Differentiation induction enhances bortezomib efficacy and overcomes drug resistance in multiple myeloma

Gu, Jun; Li, Juan; Zhou, Zheng-hai; Liu, Junru; Huang, Beihui; Zheng, Dong; Su, Chang

doi:10.1016/j.bbrc.2012.03.056

Cited by 26 publications

(26 citation statements)

References 25 publications

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“…This sensitization has not yet been reproduced in vitro as culturing MM cells in the presence of bone marrow stromal cells either had no effect [36] or reduced [37] their sensitivity to bortezomib. In culture, increases in immunoglobulin secretion sensitize myeloma [20], [32] and plasma [33] cells to bortezomib. Conversely, treatment with cycloheximide to inhibit protein synthesis de-sensitizes them to proteasome inhibitors [33].…”

Section: Discussionmentioning

confidence: 99%

Molecular Basis of Differential Sensitivity of Myeloma Cells to Clinically Relevant Bolus Treatment with Bortezomib

et al. 2013

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The proteasome inhibitor bortezomib (Velcade) is prescribed for the treatment of multiple myeloma. Clinically achievable concentrations of bortezomib cause less than 85% inhibition of the chymotrypsin-like activity of the proteasome, but little attention has been paid as to whether in vitro studies are representative of this level of inhibition. Patients receive bortezomib as an intravenous or subcutaneous bolus injection, resulting in maximum proteasome inhibition within one hour followed by a gradual recovery of activity. In contrast, most in vitro studies use continuous treatment so that activity never recovers. Replacing continuous treatment with 1 h-pulse treatment increases differences in sensitivity in a panel of 7 multiple myeloma cell lines from 5.3-fold to 18-fold, and reveals that the more sensitive cell lines undergo apoptosis at faster rates. Clinically achievable inhibition of active sites was sufficient to induce cytotoxicity only in one cell line. At concentrations of bortezomib that produced similar inhibition of peptidase activities a different extent of inhibition of protein degradation was observed, providing an explanation for the differential sensitivity. The amount of protein degraded per number of active proteasomes correlated with sensitivity to bortezomib. Thus, (i) in vitro studies of proteasome inhibitors should be conducted at pharmacologically achievable concentrations and duration of treatment; (ii) a similar level of inhibition of active sites results in a different extent of inhibition of protein breakdown in different cell lines, and hence a difference in sensitivity.

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Section: Discussionmentioning

confidence: 99%

Molecular Basis of Differential Sensitivity of Myeloma Cells to Clinically Relevant Bolus Treatment with Bortezomib

et al. 2013

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“…First, downregulation of XBP1s expression in myeloma correlates with resistance to bortezomib (136, 137). Second, using a combination of whole-genome and whole-exome sequencing of primary tumors from 38 myeloma patients, researchers discovered XBP1 mutations in two of these patients (138).…”

Section: The Role Of Endoplasmic Reticulum Stress In Diseasementioning

confidence: 99%

The Role of Endoplasmic Reticulum Stress in Human Pathology

Oakes

Papa

2015

Annu. Rev. Pathol. Mech. Dis.

1,030

820

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Numerous genetic and environmental insults impede the ability of cells to properly fold and posttranslationally modify secretory and transmembrane proteins in the endoplasmic reticulum (ER), leading to a buildup of misfolded proteins in this organelle—a condition called ER stress. ER-stressed cells must rapidly restore protein-folding capacity to match protein-folding demand if they are to survive. In the presence of high levels of misfolded proteins in the ER, an intracellular signaling pathway called the unfolded protein response (UPR) induces a set of transcriptional and translational events that restore ER homeostasis. However, if ER stress persists chronically at high levels, a terminal UPR program ensures that cells commit to self-destruction. Chronic ER stress and defects in UPR signaling are emerging as key contributors to a growing list of human diseases, including diabetes, neurodegeneration, and cancer. Hence, there is much interest in targeting components of the UPR as a therapeutic strategy to combat these ER stress–associated pathologies.

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“…Leukemia and lymphoma cell lines (K-562, Raji, IM-9 and Jurkat-R) with elevated Rad expression levels showed higher degrees of bortezomib resistance versus those (Sup-B15, JVM-2, U266 and Jurkat) with low Rad expression levels [50]. Study of Gu et al demonstrated that myeloma differentiation status is associated with myeloma sensitivity to bortezomib and that induction of differentiation, increasing the proteasome workload in myeloma cells by increasing immunoglobulin secretion, while reducing proteasome capacity by decreasing proteasome activity, can overcome myeloma resistance to bortezomib [51]. Jung et al reported that stem-like cells in mantle cell lymphoma, termed mantle cell lymphoma-initiating cells, enriched in the population that lack prototypic B-cell marker CD19.…”

Section: Introductionmentioning

confidence: 99%

The resistance mechanisms of proteasome inhibitor bortezomib

Wang

2013

Biomark Res

121

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The proteasome inhibitor, bortezomib, a boronic dipeptide which reversibly inhibit the chymotrypsin-like activity at the β5-subunit of proteasome (PSMB5), has marked efficacy against multiple myeloma and several non-Hodgkin’s lymphoma subtypes, and has a potential therapeutic role against other malignancy diseases. However, intrinsic and acquired resistance to bortezomib may limit its efficacy. In this article, we discuss recent advances in the molecular understanding of bortezomib resistance. Resistance mechanisms discussed include mutations of PSMB5 and the up-regulation of proteasome subunits, alterations of gene and protein expression in stress response, cell survival and antiapoptotic pathways, and multidrug resistance.

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Differentiation induction enhances bortezomib efficacy and overcomes drug resistance in multiple myeloma

Cited by 26 publications

References 25 publications

Molecular Basis of Differential Sensitivity of Myeloma Cells to Clinically Relevant Bolus Treatment with Bortezomib

Molecular Basis of Differential Sensitivity of Myeloma Cells to Clinically Relevant Bolus Treatment with Bortezomib

The Role of Endoplasmic Reticulum Stress in Human Pathology

The resistance mechanisms of proteasome inhibitor bortezomib

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