title: Potential use of cetrimonium bromide as an apoptosis-promoting anticancer agent for head and neck cancer.
abstract: A potential therapeutic agent for human head and neck cancer (HNC), cetrimonium bromide (CTAB), was identified through a cell-based phenotype-driven high-throughput screen (HTS) of 2000 biologically active or clinically used compounds, followed by in vitro and in vivo characterization of its antitumor efficacy. The preliminary and secondary screens were performed on FaDu (hypopharyngeal squamous cancer) and GM05757 (primary normal fibroblasts), respectively. Potential hit compounds were further evaluated for their anticancer specificity and efficacy in combination with standard therapeutics on a panel of normal and cancer cell lines. Mechanism of action, in vivo antitumor efficacy, and potential lead compound optimizations were also investigated. In vitro, CTAB interacted additively with gamma radiation and cisplatin, two standard HNC therapeutic agents. CTAB exhibited anticancer cytotoxicity against several HNC cell lines, with minimal effects on normal fibroblasts; a selectivity that exploits cancer-specific metabolic aberrations. The central mode of cytotoxicity was mitochondria-mediated apoptosis via inhibition of H(+)-ATP synthase activity and mitochondrial membrane potential depolarization, which in turn was associated with reduced intracellular ATP levels, caspase activation, elevated sub-G(1) cell population, and chromatin condensation. In vivo, CTAB ablated tumor-forming capacity of FaDu cells and delayed growth of established tumors. Thus, using an HTS approach, CTAB was identified as a potential apoptogenic quaternary ammonium compound possessing in vitro and in vivo efficacy against HNC models.
authors: Department of Medical Biophysics, University of Toronto, Ontario, Canada.
authors: Emma
authors: E
authors: Ito
authors: Kenneth W
authors: KW
authors: Yip
authors: David
authors: D
authors: Katz
authors: Sonali B
authors: SB
authors: Fonseca
authors: David W
authors: DW
authors: Hedley
authors: Sue
authors: S
authors: Chow
authors: G Wei
authors: GW
authors: Xu
authors: Tabitha E
authors: TE
authors: Wood
authors: Carlo
authors: C
authors: Bastianutto
authors: Aaron D
authors: AD
authors: Schimmer
authors: Shana O
authors: SO
authors: Kelley
authors: Fei-Fei
authors: FF
authors: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D000077286:Cetrimonium; D002593:Cetrimonium Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D002593:Cetrimonium Compounds; D000077286:Cetrimonium