Immunomodulatory derivatives of thalidomide (IMiD compounds), such as pomalidomide and lenalidomide, are highly active in multiple myeloma (MM) treatment. However, the precise mechanisms of action and resistance in MM are unresolved. Here we show that IMiD compounds down-regulate CCAAT/enhancer-binding protein-β (C/EBPβ) resulting in abrogation of cell proliferation. Overexpression of C/EBPβ rescued MM cells from IMiD-induced inhibition of proliferation, indicating that C/EBPβ is critical in mediating antiproliferative effects. IMiD-induced decrease of C/EBPβ protein led to impaired transcription of interferon regulatory factor 4 (IRF4). Down-regulation of IRF4 by lenalidomide was confirmed by longitudinal studies of bone marrow samples from 23 patients obtained before and during lenalidomide treatment using CD138⁺/IRF4⁺ double labeling. In contrast to down-regulation of C/EBPβ protein, IMiD compounds did not alter C/EBPβ mRNA levels or protein stability, suggesting translational regulation of C/EBPβ. We could demonstrate that C/EBPβ protein expression is under eIF4E-translational control in MM. Furthermore, inhibition of the eIF4E-C/EBPβ axis by IMiD compounds was not observed in IMiD-resistant MM cells. However, targeting translation at a different level by inhibiting eukaryotic translation initiation factor 4E-binding protein 1 phosphorylation overcame resistance, suggesting that this pathway is critical and might be a target to overcome drug resistance.
"The controversial sedative, thalidomide, has immunomodulatory actions that are mediated, in large part, by lowering the rate of TNF synthesis [106, 107]. Recent analogs that more effectively achieve this include 3,6′-dithiothalidomide (3,6′-DT) , which readily enters the brain  and suppresses TNF synthesis post-transcriptionally at the level of translational regulation via the 3′-untranslated region of its messenger RNA (mRNA) [108, 110] as well as through down-regulation of the eukaryotic elongation initiation factor (eIF)-4E  to allow its rapid degradation. "
[Show abstract][Hide abstract] ABSTRACT: There is increasing recognition of the involvement of the immune signaling molecule, tumor necrosis factor (TNF), in the pathophysiology of stroke and chronic brain dysfunction. TNF plays an important role both in modulating synaptic function and in the pathogenesis of neuropathic pain. Etanercept is a recombinant therapeutic that neutralizes pathologic levels of TNF. Brain imaging has demonstrated chronic intracerebral microglial activation and neuroinflammation following stroke and other forms of acute brain injury. Activated microglia release TNF, which mediates neurotoxicity in the stroke penumbra. Recent observational studies have reported rapid and sustained improvement in chronic post-stroke neurological and cognitive dysfunction following perispinal administration of etanercept. The biological plausibility of these results is supported by independent evidence demonstrating reduction in cognitive dysfunction, neuropathic pain, and microglial activation following the use of etanercept, as well as multiple studies reporting improvement in stroke outcome and cognitive impairment following therapeutic strategies designed to inhibit TNF. The causal association between etanercept treatment and reduction in post-stroke disability satisfy all of the Bradford Hill Criteria: strength of the association; consistency; specificity; temporality; biological gradient; biological plausibility; coherence; experimental evidence; and analogy. Recognition that chronic microglial activation and pathologic TNF concentration are targets that may be therapeutically addressed for years following stroke and other forms of acute brain injury provides an exciting new direction for research and treatment.
"This complex regulates DNA repair, replication and transcription, and its inhibition by thalidomide causes teratogenic effects by preventing degradation of proteins that play a crucial role in embryonic limb development (e.g. down regulation of fibroblast growth factor 8) . Drug-induced downstream effects of CRBN inhibition include cell cycle arrest with up regulation of the cyclin-dependent kinase inhibitor p21 WAF-1  and down regulation of interferon regulatory factor 4 (IRF4), a MM cell survival factor that targets critical genes like MYC, CDK6 and CASP3   . "
[Show abstract][Hide abstract] ABSTRACT: Cereblon (CRBN) mediates immunomodulatory drug (IMiD) action in multiple myeloma (MM). We demonstrate here that no patient with very low CRBN expression responded to IMiD plus dexamethasone therapy. In 53 refractory MM patients treated with pomalidomide and dexamethasone, CRBN levels predict for decreased response rates and significant differences in PFS (3.0 vs. 8.9 months, p<0.001) and OS (9.1 vs. 27.2 months, p=0.01) (lowest quartile vs. highest three quartiles). While higher CRBN levels can serve as a surrogate for low risk disease, our study demonstrates that low CRBN expression can predict resistance to IMiD monotherapy and is a predictive biomarker for survival outcomes.
Leukemia research 09/2013; 38(1). DOI:10.1016/j.leukres.2013.08.015 · 2.35 Impact Factor
"Lenalidomide causes concentration-dependent cell cycle arrest in G0-G1 phase by upregulating the CDK inhibitor p21 waf-1, a key cell cycle regulator that modulates the activity of CDKs, and down-regulating the activities of the prosurvival kinases ERK1/2 and Akt (17,18). Lenalidomide inhibits the translation of C/EBPβ by downregulating eIF4E, and IRF4 downregulation has been reported to be a critical factor controlling multiple myeloma survival and as a prognostic marker in patients with multiple myeloma associated with poor survival (19,20). In NSCLC, objective responses have been observed with lenalidomide-based therapy, suggesting that lenalidomide is a potent drug for NSCLC treatment. "
[Show abstract][Hide abstract] ABSTRACT: Non-small cell lung cancer (NSCLC) is the most deadly type of cancer worldwide. Although a number of therapies are used in NSCLC treatment, their therapeutic efficacy remains low. Lenalidomide was originally approved for use in patients with myelodysplastic syndromes, which are associated with 5q deletions, and multiple myeloma. Recently, lenalidomide was investigated as a new NSCLC treatment, and it exerted anticancer effects. However, the primary cellular mechanism of its effects in NSCLC is largely unknown. Therefore, we attempted to elucidate a molecular portrait of lenalidomide-mediated cellular events in NSCLC. Lenalidomide reduced the viability of several NSCLC cell lines in a concentration-dependent manner. In addition, array-based gene expression analysis revealed that lenalidomide regulated the expression of several genes associated with cell survival, apoptosis and development, including BH3-interacting domain death agonist (BID), v-fos FBJ murine osteosarcoma viral oncogene homolog (FOS) and NK2 homeobox1 (NKX2-1). BID and FOS, which are known apoptosis activators, were upregulated by lenalidomide treatment, whereas NKX2-1, which is used as an immunohistochemistry marker for NSCLC, was downregulated. These results provide evidence that lenalidomide directly induces antiproliferative effects by altering the expression of genes associated with cell proliferation and apoptosis.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.