for the first time, evidence that Nurr1 is expressed in a panel of 11 human bladder cancer cell lines. A new class of methylene-substituted diindolylmethanes (C-DIM) were screened and 1,1-bis(3'-indolyl)-1-(p-chlorophenyl)methane (DIM-C-pPhCl) activated the ligand-binding domain of Nurr1. Treatment of bladder cancer cells with Nurr1-active C-DIM resulted in decreased cell survival (MTT assay) and induction of cell death pathways, resulting in poly(ADP-ribose) polymerase cleavage and DNA fragmentation. The specificity of the Nurr1-active compound was shown using RNA interference in 253J B-V cells, whereby small interfering RNA against Nurr1 attenuated ligand-dependent activation of Nurr1 and poly(ADP-ribose) polymerase cleavage. Furthermore, activation of Nurr1 resulted in stimulation of tumor necrosis factor-related apoptosis-inducing ligand and small interfering RNA experiments attenuated tumor necrosis factor-related apoptosis-inducing ligand production. In an orthotopic model of human bladder tumors established in nude mice, administration of a Nurr1-active C-DIM suppressed bladder cancer growth. These results identify Nurr1 as a potential target for bladder cancer therapy and also identify a novel agent for activating Nurr1.

• Authors: Teruo Inamoto, Sabitha Papineni, Sudhakar Chintharlapalli, Sung-Dae Cho, Stephen Safe, Ashish M Kamat
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 7 Issue 12 Pg. 3825-33 (Dec 2008) ISSN: 1535-7163 [Print] United States
• PMID: 19074857 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 1,1-bis(3'-indolyl)-1-(4-chlorophenyl)methane
• Benzhydryl Compounds
• DNA-Binding Proteins
• Indoles
• Ligands
• NR4A2 protein, human
• Nr4a2 protein, mouse
• Nuclear Receptor Subfamily 4, Group A, Member 2
• Tetrazolium Salts
• Thiazoles
• Transcription Factors
• thiazolyl blue

Topics

• Animals
• Benzhydryl Compounds (pharmacology)
• Cell Line, Tumor
• Cell Survival
• DNA-Binding Proteins (physiology)
• Humans
• Indoles (chemistry, pharmacology)
• Ligands
• Male
• Mice
• Mice, Nude
• Models, Biological
• Neoplasm Transplantation
• Nuclear Receptor Subfamily 4, Group A, Member 2
• RNA Interference
• Tetrazolium Salts (pharmacology)
• Thiazoles (pharmacology)
• Transcription Factors (physiology)
• Urinary Bladder Neoplasms (drug therapy, pathology)