Abstract
Thalidomide (Thal) achieves responses even in the setting of refractory multiple myeloma (MM). Although increased angiogenesis in MM bone marrow and the antiangiogenic effect of Thal formed the empiric basis for its use in MM, we have shown that Thal and its immunomodulatory analogs (IMiDs) directly induce apoptosis or growth arrest of MM cells, alter adhesion of MM cells to bone marrow stromal cells, inhibit the production of cytokines (interleukin-6 and vascular endothelial growth factor) in bone marrow, and stimulate natural killer cell anti-MM immunity. In the present study, we demonstrate that the IMiDs trigger activation of caspase-8, enhance MM cell sensitivity to Fas-induced apoptosis, and down-regulate nuclear factor (NF)-kappa B activity as well as expression of cellular inhibitor of apoptosis protein-2 and FLICE inhibitory protein. IMiDs also block the stimulatory effect of insulinlike growth factor-1 on NF-kappa B activity and potentiate the activity of TNF-related apoptosis-inducing ligand (TRAIL/Apo2L), dexamethasone, and proteasome inhibitor (PS-341) therapy. These studies both delineate the mechanism of action of IMiDs against MM cells in vitro and form the basis for clinical trials of these agents, alone and coupled with conventional and other novel therapies, to improve outcome in MM.
Highlights
Introduction dothelial growth factor) in bone marrow, and stimulate natural killer cell anti-MM immunity
Our studies have demonstrated multiple anti-MM activities of Thal other than antiangiogenesis: direct induction of apoptosis or growth arrest in MM cells,[4] inhibition of interleukin-6 and vascular endothelial growth factor (VEGF) secretion triggered by MM cell adhesion to bone marrow stromal cells,[5] inhibition of VEGF-mediated MM cell growth and migration,[6] inhibition of tumor necrosis factor ␣ (TNF-␣) signaling,[4] and stimulation of patients’ natural killer cell anti-MM immunity.[7]
We found that the IMiDs induce caspase-8–dependent MM cell apoptosis, down-regulate nuclear factor (NF)-B transcriptional activity, and sensitize MM cells to apoptosis induced by Fas cross-linking, TRAIL/Apo2L, Dex, and PS-341
Summary
Introduction dothelial growth factor) in bone marrow, and stimulate natural killer cell anti-MM immunity. One hypothesis suggests that Thal or its breakdown product(s) inhibits the stimulatory effects of insulinlike growth factor 1 (IGF-1) and fibroblast growth factor 2 (FGF-2) on angiogenesis in the developing limb bud,[10,11] resulting in limb malformation This hypothesis is supported by the fact that Thal is an inhibitor of angiogenesis induced by bFGF in a rabbit cornea micropocket assay and that its antiangiogenic activity correlates with teratogenicity, but not with the sedation or the immunosuppression.[3,12] high pretreatment plasma bFGF levels in patients with progressive MM are associated with subsequent response to Thal therapy.[13] Because there is increasing evidence that IGF-1 is an important growth and survival factor in MM,[14,15] inhibition of IGF-1 signaling by Thal may contribute to its anti-MM activity.
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