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Molecular Pharmacology

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Potential Use of Cetrimonium Bromide as an Apoptosis-Promoting Anticancer Agent for Head and Neck Cancer

Emma Ito, Kenneth W. Yip, David Katz, Sonali B. Fonseca, David W. Hedley, Sue Chow, G. Wei Xu, Tabitha E. Wood, Carlo Bastianutto, Aaron D. Schimmer, Shana O. Kelley and Fei-Fei Liu
Molecular Pharmacology November 2009, 76 (5) 969-983; DOI: https://doi.org/10.1124/mol.109.055277
Emma Ito
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Kenneth W. Yip
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David Katz
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Sonali B. Fonseca
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David W. Hedley
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Sue Chow
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G. Wei Xu
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Tabitha E. Wood
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Carlo Bastianutto
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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 γ 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-G1 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.

  • HNC, head and neck cancer
  • RT, radiation therapy
  • HTS, high-throughput screen
  • CTAB, cetrimonium bromide
  • DMSO, dimethyl sulfoxide
  • CCCP, carbonyl cyanide m-chlorophenylhydrazone
  • Z-VAD-FMK, N-benzyloxycarbonyl-valine-alanine-aspartate fluoromethylketone
  • MTS, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt
  • Gy, gray
  • PBS, phosphate-buffered saline
  • PI, propidium iodide
  • DiIC1(5), 1,1′,3,3,3′,3′-hexamethylindodicarbocyanine
  • ΔΨM, mitochondrial membrane potential(s)
  • AM, acetoxymethyl ester
  • JC-1, 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolylcarbocyanine iodide
  • ΔΨP, plasma membrane potential(s)
  • ATPase, ATP synthase
  • DiBAC4(3), bis-(1,3-dibutylbarbituric acid)trimethine oxonol
  • SCID, severe combined immunodeficient
  • TLD, tumor-plus-leg diameter
  • ER, endoplasmic reticulum
  • DLC, delocalized lipophilic cation
  • OXPHOS, oxidative phosphorylation.

Footnotes

  • This work was supported by the Canadian Institutes of Health Research [Grant 69023] and the Elia Chair in Head and Neck Cancer Research. E.I. is a recipient of a Natural Sciences and Engineering Research Council of Canada scholarship.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.109.055277

  • ABBREVIATIONS:

    • Received February 3, 2009.
    • Accepted August 4, 2009.
  • © 2009 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 76 (5)
Molecular Pharmacology
Vol. 76, Issue 5
November 2009
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Potential Use of Cetrimonium Bromide as an Apoptosis-Promoting Anticancer Agent for Head and Neck Cancer

Emma Ito, Kenneth W. Yip, David Katz, Sonali B. Fonseca, David W. Hedley, Sue Chow, G. Wei Xu, Tabitha E. Wood, Carlo Bastianutto, Aaron D. Schimmer, Shana O. Kelley and Fei-Fei Liu
Molecular Pharmacology November 1, 2009, 76 (5) 969-983; DOI: https://doi.org/10.1124/mol.109.055277

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Potential Use of Cetrimonium Bromide as an Apoptosis-Promoting Anticancer Agent for Head and Neck Cancer

Emma Ito, Kenneth W. Yip, David Katz, Sonali B. Fonseca, David W. Hedley, Sue Chow, G. Wei Xu, Tabitha E. Wood, Carlo Bastianutto, Aaron D. Schimmer, Shana O. Kelley and Fei-Fei Liu
Molecular Pharmacology November 1, 2009, 76 (5) 969-983; DOI: https://doi.org/10.1124/mol.109.055277
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