Cytotoxicity of phenothiazines: studies with aerated and hypoxic cells

A number of phenothiazines have been studied with respect to their cytotoxic activity using an in vitro screening system. All the drugs studied showed some degree of cytotoxic effect under both aerated and hypoxic conditions. Toxicity was found to be influenced by modification of the phenothiazine ring, substitution of CF3 at the 2 position (Trifluoperazine and Trifluopromazine) resulting in enhanced toxicity. Modification of the side chain also changed the cytotoxic potential of the drug, with incorporation of the amino group into a piperazine ring increasing toxicity. The most toxic drug tested was Thioridazine with SCH3 at position 2 and the amino group incorporated into a piperazine ring. Thiorizadine also showed the greatest degree of specificity for hypoxic cells. The ranking of phenothiazines, in terms of cytotoxic activity corresponds with that reported in the literature for calmodulin-inhibiting potency. It is conjectured that the cytotoxic effect of phenothiazines could be wholly or partially explained on the basis of their interaction with calmodulin.