Mechanism of Action of Sulindac and Diindolylmethane Analogs as Anticancer Agents
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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.
Li, Xi (2014). Mechanism of Action of Sulindac and Diindolylmethane Analogs as Anticancer Agents. Doctoral dissertation, Texas A & M University. Available electronically from