Proteomic approach for understanding milder neurotoxicity of Carfilzomib against Bortezomib

Karademir, Betül; Sarı, Gülce; Jannuzzi, Ayşe Tarbın; Musunuri, Sravani; Wicher, Grzegorz; Grune, Tilman; Mi, Jia; Hacioglu-Bay, Husniye; Forsberg-Nilsson, Karin; Bergquist, Jonas; Jung, Tobias

doi:10.1038/s41598-018-34507-3

Cited by 28 publications

(22 citation statements)

References 46 publications

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“…Recent studies have shown that bortezomib causes acute cytoskeletal damage, which is relevant in neural cell integrity. In addition, it has been demonstrated that bortezomib causes excessive protein carbonylation and destabilization of actin filaments [17]. Our current study provided interesting results that indicate a significant dysregulation of genes in neuronal cells, which may be characteristic for bortezomib activity (Figures 2, 3 and 8).…”

Section: Discussionsupporting

confidence: 59%

Effect of Bortezomib on Global Gene Expression in PC12-Derived Nerve Cells

Łuczkowska¹,

Rogińska²,

Ulańczyk³

2020

IJMS

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Peripheral neuropathy is one of the main side-effects of novel therapeutics used in oncohematological diseases, but the molecular basis underlying its development and progression as well as neurotoxicity mechanisms induced by the use of these therapeutics are still not fully elucidated. The aim of this study was to demonstrate the effect of bortezomib on global gene and miRNA expression on PC12-derived nerve cells. Microarray analysis showed that expression of 1383 genes was downregulated at least two fold and 671 genes were upregulated at least two fold in PC12-derived nerve cells treated with bortezomib compared to untreated/control cells. Analysis of functional annotations mainly identified downregulated processes (e.g., regulation of cell cycle, DNA replication and repair, regulation of cell migration, neuron projection morphogenesis and neurotransmitter secretion). The result of miRNA expression analysis demonstrated only 11 significantly downregulated miRNAs (at least two fold) in bortezomib-treated PC12-derived nerve cells vs. control cells. MiRNAs regulate gene expression, therefore we decided to conduct an analysis comparing the outcomes of miRNA microarray expression data to the obtained mRNA data. The most interesting miRNA–target gene correlation is downregulated expression of miR-130a-3p and miR-152-3p and as a result of this downregulation the expression of the Gadd45 increased. This gene is a member of a group of genes, the transcript expression of which is enhanced after stressful growth arrest conditions and treatment with DNA-damaging agents like drugs or mutagens.

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Section: Discussionsupporting

confidence: 59%

Effect of Bortezomib on Global Gene Expression in PC12-Derived Nerve Cells

Łuczkowska¹,

Rogińska²,

Ulańczyk³

2020

IJMS

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“…Under current-clamp potential recordings, the addition of CFZ was found to depolarize the cells, to widen AP duration, and to raise the firing frequency of spontaneous APs recorded from GH 3 cells in a concentration-dependent fashion. It is thus most likely that CFZ-induced increase of I K(DR) inactivation in endocrine or neuroendocrine cells may enhance a process of long-lasting facilitation or potentiation (Lin et al, 2008; Wang et al, 2008b; Wu et al, 2008; Kuo et al, 2018), which is conceivably associated with the toxicological actions of CFZ and other structurally similar compounds including variable forms of peripheral neuropathy (Cai et al, 2016; Kaplan et al, 2017; Karademir et al, 2018; Luczkowska et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…Predominantly through the inhibition of proteasome-mediated proteolysis, the presence of CFZ can induce cell cycle arrest and apoptosis in different types of human cancer cell lines including multiple myeloma, lymphoma, and various solid tumors (Demo et al, 2007; Zhang and Sidhu, 2014; Kaplan et al, 2017). Moreover, there were case reports on CFZ associated neurotoxicity (Kaplan et al, 2017; Karademir et al, 2018; Luczkowska et al, 2018). However, how this agent and other structurally similar compounds exert any perturbations on membrane ionic currents is not thoroughly investigated, although CFZ might manipulate the energy and redox metabolism through a mechanism independent of its inhibition of proteasome activity (Soriano et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

High Effectiveness in Actions of Carfilzomib on Delayed-Rectifier K+ Current and on Spontaneous Action Potentials

Liu

Lee

et al. 2019

Front. Pharmacol.

