Proteasome inhibitors in multiple myeloma: 10 years later

Moreau, Philippe; Richardson, Paul G.; Cavo, Michèle; Orłowski, Robert Z.; Miguel, Jesús F. San; Palumbo, Antônio; Harousseau, Jean Luc

doi:10.1182/blood-2012-04-403733

Cited by 447 publications

(381 citation statements)

References 77 publications

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“…This indicates that the proteasome inhibitors investigated are not activators of PXR, which usually mediates the induction of genes, including ABCB1, ABCC2 and ABCG2 (32)(33)(34). This is concordant with previous in vitro studies that reported no significant changes in the expression of certain drug transporter genes (ABCB1, ABCC1 and ABCG2), even following long-term exposure to bortezomib (35) or an increase in ABCB1 expression following six months of treatment with increasing concentrations of carfilzomib only (36).…”

Section: Discussionsupporting

confidence: 80%

Bortezomib, carfilzomib and ixazomib do not mediate relevant transporter-based drug-drug interactions

et al. 2017

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Abstract. In order to optimize the clinical application of an increasing number of proteasome inhibitors, investigations into the differences between their respective pharmacodynamic and pharmacokinetic profiles, including their ability to act as a perpetrator in drug-drug interactions, are warranted. Therefore, in the present in vitro study, it was investigated whether bortezomib, carfilzomib and ixazomib are able to alter the expression, and/or the activity, of specific drug transporters generally relevant for pharmacokinetic drug-drug interactions. Through induction experiments, the current study demonstrated that the aforementioned three proteasome inhibitors do not induce mRNA expression of the transporter genes ATP binding cassette (ABC)B1, C1, C2 and G2 in the LS180 cell line, which was used as a model for systemic induction. By contrast, in certain myeloma cell lines, ixazomib provoked minor alterations in individual transporter gene expression. None of the proteasome inhibitors tested relevantly inhibited drug transporters within the range of physiological plasma concentrations. Taken together, transporter-based drug-drug interactions are unlikely to be a primary concern in the clinical application of the tested compounds.

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Section: Discussionsupporting

confidence: 80%

Bortezomib, carfilzomib and ixazomib do not mediate relevant transporter-based drug-drug interactions

et al. 2017

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“…1,2 An enzymatically active proteasome is composed of a 20S core and at least one proteasomal activator complex. 3 The 20S is the catalytic core that is activated through association with proteasomal activators.…”

mentioning

confidence: 99%

Regulation of c-Myc protein stability by proteasome activator REGγ

Jiang

Pan

et al. 2014

Cell Death Differ

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-Myc is a key transcriptional factor that has a prominent role in cell growth, differentiation and tumor development. Its protein levels are tightly controlled by ubiquitin-proteasome pathway and frequently deregulated in various cancers. Here, we report that the 11S proteasomal activator REGγ is a novel regulator of c-Myc abundance in cells. We showed that overexpression of wild-type REGγ, but not inactive mutants including N151Y and G250S, significantly promoted the degradation of c-Myc. Depletion of REGγ markedly increased the protein stability of c-Myc. REGγ interacts with the C-terminal region of c-Myc and regulates c-Myc protein turnover. Functionally, REGγ negatively regulates c-Myc-mediated cell proliferation. Interestingly, depletion of the Drosophila Reg homolog (dReg) in developing wings induced the upregulation of Drosophila Myc, which contributes to cell death. Collectively, these results suggest that REGγ proteasome has a conserved role in the regulation of Myc abundance in both mammalian cells and Drosophila.

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“…For example, combination with lenalidomide or thalidomide may improve clinical benefit as these agents alter cytokine production and enhance T-and NK-cellmediated immune responses [52,53]. In addition, as proteasome inhibition stimulates apoptosis, reduces angiogenesis, cytokine signaling and cell adhesion, and can increase the susceptibility of multiple myeloma cells to NK cell-mediated killing [54,55], combination with bortezomib may also be effective [56,57]. In preclinical studies, overnight pretreatment of multiple myeloma cells with antibodies enhanced the efficacy of the ADCC-mediating mAb trastuzumab [62].…”

Section: Elotuzumab-based Combination Therapy Preclinical Rationalementioning

confidence: 99%

Preclinical and clinical evaluation of elotuzumab, a SLAMF7-targeted humanized monoclonal antibody in development for multiple myeloma

Palumbo

Sonneveld

2015

Expert Review of Hematology

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Proteasome inhibitors in multiple myeloma: 10 years later

Cited by 447 publications

References 77 publications

Bortezomib, carfilzomib and ixazomib do not mediate relevant transporter-based drug-drug interactions

Bortezomib, carfilzomib and ixazomib do not mediate relevant transporter-based drug-drug interactions

Regulation of c-Myc protein stability by proteasome activator REGγ

Preclinical and clinical evaluation of elotuzumab, a SLAMF7-targeted humanized monoclonal antibody in development for multiple myeloma

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