The orphan nuclear receptor NR4A1 (nuclear receptor 4A1) exhibits pro-oncogenic activity in cancer cell lines. NR4A1 activates mTOR signaling, regulates genes such as thioredoxin domain containing 5 and isocitrate dehydrogenase 1 that maintain low oxidative stress, and coactivates specificity protein 1 (Sp1)-regulated pro-survival and growth promoting genes. DIM-C-pPhOH binds NR4A1 and act as antagonists. DIM-C-pPhOH (20 μM; 18 hr) inhibited growth and induced apoptosis in ACHN and 786-O cells, and the functional and genomic effects of it were comparable to those observed after NR4A1 knockdown. Moreover, treatment of these cells with 0–20 μM of the NR4A1 antagonist DIM-C-pPhOH also significantly decreased cell proliferation. IC50 values for DIM-C-pPhOH were 13.6 μM and 13.0 μM in ACHN cells and 786-O cells, respectively. Moreover, treatment of athymic nude mice bearing ACHN cells as xenografts with DIM-C-pPhOH (30 mg/kg/d) for 50 days also resulted in a significant inhibition of tumor growth and complemented results of the in vitro studies. In addition, researchers also observed decreased expression of survivin, bcl-2, EGFR and induced PARP cleavage in tumor lysates from nude mice bearing ACHN cells as a xenograft and treated with DIM-C-pPhOH (30 mg/kg/d)[1].
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