The active second-generation proteasome inhibitor oprozomib reverts the oxaliplatin-induced neuropathy symptoms

Abstract

Oxaliplatin-induced neuropathy (OXAIN) is a major adverse effect of this antineoplastic drug, widely used in the treatment of colorectal cancer. Although its molecular mechanisms remain poorly understood, recent evidence suggest that maladaptive neuroplasticity and oxidative stress may participate to the development of this neuropathy. Given the role played on protein remodeling by ubiquitin-proteasome system (UPS) in response to oxidative stress and in neuropathic pain, we investigated whether oxaliplatin might cause alterations in the UPSmediated degradation pathway, in order to identify new pharmacological tools useful in OXAIN. In a rat model of OXAIN (2.4 mg kg − 1 i.p., daily for 10 days), a significant increase in chymotrypsin-(β5) like activity of the constitutive proteasome 26S was observed in the thalamus (TH) and somatosensory cortex (SSCx). In addition, the selective up-regulation of β5 and LMP7 (β5i) subunit gene expression was assessed in the SSCx. Furthermore, this study revealed that oprozomib, a selective β5 subunit proteasome inhibitor, is able to normalize the spinal prodynorphin gene expression upregulation induced by oxaliplatin, as well as to revert mechanical allodynia and thermal hyperalgesia observed in oxaliplatin-treated rats. These results underline the relevant role of UPS in the OXAIN and suggest new pharmacological targets to counteract this severe adverse effect.This preclinical study reveals the involvement of the proteasome in the oxaliplatin-induced neuropathy and adds useful information to better understand the molecular mechanism underlying this pain condition. Moreover, although further evidence is required, these findings suggest that oprozomib could be a therapeutic option to counteract chemotherapy-induced neuropathy.

Interplay between Prokineticins and Histone Demethylase KDM6A in a Murine Model of Bortezomib-Induced Neuropathy

“…Pathological mechanisms of BTZ-induced neuropathy are not yet clearly understood. Similar, however, to what has been suggested for other CIN conditions, involvement of different phenomena, such as oxidative stress, mitochondrial damage, and ion channel dysfunction have been proposed in its development [ 3 , 4 , 5 , 6 , 7 ]. In addition, a role for the immune system in neuroinflammatory processes in this pathological condition has also been indicated [ 8 , 9 , 10 ] .…”

Effects of Different Opioid Drugs on Oxidative Status and Proteasome Activity in SH-SY5Y Cells

“…Proteasome β2 trypsin-like and β5 chymotrypsin-like activities were analyzed by monitoring the cleavage of benzyloxycarbonyl-Ala-Arg-Arg-7-amino-4-methylcoumarin (Z-ARR-AMC) and succinyl-Leu-Leu-Val-Tyr-7-amino-4-methylcoumarin (Suc-LLVY-AMC) (both purchased from Merck Millipore, Roma, Italy), respectively, using 25 μg of cell lysate proteins per sample [ 67 ]. The assay is based on the detection of the fluorophore 7-amino-4-methylcoumarin (AMC) after cleavage from the labeled substrates.…”

The Microglial Activation Inhibitor Minocycline, Used Alone and in Combination with Duloxetine, Attenuates Pain Caused by Oxaliplatin in Mice

“…Molecular mechanisms that contribute to the development of acute neuropathy in oxaliplatin-treated patients comprise various mechanisms, such as transient activation of voltage-gated ion (sodium (Na v ), calcium (Ca v )) channels, impaired axonal transport, calcium homeostasis, microglial activation and increased oxidative stress in the peripheral nervous system, which results in the hyperexcitability of neuronal cell membranes [2,[7][8][9][10][11][12]. Therefore, there is still a strong medical need to develop novel treatment options to not only relieve neuropathic pain in pre-existing CIPN caused by oxaliplatin, but also to develop effective, mechanism-based preventative therapies for CIPN [13].…”