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Carfilzomib (CFZ, Kyprolis®) is widely recognized as an irreversible inhibitor of proteasome activity; however, its actions on ion currents in electrically excitable cells are largely unresolved. The possible actions of CFZ on ionic currents and membrane potential in pituitary GH3, A7r5 vascular smooth muscle, and heart-derived H9c2 cells were extensively investigated in this study. The presence of CFZ suppressed the amplitude of delayed-rectifier K+ current (I K(DR)) in a time-, state-, and concentration-dependent manner in pituitary GH3 cells. Based on minimal reaction scheme, the value of dissociation constant for CFZ-induced open-channel block of I K(DR) in these cells was 0.33 µM, which is similar to the IC50 value (0.32 µM) used for its efficacy on inhibition of I K(DR) amplitude. Recovery from I K(DR) block by CFZ (0.3 µM and 1 µM) could be well fitted by single exponential with 447 and 645 ms, respectively. The M-type K+ current, another type of K+ current elicited by low-threshold potential, was slightly suppressed by CFZ (1 µM). Under current-clamp condition, addition of CFZ depolarized GH3 cells, broadened the duration of action potentials as well as raised the firing frequency. In A7r5 vascular smooth muscle cells or H9c2 cardiac cells, the CFZ-induced inhibition of I K(DR) remained efficacious. Therefore, our study led us to reflect that CFZ or other structurally similar compounds should somehow act on the activity of membrane KV channels through which they influence the functional activities in different types of electrically excitable cells such as endocrine, neuroendocrine cells, smooth muscle cells, or heart cells, if similar in vivo findings occur.

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“…The altered microtubule dynamics result in decreased neurite elongation and impaired axonal transport of mitochondria in mice and rat DRG neuronal cultures, respectively [90,91]. In addition, bortezomib can affect another major component of the cytoskeleton, the actin filaments, as observed in mouse neural stem cells [92].…”

Section: Peripheral Neuropathy: the Key Dose-limiting Toxicitymentioning

confidence: 99%

Non-Hematologic Toxicity of Bortezomib in Multiple Myeloma: The Neuromuscular and Cardiovascular Adverse Effects

Pancheri

Guglielmi

Wilczyński

et al. 2020

Cancers

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The overall approach to the treatment of multiple myeloma (MM) has undergone several changes during the past decade. and proteasome inhibitors (PIs) including bortezomib, carfilzomib, and ixazomib have considerably improved the outcomes in affected patients. The first-in-class selective PI bortezomib has been initially approved for the refractory forms of the disease but has now become, in combination with other drugs, the backbone of the frontline therapy for newly diagnosed MM patients, as well as in the maintenance therapy and relapsed/refractory setting. Despite being among the most widely used and highly effective agents for MM, bortezomib can induce adverse events that potentially lead to early discontinuation of the therapy with negative effects on the quality of life and outcome of the patients. Although peripheral neuropathy and myelosuppression have been recognized as the most relevant bortezomib-related adverse effects, cardiac and skeletal muscle toxicities are relatively common in MM treated patients, but they have received much less attention. Here we review the neuromuscular and cardiovascular side effects of bortezomib. focusing on the molecular mechanisms underlying its toxicity. We also discuss our preliminary data on the effects of bortezomib on skeletal muscle tissue in mice receiving the drug.

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Proteomic approach for understanding milder neurotoxicity of Carfilzomib against Bortezomib

Cited by 28 publications

References 46 publications

Effect of Bortezomib on Global Gene Expression in PC12-Derived Nerve Cells

Effect of Bortezomib on Global Gene Expression in PC12-Derived Nerve Cells

High Effectiveness in Actions of Carfilzomib on Delayed-Rectifier K+ Current and on Spontaneous Action Potentials

Non-Hematologic Toxicity of Bortezomib in Multiple Myeloma: The Neuromuscular and Cardiovascular Adverse Effects

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