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The Farnesyltransferase Inhibitor L744832 Potentiates UCN-01–Induced Apoptosis in Human Multiple Myeloma Cells

Authors' Affiliations: Departments of ¹ Medicine, ² Biochemistry, ³ Pharmacology, and ⁴ Radiation Oncology, Virginia Commonwealth University/Medical College of Virginia, Richmond, Virginia

Requests for reprints: Steven Grant, Division of Hematology/Oncology, Virginia Commonwealth University/Medical College of Virginia, Medical College of Virginia Station Box 230, Richmond, VA 23298. Phone: 804-828-5211; Fax: 804-828-8079; E-mail: stgrant{at}hsc.vcu.edu.

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, caspase 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 inactivation 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. L744832/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-I, 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 UCN-01 could represent a novel therapeutic strategy in multiple myeloma.

Key Words: Apoptosis • multiple myeloma • UCN-01 • farnesyltransferase inhibitor • drug resistance

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