This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Yip, K. W. Articles by Liu, F.-F. Search for Related Content PubMed PubMed Citation Articles by Yip, K. W. Articles by Liu, F.-F.

Benzethonium Chloride: A Novel Anticancer Agent Identified by Using a Cell-Based Small-Molecule Screen

Authors' Affiliations: ¹ Departments of Medical Biophysics, ² Chemistry, and ³ Radiation Oncology, University of Toronto; Divisions of ⁴ Applied Molecular Oncology and ⁵ Cancer Genomics and Proteomics, Ontario Cancer Institute, ⁶ The Advanced Medical Discovery Institute, and Departments of ⁷ Medical Oncology and Hematology and ⁸ Radiation Oncology, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada

Requests for reprints: Fei-Fei Liu, Department of Radiation Oncology, Princess Margaret Hospital/Ontario Cancer Institute, Room 10-203, 610 University Avenue, Toronto, Ontario, Canada M5G 2M9. Phone: 416-946-2123; Fax: 416-946-4586; E-mail: Fei-Fei.Liu{at}rmp.uhn.on.ca.

Purpose: This study aims to identify a novel therapeutic agent for head and neck cancer and to evaluate its antitumor efficacy.

Experimental Design: A cell-based and phenotype-driven high-throughput screening of 2,400 biologically active or clinically used compounds was done using a tetrazolium-based assay on FaDu (hypopharyngeal squamous cancer) and NIH 3T3 (untransformed mouse embryonic fibroblast) cells, with secondary screening done on C666-1 (nasopharyngeal cancer) and GM05757 (primary normal human fibroblast) lines. The "hit" compound was assayed for efficacy in combination with standard therapeutics on a panel of human cancer cell lines. Furthermore, its mode of action (using transmission electron microscopy and flow cytometry) and its in vivo efficacy (using xenograft models) were evaluated.

Results: Benzethonium chloride was identified as a novel cancer-specific compound. For benzethonium (48-hour incubation), the dose required to reduce cell viability by 50% was 3.8 µmol/L in FaDu, 42.2 µmol/L in NIH 3T3, 5.3 µmol/L in C666-1, and 17.0 µmol/L in GM05757. In vitro, this compound did not interfere with the effects of cisplatin, 5-fluorouracil, or -irradiation. Benzethonium chloride induced apoptosis and activated caspases after 12 hours. Loss of mitochondrial membrane potential (_M) preceded cytosolic Ca²⁺ increase and cell death. In vivo, benzethonium chloride ablated the tumor-forming ability of FaDu cells, delayed the growth of xenograft tumors, and combined additively with local tumor radiation therapy. Evaluation of benzethonium chloride on the National Cancer Institute/NIH Developmental Therapeutics Program 60 human cancer cell lines revealed broad-range antitumor activity.

Conclusions: This high-throughput screening identified a novel antimicrobial compound with significant broad-spectrum anticancer activity.