Tumor-specific cytotoxic activity and type of cell death induced by 4-trifluoromethylimidazoles in human oral squamous cell carcinoma cell lines

Fourteen 4-trifluoromethylimidazole derivatives were investigated for their cytotoxicity against three human normal cells (gingival fibroblast HGF, pulp cell HPC and periodontal ligament fibroblast HPLF) and four human tumor cell lines (oral squamous cell carcinoma HSC-2, HSC-3, HSC-4 and promyelocytic leukemia HL-60). Among these compounds, 4-trifluoromethyl-1,2-diphenylimidazole (IM5), 1-benzyl-4-trifluoromethyl-2-phenylimidazole (IM7) and 5-[1-ethoxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]-1-methyl-2-phenyl-1H-imidazole (IM12) showed much higher cytotoxicity and tumor-specificity than the other compounds. IM5, the most potent compound, induced different types of cell death depending on the target cells. IM5 induced DNA fragmentation of oligonucleosomal units (a biochemical hallmark of apoptosis) in the HL-60 cells, but not in such a clear-cut laddering pattern in the HSC-2 cells. On the other hand, IM5 produced secondary lysosomes digesting broken organelles, without induction of internucleosomal DNA fragmentation and disappearance of cell surface microvilli in the HSC-4 cells, even though the HSC-2 and HSC-4 cells showed comparable sensitivity to IM5. These data suggest that the type of cell death is determined by the type of target cells, but not by the drug-sensitivity of the cells.