pd-184352 and Lymphoma--Large-B-Cell--Diffuse

Interactions between the multi-kinase inhibitor sorafenib and MEK1/2 inhibitors were investigated in DLBCL cells. Sorafenib (3-10 microM) triggered apoptosis in multiple GC and ABC lymphoma cells. Unexpectedly, sorafenib did not cause sustained ERK1/2 inactivation, and in SUDHL-6 and -16 cells, triggered ERK1/2 activation. Marginally toxic MEK1/2 inhibitor concentrations (5 microM PD184352) abrogated ERK1/2 activation in sorafenib-treated cells and synergistically potentiated apoptosis. MEK1 shRNA transfection also significantly increased sorafenib-mediated lethality. Sorafenib/PD184352 co-administration accelerated Mcl-1 down-regulation without up-regulating Bim(EL). Finally, ectopic Mcl-1 expression attenuated sorafenib/PD184352-mediated apoptosis. Together, these findings provide a theoretical basis for potentiating sorafenib anti-lymphoma activity by MEK1/2 inhibitors.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzamides; Benzenesulfonates; Blotting, Western; Cell Line, Tumor; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; Humans; Lymphoma, Large B-Cell, Diffuse; MAP Kinase Kinase Kinases; Niacinamide; Phenylurea Compounds; Pyridines; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Sorafenib; Transfection