CLOFAZIMINE ALTERS THE ENERGY-METABOLISM AND INHIBITS THE GROWTH-RATEOF A HUMAN LUNG-CANCER CELL-LINE IN-VITRO AND IN-VIVO

The anti-leprosy drug Clofazimine is known to inhibit respiratory func tion and hence energy metabolism in yeast and in transformed fibroblas ts. The aim of this study was to examine the effect of Clofazimine on the energy metabolism of a chemoresistant human non-small-cell bronchi al-carcinoma cell line (WIL) and to determine whether this agent might inhibit the growth rate of this cell line in vitro and in vivo. Oxida tive phosphorylation was estimated in vitro by measuring oxygen consum ption polarographically and glycolysis was estimated from lactate prod uction. In cells that had been pre-treated with an ATP synthetase inhi bitor (oligomycin), the addition of Clofazimine resulted in an increas e in oxygen consumption similar to that observed with 2,4-dinitropheno l, a classical inhibitor of oxidative phosphorylation. This inhibition of mitochondrial function was associated with an increase in lactate production. Cellular ATP levels were maintained, possible indicating a compensatory increase in ATP production via glycolysis. Clofazimine w as shown to have a direct cytotoxic effect in vitro with an ID50 of 10 .2 mu M. When Clofazimine was administered to athymic mice bearing WIL as a subcutaneous xenograft, tumour growth rate was significantly red uced, so that after 3 weeks, tumour size was one third that of control s (p < 0.01). These results suggest that selective inhibition of tumou r energy metabolism with agents such as Clofazimine is a potential nov el approach to cancer treatment. (C) 1994 Wiley-Liss, Inc.