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.
Department of Experimental Pharmacology, Medical School, University of Athens, GR-11527 Athens, Greece. aityliga@med.uoa.gr
Ekaterini
E
Tiligada
Konstantinos
K
Papamichael
Ioanna
I
Vovou
Andreas
A
Delitheos
D000222:Adaptation, Physiological / Q000187:drug effects / Q000502:physiology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D018869:Heat-Shock Response / Q000187:drug effects* / Q000502:physiology; D000077146:Irinotecan; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000502:physiology; D013498:Suramin / Q000494:pharmacology
D000972:Antineoplastic Agents, Phytogenic; D013498:Suramin; D000077146:Irinotecan; D003513:Cycloheximide; D002166:Camptothecin