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Research Articles: Therapeutics

Potential use of alexidine dihydrochloride as an apoptosis-promoting anticancer agent

Departments of ¹ Medical Biophysics and ² Radiation Oncology, University of Toronto; Divisions of ³ Applied Molecular Oncology and ⁴ Cancer Genomics and Proteomics, Ontario Cancer Institute; ⁵ The Advanced Medical Discovery Institute; and Departments of ⁶ Medical Oncology and Hematology and ⁷ 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, 610 University Avenue, Room 10-203, Toronto, Ontario, Canada M5G 2M9. Phone: 416-946-2123; Fax: 416-946-4586. E-mail: Fei-Fei.Liu{at}rmp.uhn.on.ca

Despite advances in surgery, radiation, and chemotherapy, novel therapeutics are needed for head and neck cancer treatment. The objective of this current study was to evaluate alexidine dihydrochloride as a novel compound lead for head and neck cancers. Using a tetrazolium-based assay, the dose required to reduce cell viability by 50% (ED₅₀) was found to be 1.8 µmol/L in FaDu (human hypopharyngeal squamous cancer) and 2.6 µmol/L in C666-1 (human undifferentiated nasopharyngeal cancer) cells. In contrast, the ED₅₀ values were much higher in untransformed cells, specifically at 8.8 µmol/L in GM05757 (primary normal human fibroblast), 8.9 µmol/L in HNEpC (primary normal human nasal epithelial), and 19.6 µmol/L in NIH/3T3 (mouse embryonic fibroblast) cells. Alexidine dihydrochloride did not interfere with the activities of cisplatin, 5-fluorouracil, or radiation, and interacted in a less-than-additive manner. DNA content analyses and Hoechst 33342 staining revealed that this compound induced apoptosis. Alexidine dihydrochloride–induced mitochondrial damage was visualized using transmission electron microscopy. Mitochondrial membrane potential (_M) depolarization was detectable after only 3 hours of treatment, and was followed by cytosolic Ca²⁺ increase along with loss of membrane integrity/cell death. Caspase-2 and caspase-9 activities were detectable at 12 hours, caspase-8 at 24 hours, and caspase-3 at 48 hours. FaDu cell clonogenic survival was reduced to <5% with 1 µmol/L alexidine dihydrochloride, and, correspondingly, this compound decreased the in vivo tumor-forming potential of FaDu cells. Thus, we have identified alexidine dihydrochloride as the first bisbiguanide compound with anticancer specificity. [Mol Cancer Ther 2006;5(9):2234–40]

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Received 3/13/06; revised 6/18/06; accepted 6/29/06.

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