Increased resistance to anticancer therapy of mouse cells lacking the poly(ADP-ribose) polymerase attributable to up-regulation of the multidrug resistance gene product P-glycoprotein

Mouse embryo fibroblasts lacking poly(ADP-ribose) polymerase (PARP)-1 expre ss a barely detectable level of wild-type (wt) p53 protein. Doxorubicin at concentrations activating wt p53 in normal mouse embryo fibroblasts failed to induce it in mutant cells. wt p53 was only activated in response to a 10 -fold higher doxorubicin dose. Treatment with higher doxorubicin concentrat ions was cytotoxic for normal but not for PARP-1 -/- cells. The latter was also resistant to other anticancer agents. The increased resistance of muta nt cells to drugs resembled a unique phenomenon known as multidrug resistan ce (MDR), Interestingly, the MDR gene product P-glycoprotein was clearly up -regulated in PARP-1-deficient cells as compared with normal counterparts. Pretreatment with verapamil reversed the MDR phenotype.