The farnesyltransferase inhibitor L744832 potentiates UCN-01-induced apoptosis in human multiple myeloma cells

Purpose: The purpose of this study was to characterize interactions between the farnesyltransferase inhibitor L744832 and the checkpoint abrogator UCN-01 in drug-sensitive and drug-resistant human myeloma cell lines and primary CD138⁺ multiple myeloma cells. Experimental Design: Wild-type and drug-resistant myeloma cell lines were exposed to UCN-01 ±L744832 for 24 hours, after which mitochondrial injury, caspaee activation, apoptosis, and various perturbations in signaling and survival pathways were monitored. Results: Simultaneous exposure of myeloma cells to marginally toxic concentrations of L744832 and UCN-01 resulted in a synergistic induction of mitochondrial damage, caspase activation, and apoptosis, associated with activation of p34^cdc2 and c-Jun-NH₂-kinase and ihactivation Of extracellular signal-regulated kinase, Akt, GSK-3, p70 ^S6K, and signal transducers and activators of transcription 3 (STAT3). Enhanced lethality for the combination was also observed in primary CD138⁺ myeloma cells, but not in their CD138⁺ counterparts. L44832/UCN-01-mediated lethality was not attenuated by conventional resistance mechanisms to cytotoxic drugs (e.g., melphalan or dexamethasone), addition of exogenous interleukin-6 or insulin-like growth factor-1, or the presence of stromal cells. In contrast, enforced activation of STAT3 significantly protected myeloma cells from L744832/UCN-01-induced apoptosis. Conclusions: Coadministration of the farnesyltransferase inhibitor L744832 promotes UCN-01-induced apoptosis in human multiple myeloma cells through a process that may involve perturbations in various survival signaling pathways, including extracellular signal-regulated kinase, Akt, and STAT3, and through a process capable of circumventing conventional modes of myeloma cell resistance, including growth factor- and stromal cell-related mechanisms. They also raise the possibility that combined treatment with farnesyltransferase inhibitors and UGN-01 could represent a novel therapeutic strategy in multiple myeloma.