Evaluation of tubulin polymerization and chronic inhibition of proteasome as citotoxicity mechanisms in bortezomib-induced peripheral neuropathy

Meregalli, C; Chiorazzi, A; Carozzi, Valentina Alda; Canta, A; Sala, Barbara; Colombo, Matteo; Oggioni, N; Ceresa, C; Foudah, Dana; Russa, Federica La; Miloso, Mariarosaria; Nicolini, Gabriella; Marmiroli, P; Bennett, David L.H.; Cavaletti, Guido

doi:10.4161/cc.27476

Cited by 61 publications

(63 citation statements)

References 43 publications

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“…Systemic injection of bortezomib on four alternate days at a clinically relevant dose (0.2 mg/kg) (Meregalli et al, 2014) caused a gradual decrease in the tactile and pressure withdrawal thresholds in 7 rats (Fig. 1).…”

Section: Resultsmentioning

confidence: 98%

“…We examined the translocation of PKC-δ and PKC-ε at 0.5, 1 and 6 h after incubation of F11 cells with 10 nM bortezomib. It has been shown that bortezomib at 10 nM is effective in inhibiting proteasome activity (Bil et al, 2010; Meregalli et al, 2014). Our Western blotting analysis demonstrated that the immunoreactivity of PKC-δ and PKC-ε was potentiated on the plasma membrane, whereas their protein levels in the cytosolic fraction were reduced by bortezomib exposure.…”

Section: Resultsmentioning

confidence: 99%

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Bortezomib induces neuropathic pain through protein kinase C-mediated activation of presynaptic NMDA receptors in the spinal cord

Xie

Chen

et al. 2017

Neuropharmacology

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Chemotherapeutic drugs, including bortezomib, often cause painful peripheral neuropathy, which is a severe dose-limiting adverse effect experienced by many cancer patients. The glutamate N-methyl-D-aspartate receptors (NMDARs) at the spinal cord level are critically involved in the synaptic plasticity associated with neuropathic pain. In this study, we determined whether treatment with bortezomib, a proteasome inhibitor, affects the NMDAR activity of spinal dorsal horn neurons. Systemic treatment with bortezomib in rats did not significantly affect postsynaptic NMDAR currents elicited by puff application of NMDA directly to dorsal horn neurons. Bortezomib treatment markedly increased the baseline frequency of miniature excitatory postsynaptic currents (EPSCs), which was completely normalized by the NMDAR antagonist 2-amino-5-phosphonopentanoic acid (AP5). AP5 also reduced the amplitude of monosynaptic EPSCs evoked by dorsal root stimulation in bortezomib-treated, but not vehicle-treated, rats. Furthermore, inhibition of protein kinase C (PKC) with chelerythrine fully reversed the increased frequency of miniature EPSCs and the amplitude of evoked EPSCs in bortezomib-treated rats. Intrathecal injection of AP5 and chelerythrine both profoundly attenuated mechanical allodynia and hyperalgesia induced by systemic treatment with bortezomib. In addition, treatment with bortezomib induced striking membrane translocation of PKC-βII, PKC-δ, and PKC-ε in the dorsal root ganglion. Our findings indicate that bortezomib treatment potentiates nociceptive input from primary afferent nerves via PKC-mediated tonic activation of presynaptic NMDARs. Targeting presynaptic NMDARs and PKC at the spinal cord level may be an effective strategy for treating chemotherapy-induced neuropathic pain.

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Bortezomib induces neuropathic pain through protein kinase C-mediated activation of presynaptic NMDA receptors in the spinal cord

Xie

Chen

et al. 2017

Neuropharmacology

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“…*p \ 0.05 Neurotox Res higher than the ones of our study (Staff et al 2013). However, a previous study already demonstrated that embryonic and adult DRG neurons had different sensitivity to bortezomib (Meregalli et al 2013). Therefore, to study the chemotherapy-induced neurotoxicity in vitro, it seems more adequate the use of adult primary neuronal cultures since it is closer to the in vivo model and, thus, to the clinical situation (Staff et al 2013;Meregalli et al 2013).…”

Section: Methodological Differences Between In Vitro Studiesmentioning

confidence: 96%

“…Conversely, other studies proposed that BIPN was mainly due to dysfunctions at the neuronal level, and changes in axons and myelin might be secondary to this initial event (Bruna et al 2010). Other studies reported neuronal alterations after bortezomib exposure, proposing that the neurotoxicity is related either to microtubule polymerization and stabilization (Poruchynsky et al 2008;Staff et al 2013;Meregalli et al 2013) or to nuclear accumulation of ubiquitylated proteins and poly(A)RNAs in nuclear granules, with consequent reduction of transcription and alteration of mRNA translation (Casafont et al 2010;Palanca et al 2013).…”

Section: Introductionmentioning

confidence: 91%

“…Microtubules and intermediate filaments are related to the maintenance of cell architecture, intracellular trafficking, and cell motility and are key players not only in survival of tumoral cells but also of neurons. Therefore, the effects of anti-tumoral drugs on proteins involved in cytoskeleton homeostasis can explain, at least partially, the neurotoxicity induced by these treatments (Poruchynsky et al 2008;Staff et al 2013;Meregalli et al 2013).…”

Section: Cytoskeleton Alterations Induced By Bortezomibmentioning

confidence: 98%

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Toxic Effects of Bortezomib on Primary Sensory Neurons and Schwann Cells of Adult Mice

et al. 2015

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The proteasome inhibitor bortezomib is nowadays first line treatment for multiple myeloma. One of the most significant adverse events is peripheral neuropathy, mainly involving sensory nerve fibers that can lead to withdrawal of treatment. Here we develop an in vitro model to compare the effects of bortezomib on primary sensory neurons and Schwann cells of adult mice. We observed that sensory neurons were more susceptible to bortezomib, and their viability was reduced at a concentration of 6 nM, that only affected Schwann cell proliferation but not survival. At concentration higher than 8 nM Schwann cell viability was also compromised. Already at low concentrations, surviving neurons presented alterations in neurite outgrowth. Neurites were shorter and had dystrophic appearance, with alterations in neurofilament staining. However, neurites were able to regrow after removing bortezomib from the medium, thus indicating reversibility of the neurotoxicity. We confirmed in vivo that bortezomib produced alterations in neurofilaments at early stages of the treatment. After an accumulated dose of 2 mg/kg bortezomib, dorsal root ganglia neurons of treated animals showed accumulation of neurofilament in the soma. To evaluate if this accumulation was related with alterations in axonal transport, we tested the ability of sensory neurons to retrogradely transport a retrotracer applied at the distal nerve. Treated animals showed a lower amount of retrotracer in the soma 24 h after its application to the tibial nerve, therefore suggesting that axonal transport was affected by bortezomib.

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Manifestations of Drug Toxicity on Mitochondria in the Nervous System

Prehn

Llorente‐Folch

2018

Mitochondrial Dysfunction Caused by Drugs and Environmental Toxicants

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Evaluation of tubulin polymerization and chronic inhibition of proteasome as citotoxicity mechanisms in bortezomib-induced peripheral neuropathy

Cited by 61 publications

References 43 publications

Bortezomib induces neuropathic pain through protein kinase C-mediated activation of presynaptic NMDA receptors in the spinal cord

Bortezomib induces neuropathic pain through protein kinase C-mediated activation of presynaptic NMDA receptors in the spinal cord

Toxic Effects of Bortezomib on Primary Sensory Neurons and Schwann Cells of Adult Mice

Manifestations of Drug Toxicity on Mitochondria in the Nervous System

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