Effect of Inhibitors of Poly(ADP-ribose) Polymerase on the Induction of GRP78 and Subsequent Development of Resistance to Etoposide1

We have recently demonstrated that cell lines deficient in poly(ADP ribose)synthesisdue to deficiencyin the enzymepoly(ADP-rlbose) po lymerase (PADPRP) or depletion of its substrate NAD@ overexpress GRP78. Furthermore, this overexpression ofGRP78 is assodated with the acquisition of resistanceto topoisomerase11-directeddrugs such as eta poside (VP-16); (S. Chatterjee et aL, Cancer Res., 54: 4405—4411, 1994). Thus, our studies suggest that interference with NAD@-PADPRP metab olism could provide an Important approach to (a) define pathways of GRP78 Induction, (b) study the effect of GRP78 on other cellular pro ceases, (c) elucidate the mechanism of GRP7S-dependent resistance to topoisomerase H targeted drugs, and (d) modulate responses to chemo therapy in normal and tumor tissues.However,In the in vivosituation, It Is impractical to interfere with NAD@-PADPRPmetabolism by mute tional InactivatIon of PADPRP or by depletion of its substrate NAD@. Therefore, we have examined several inhibitors of NAD@-PADPRP me tabolism including 3-aminobenzamide, PD128763, and 6-aminonicotl namide for their abifity to reproduce the results obtained with cell lines deficient in NAD@-PADPRP metabolism relative to the induction of GRP78 and subsequent development of resistance to VP-16. Our studies showthat6-aminonicotlnamide treatmentishighlyeffectivein theInduc tion of GRP78 and subsequentdevelopment of resistance to VP-16, whereas treatment with 3-aminobenzamlde or PD128763 does not induce GRP78 and thus does not result in VP-16 resistance.