Cell cycle effects of the phenothiazines: trifluoperazine and chlorpromazine in Candida albicans.

The study demonstrates the in vitro effectiveness of phenothiazine compounds, i.e. chlorpromazine and trifluoperazine against Candida albicans. Anticandidal effect of these drugs is suggested to be because of their interaction with Ca(2+)/calmodulin dependent protein phosphorylation. 3H-thymidine uptake studies revealed that both these compounds affect the DNA synthesis along with decrease in activities of nuclear calmodulin (CaM) and Ca(2+)/calmodulin dependent protein kinase (CaMPK). Failure in cell growth was due to defect in CaM mediated cell cycle arrest. Flow cytometric analysis showed that progression through G(1) and mitotic phase was affected when cells after alpha-factor arrest were grown in the presence of chlorpromazine or trifluoperazine. These drugs also produced significant decline in the cellular lipids and phospholipids. 14C-acetate incorporation studies further substantiated these results. We suggest that chlorpromazine or trifluoperazine affect the cell cycle through DNA synthesis (S phase) and cell division phases which are governed by calmodulin and Ca(2+)/calmodulin dependent protein phosphorylation and lipids and phospholipids appear to be additional targets of phenothiazine compounds in C. albicans. These results will have important significance in the development of new anticandidal compounds.