351. Bromoethylindole (BEI-9) redirects NF-κB signaling induced by camptothecin and TNFα to promote cell death in colon cancer cells.
- Author
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Chowdhury R, Gales D, Valenzuela P, Miller S, Yehualaeshet T, Manne U, Francia G, and Samuel T
- Subjects
- Apoptosis drug effects, Camptothecin administration & dosage, Caspases metabolism, Cell Cycle drug effects, Cell Line, Tumor, Colonic Neoplasms drug therapy, Dose-Response Relationship, Drug, Drug Synergism, Humans, Indoles administration & dosage, Receptor-Interacting Protein Serine-Threonine Kinases metabolism, Time Factors, bcl-X Protein genetics, Camptothecin pharmacology, Cell Death drug effects, Colonic Neoplasms metabolism, Indoles pharmacology, NF-kappa B metabolism, Signal Transduction drug effects, Tumor Necrosis Factor-alpha pharmacology
- Abstract
Chemotherapeutic regimens containing camptothecin (CPT), 5-fluorouracil, and oxaliplatin are used to treat advanced colorectal cancer. We previously reported that an indole derivative, 3-(2-bromoethyl)indole (BEI-9), inhibited the proliferation of colon cancer cells and suppressed NF-κB activation. Here, we show that a combination of BEI-9 with either CPT or tumor necrosis factor alpha (TNFα) enhances cell death. Using colorectal cancer cells, we examined the activation of NF-κB by drugs, the potential of BEI-9 for inhibiting drug-induced NF-κB activation, and the enhancement of cell death by combination treatments. Cells were treated with the chemotherapeutic drugs alone or in combination with BEI-9. NF-κB activation, cell cycle profiles, DNA-damage response, markers of cell death signaling and targets of NF-κB were evaluated to determine the effects of single and co-treatments. The combination of BEI-9 with CPT or TNFα inhibited NF-κB activation and reduced the expression of NF-κB-responsive genes, Bcl-xL and COX2. Compared to CPT or BEI-9 alone, sequential treatment of the cells with CPT and BEI-9 significantly enhanced caspase activation and cell death. Co-treatment with TNFα and BEI-9 also caused more cytotoxicity than TNFα or BEI-9 alone. Combined BEI-9 and TNFα enhanced cell death through caspase activation and cleavage of the switch-protein, RIP1 kinase. BEI-9 reduced the expression of COX2 both alone and in combination with CPT or TNF. We postulate that BEI-9 enhances the effects of these drugs on cancer cells by turning off or redirecting NF-κB signaling. Therefore, the combination of BEI-9 with drugs that activate NF-κB needs to be evaluated for clinical applications.
- Published
- 2017
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