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


METHODS
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 p34cdc2 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.
Pei
Xin-Yan
XY
Department of Medicine, Virginia Commonwealth University/Medical College of Virginia, Richmond, Virginia 23298, USA.
Dai
Yun
Y
Rahmani
Mohamed
M
Li
Weiqun
W
Dent
Paul
P
Grant
Steven
S
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D016203:CDC2 Protein Kinase / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D051231:Farnesyltranstransferase; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008715:Methionine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D050796:STAT3 Transcription Factor; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D015534:Trans-Activators
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C096898:L 744832; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; C054852:7-hydroxystaurosporine; D045304:Cytochromes c; D008715:Methionine; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D016203:CDC2 Protein Kinase; D048031:JNK Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D019311:Staurosporine