The paradoxical pharmacological mechanisms of lenalidomide and bortezomib in the treatment of multiple myeloma
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The combination of bortezomib (Velcade, PS-341) and lenalidomide (Revlimid) for the treatment of multiple myeloma was proved by USA Food and Drug Administration in 2006. Lenalidomide prevents the proliferation of multiple myeloma cells through binding to cereblon and promoting the ubiquitinational degradation of IKZF1 (Ikaros)/IKZF3 (Aiolos). However, the proteasome inhibitor bortezomib would inhibit the ubiquitinational degradation of IKZF1/IKZF3. How bortezomib could not block the antiproliferative effect of lenalidomide on multiple myeloma cells, which is the paradoxical pharmacological mechanisms in multiple myeloma. In this review, we summarized recent advances in molecular mechanisms underlying the combination of bortezomib and lenalidomide for the treatment multiple myeloma, discussed the paradoxical pharmacological mechanisms of lenalidomide and bortezomib in the treatment of multiple myeloma.Keywords:
Cereblon
Half a century ago, thalidomide was developed as a sedative drug and was wildly used over 40 countries. However the drug has serious birth defects such as amelia and phocomelia. Now thalidomide is regarded as a clinically effective drug and used for the treatment of multiple myeloma under strict controls. The direct target of thalidomide had been a long-standing question. We identified cereblon as a primary direct target protein for thalidomide teratogenicity using new affinity bead technology in 2010. In this review, we introduce an overview of thalidomide teratogenicity, a story about how we identified cereblon, and recent advances in cereblon studies.
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Thalidomide was sold worldwide as a sedative over 60 years ago, but it was quickly withdrawn from the market due to its teratogenic effects. Thalidomide was later found to have therapeutic effects in several diseases, although the molecular mechanisms remained unclear. The discovery of cereblon (CRBN), the direct target of thalidomide, a decade ago greatly improved our understanding of its mechanism of action. Accumulating evidence has shown that CRBN functions as a substrate of Cullin RING E3 ligase (CRL4CRBN), whose specificity is controlled by ligands such as thalidomide. For example, lenalidomide and pomalidomide, well-known thalidomide derivatives, degrade the neosubstrates Ikaros and Aiolos, resulting in anti-proliferative effects in multiple myeloma. Recently, novel CRBN-binding drugs have been developed. However, for the safe handling of thalidomide and its derivatives, a greater understanding of the mechanisms of its adverse effects is required. The teratogenic effects of thalidomide occur in multiple tissues in the developing fetus and vary in phenotype, making it difficult to clarify this issue. Recently, several CRBN neosubstrates (e.g., SALL4 (Spalt Like Transcription Factor 4) and p63 (Tumor Protein P63)) have been identified as candidate mediators of thalidomide teratogenicity. In this review, we describe the current understanding of molecular mechanisms of thalidomide, particularly in the context of its teratogenicity.
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Immunomodulatory drug lenalidomide is a synthetic compound derived by modifying the chemical structure of thalidomide to improve its potency and reduce its side effects. Lenalidomide is a 4-amino-glutamyl analogue of thalidomide that has emerged as a drug with activity against various hematological and solid malignancies. It is approved by FDA in USA for clinical use in myelodysplastic syndromes with deletion of chromosome 5q and multiple myeloma. Studies have shown that lenalidomide exert anti-tumor activity probably by various mechanisms in hematologic malignancies, such as immunomodulation, anti-angiogenesis and effects on signal transduction. In this article, the progresses of study on these problems are reviewed.
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Thalidomide, lenalidomide and pomalidomide are synthetic immunomodulatory drugs (IMiDs) that have recently drawn attention in both clinics and basic research. Thalidomide was synthesized from glutamic acid and was banned due to its teratogenicity in pregnant women [1]. Lenalidomide is a 4-amino-glutamyl analogue of thalidomide and is approved for the treatment of certain hematologic malignancies. Lenalidomide is used for the treatment of lower-risk red blood cell (RBC) transfusiondependent myelodysplastic syndromes (MDS) with deletion of chromosome 5q (del(5q)) with or without additional cytogenetic abnormalities
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Thalidomide is effective in the treatment of multiple myeloma. The immunomodulatory drug and thalidomide analogue lenalidomide is currently in late stage clinical development for MDS and multiple myeloma. This minireview highlights the course of initial and ongoing lenalidomide clinical development in oncology with reference to earlier thalidomide studies.
