THE EFFECT OF MONENSIN AND CHLOROQUINE ON THE ENDOCYTOSIS AND TOXICITY OF CHIMERIC TOXINS

The toxicity of two conjugates containing ribosome-inactivating protei ns (RIPs, i.e. saporin and ricin-A chain x-linked to transferrin) has been measured on a prostatic cancer line (PC3) naturally overexpressin g the transferrin receptor, in the presence of monensin and chloroquin e. This paper investigates whether the increased toxicity of Tf-RIPs i nduced by monensin and chloroquine may be due to alterations of the no rmal endocytotic pathway of the complexes mediated by the transferrin receptor. Monensin, besides inducing alkalinization of normally acid i ntracellular compartments, causes an accumulation of the receptor-boun d Tf-RIP in a perinuclear region contiguous to the cisternae of the tr ans-Golgi network. Chloroquine, though increasing the intracellular pi -I, seems not to modify the endocytotic pathway of these chimeric mole cules. We believe that the enhanced toxicity of the Tf-RIPs may be rel ated to intracellular alkalinization (i.e, endosomal or lysosomal pH) rather than to the effects on the recycling of transferrin receptor-bo und toxins. We conclude that the efficacy of chimeric toxins may be mo dulated not only by the carrier used for their engineering but also by addition of drugs able to influence the stability and activation of t he toxins inside the cell.