Downregulation of JNK/SAPK activity is associated with the cross-resistance to P-glycoprotein-unrelated drugs in multidrug-resistant FM3A/M cells overexpressing P-glycoprotein

In the present study; cross-drug resistance in multidrug-resistant (MDR) ce lls, which overexpress P-glycoprotein (Pgp), a mdr1 gene product, against P gp-unrelated drugs, and its relevance to c-Jun N-terminal kinase (JNK)/stre ss-activated protein kinase (SAPK) activity were examined. The multidrug-re sistant FB3A/M cells overexpressing Pgp were resistant to apoptotic cell de ath induced either by Pgp-related drugs including vincristine and vinblasti ne, which are pumped out by Pgp, or by the Pgp-unrelated drugs including 5' -fluorouracil (5-FU) and bleomycin, which are not targets for Pgp, compared with the parental FM3A cells. Verapamil reversed the resistance of FM3A/M cells to apoptosis induced by the Pgp-related drugs but not that induced by the Pgp-unrelated drugs. Interestingly, FM3A/M cells have shown significan tly lower basal and drug-stimulated JNK/SAPK activities than FM3A cells. Af ter transfection with pEBG-SEK or pEBG-SAPK constructs, FM3A/M cells recove red the basal and Pgp-unrelated drug-stimulated activities of JNK/SAPK and the susceptibility to Pgp-unrelated drug-induced apoptotic cell death compa rable to those of FM3A cells. Furthermore, FM3A cells became resistant to a poptotic cell death induced by vincristine and 5-FU after transfect ion wit h pEBG-SEK(K --> R), a dominant negative inhibitory mutant of SEK. These re sults suggest that downregulation of JNK/SAPK activity appears to confer on Pgp-associated FM3A/M cells a cross-resistance to Pgp-unrelated drugs. (C) 2000 Academic Press.