| dc.description.abstract | Cancer accounts for one in eight deaths worldwide and one in four deaths in the United States. Chemotherapy is the most common treatment option for cancer; however, many chemotherapeutic drugs have toxic side effects. Our studies focused on molecular mechanisms of two groups of relatively non-toxic agents that exhibit potent anticancer activities in colon and pancreatic cancer cells.
The first group includes a nonsteroidal anti-inflammatory drug (NSAID), sulindac, and its sulfone and sulfide metabolites; among them, sulindac sulfide was the most active compound in inhibiting colon cancer cell proliferation in our studies. Sulindac sulfide induced reactive oxygen species (ROS), decreased oncogenic microRNA-27a and upregulated the transcriptional repressor, ZBTB10. As a result, sulindac sulfide downregulated Sp1, Sp3 and Sp4 transcription factors and Sp-regulated pro-oncogenic genes, including survivin, Bcl-2, epidermal growth factor receptor (EGFR), cyclin D1, NFKB-p65 and vascular endothelial growth factor (VEGF). Our results suggest that the anticancer activity of sulindac sulfide is due, in part, to downregulation of Sp-dependent gene expression.
The second group includes methylene-substituted analogs of a natural compound diindolylmethane (i.e. C-DIM). We screened a library of C-DIMs and identified several activators of NR4A2 nuclear receptor (Nurr1) by transactivation assays using GAL4-UAS system; additional assays using NBRE and NurRE response elements confirmed that C-DIMs transactivated Nurr1 in pancreatic cancer cells. We also investigated the structure-activity relationships of C-DIM analogs/isomers and determined that C-DIMs with para-substituted-phenyl (DIM-C-pPh-substituent) are potent Nurr1 activators. Furthermore, DIM-C-pPhBr activated both N- and C-terminal domains of Nurr1 through site-specific phosphorylation and this activation resulted in transcriptional induction/repression of Nurr1-regulated genes in pancreatic cancer cells.
In contrast, our studies in colon cancer cells demonstrate a direct interaction between several C-DIMs and the ligand-binding domain (LBD) of NR4A1 nuclear receptor (TR3); this binding inactivated both wild type and truncated TR3 (with LBD). In addition, several C-DIMs also inactivated truncated TR3 containing transactivation domains (without LBD). Furthermore, a TR3 inactivator, DIM-C-pPhOH, downregulated survivin, induced caspase-dependent apoptosis and inhibited p53-dependent mTOR signaling in colon cancer cells. Our studies with C-DIMs suggest that their anticancer activities are due, in part, to modulation of NR4A nuclear receptors, TR3 and Nurr1. | en |
