Circumvention of Camptothecin-induced Resistance During the Adaptive Cellular Stress Response

Camptothecin-11 (CPT-11) induces the adaptive stress response in yeast, conferring resistance via not fully characterized mechanisms. This study aimed at exploring, pharmacologically, the mechanisms underlying the CPT-11-induced resistance in yeast. Post-logarithmic yeast cultures were submitted to heat shock following preconditioning with suramin and with CPT-11, either alone or in combination with suramin, cycloheximide, sodium molybdate, okadaic acid, or verapamil. The stress response was evaluated by determining cell viability after heat shock. Preconditioning with CPT-11 or suramin conferred thermotolerance to yeast cells. Co-administration of CPT-11 with suramin, cycloheximide or okadaic acid reversed the CPT-11-induced thermotolerant phenotype, while sodium molybdate and verapamil had no effect on CPT-11-induced resistance. The antagonistic effect of the thermotolerance-inducers and the possible contribution of topoisomerase II activity and post-translational modifications mediated by the phosphatases PP1/2A in CPT-11-induced resistance may have important implications on the acquisition of resistance to stress in eukaryotic cells.