Mechanism of inhibition of FaDu hypopharyngeal carcinoma cell growth by tetraphenylphosphonium chloride.

Cationic phosphonium salts are interesting because they inhibit the proliferation of carcinoma cells more than untransformed epithelial cells in vitro. This differential anti-proliferative effect has been used to identify phosphonium salts and other lipophilic cations that later demonstrated effects in animals. Using 6 carcinoma-derived and 2 untransformed epithelial cell lines, tetraphenylphosphonium chloride (TPP) and other cationic aryl phosphonium salts (CAPS) demonstrated a growth inhibition pattern similar to that of cation rhodamine 123, suggesting that CAPS may inhibit mitochondrial function. We tested this hypothesis for the effect of phosphonium salt TPP on FaDu human hypopharyngeal carcinoma cells. TPP inhibited the proliferation of FaDu carcinoma cells at submicromolar concentrations. Uptake of 3H-TPP by FaDu cells was partially inhibited in medium containing high K+ and fully inhibited by valinomycin in this medium, indicating that TPP accumulates preferentially in mitochondria, and to a lesser extent in the cytoplasm. FaDu cells exposed to TPP exhibited damage to mitochondrial inner membranes, reduced ATP/ADP ratios, decreased oxygen uptake rates and decreased mitochondrial membrane potentials. The treated cells secreted lactate more rapidly than untreated controls and exhibited hypersensitivity to 2-deoxyglucose, an inhibitor of glycolysis. TPP's antimitochondrial effects apparently enhance cytoplasmic glycolysis. In conclusion, TPP inhibits FaDu carcinoma cell growth by inhibiting mitochondrial respiration and ATP synthesis. Cationic phosphonium salts that inhibit carcinoma cell growth through antimitochondrial effects might be used to treat solid tumors without the risk of secondary tumors associated with agents affecting nuclear DNA.