Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications
Open accessAbstract
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)-κB 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-κB 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.
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The clinical evaluation of lenalidomide was motivated by phenotypic assays for caspase cleavage of thalidomide analogs.
“The clinical evaluation of lenalidomide, one of the aforementioned CRBN-modulating IMiDs, was motivated by phenotypic assays for caspase cleavage of thalidomide analogs.166”
From Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence (2023) · cites this paper as [166]
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“…phenotypic assays, which allowed candidates including lenalidomide to translate to the clinic before the molecular mechanism was fully elucidated (Mitsiades et al. 2002). the first breakthrough came when the primary cellular target of thalidomide was identified: cereblon (cRBN), a substrate…”
- Authors
- Mitsiades, N., Mitsiades, C. S., Poulaki, V., Chauhan, D., Richardson, P. G., Hideshima, T., Munshi, N. C., Treon, S. P., & Anderson, K. C.
- Affiliations
- Massachusetts Eye and Ear Infirmary (US)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2002-06-15
- Volume
- 99
- Issue
- 12
- Pages
- 4525-4530
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2142149038
- Cited by
- 669
- References
- 35
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 5 · 2023: 11 · 2022: 15 · 2021: 13 · 2020: 12 · 2019: 16 · 2018: 25 · 2017: 17 · 2016: 25 · 2015: 25 · 2014: 33 · 2013: 41 · 2012: 44
- FWCI
- 17.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- U.S. Public Health Service (P0178378)
- Topics
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- thalidomide, immunomodulators, multiple myeloma, apoptosis, caspase-8, Fas-mediated apoptosis, NF-κB, c-FLIP, insulin-like growth factor I, TRAIL, dexamethasone, bortezomib, combination therapy, angiogenesis
- MeSH terms
- Adjuvants, Immunologic, Drug Synergism, Enzyme Inhibitors, Humans, Ligands, Multiple Myeloma, Thalidomide, Tumor Cells, Cultured, Signal Transduction, NF-kappa B, Apoptosis, Caspases, Caspase 8, Caspase 9, Caspase Inhibitors
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