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Thalidomide was developed as a sedative drug during the 1950s. Unfortunately, it has serious teratogenic properties. When pregnant women ingested thalidomide, their infants developed serious malformations such as short limbs. However, thalidomide is now recognized as a clinically useful drug, with several countries approving it as an anti-myeloma treatment. Although the direct target of thalidomide was largely debated until recently, our groups discovered cereblon (CRBN), a substrate receptor of an E3 ubiquitin ligase as a primary target of thalidomide in 2010. CRBN binds not only to thalidomide, but also to various thalidomide derivatives such as lenalidomide and pomalidomide, as well as compounds containing a thalidomide moiety. These compounds are known as cereblon modulators, which induced specific neosubstrates of CRBN E3 ubiquitin ligase such as Ikaros and Aiolos. Several groups have now joined the CRBN research and have reported the basic mechanism of CRBN and its binding compounds. In this review, we present our findings as well as recent advances in this subject area.
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Downregulation of cereblon (CRBN) gene expression is associated with resistance to the immunomodulatory drug lenalidomide and poor survival outcomes in multiple myeloma (MM) patients. However, the importance of CRBN gene expression in patients with myelodysplastic syndrome (MDS) and its impact on lenalidomide therapy are not clear. In this study, we evaluate cereblon expression in mononuclear cells isolated from bone marrow [23 lower risk MDS patients with isolated 5q deletion (5q-), 37 lower risk MDS patients with chromosome 5 without the deletion of long arms (non-5q-), and 24 healthy controls] and from peripheral blood (38 patients with 5q-, 52 non-5q- patients and 25 healthy controls) to gain insight into, firstly, the role of cereblon in lower risk MDS patients with or without 5q deletion and, secondly, into the mechanisms of lenalidomide action. Patients with 5q- lower risk MDS have the highest levels of CRBN mRNA in comparison with both lower risk MDS without the deletion of long arms of chromosome 5 and healthy controls. CRBN gene expression was measured using the quantitative TaqMan real-time PCR. High levels of CRBN mRNA were detected in all lenalidomide responders during the course of therapy. A significant decrease of the CRBN mRNA level during lenalidomide treatment is associated with loss of response to treatment and disease progression. These results suggest that, similar to the treatment of MM, high levels of full-length CRBN mRNA in lower risk 5q- patients are necessary for the efficacy of lenalidomide.
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ABSTRACT Thalidomide was originally developed in 1954 as a sedative that was commonly used to ameliorate morning sickness. However, thalidomide exposure during the first trimester of pregnancy caused multiple birth defects (e.g. phocomelia and amelia), affecting ∼10 000 children worldwide in the late 1950s and early 1960s. Thalidomide is now recognized as a clinically effective, albeit strictly restricted, drug for the treatment of leprosy and multiple myeloma. Investigators have studied thalidomide teratogenicity for half a century, proposing over 30 hypotheses to account for its actions. Among these, the anti‐angiogenesis and oxidative stress models have gained widespread support. Nonetheless, the precise molecular mechanisms and direct targets of thalidomide have not heretofore been elucidated. We developed ferrite‐glycidyl methacrylate beads that enable magnetic separation and efficient purification of ligand‐binding molecules; the beads were recently employed to identify cereblon as a primary target of thalidomide. Cereblon forms an E3 ubiquitin ligase complex with DDB1, Cul4A, and Roc1, which is important for the expression of fibroblast growth factor 8, an essential regulator of limb development. Expression of a drug binding‐deficient mutant of cereblon suppressed thalidomide‐induced effects in zebrafish and chicks. This suggests that thalidomide downregulates fibroblast growth factor 8 expression and induces limb malformation by binding to wild‐type cereblon, inhibiting the function of the associated E3 ubiquitin ligase. The present review summarizes the teratogenicity of thalidomide, including existing models for its mode of action, and discusses the identification of cereblon as a key molecule for deciphering the longstanding mystery of thalidomide teratogenicity.
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