The acidic intracellular environment or low intracellular pH ( pH i) increases the thermosensitivity of mammalian cells. The cells in a hypoxic environment produce a greater amount of acidic metabolites than those in an oxygenated environment. However, the hypoxic cells are not more thermosensitive than oxygenated cells since the decrease in pH i is minimized by the mechanisms that regulate the pH i such as Na+/ H+ antiport. We hypothesized, therefore, that blocking the regulation of pH i might greatly reduce the pH i and increase the thermosensitivity of hypoxic cells. We tested our hypothesis by heating SCK tumor cells under oxygenated and hypoxic conditions in pH 7.5 or 6.6 medium with or without amiloride, an inhibitor of Na+/ H+ antiport. We observed that amiloride increased the thermosensitivity of hypoxic cells markedly. Such a thermosensitization of hypoxic cells by amiloride was more pronounced in an acidic environment, with an enhancement ratio of 1.8, than in a neutral environment, with an enhancement ratio of 1.5. We concluded that lowering the pH i by blocking the regulation of pH i in combination with hyperthermia may be a useful way to eliminate the radioresistant hypoxic cells.

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