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 UPS-mediated 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.

Caputi F.F., Di Cesare Mannelli L., Rullo L., Micheli L., Stamatakos S., Posa L., et al. (2020). The active second-generation proteasome inhibitor oprozomib reverts the oxaliplatin-induced neuropathy symptoms. BIOCHEMICAL PHARMACOLOGY, 182, 1-11 [10.1016/j.bcp.2020.114255].

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

Caputi F. F.;Rullo L.;Stamatakos S.;Romualdi P.
;
Candeletti S.
2020

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 UPS-mediated 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.
2020
Caputi F.F., Di Cesare Mannelli L., Rullo L., Micheli L., Stamatakos S., Posa L., et al. (2020). The active second-generation proteasome inhibitor oprozomib reverts the oxaliplatin-induced neuropathy symptoms. BIOCHEMICAL PHARMACOLOGY, 182, 1-11 [10.1016/j.bcp.2020.114255].
Caputi F.F.; Di Cesare Mannelli L.; Rullo L.; Micheli L.; Stamatakos S.; Posa L.; Ghelardini C.; Romualdi P.; Candeletti S.
File in questo prodotto:
File Dimensione Formato  
TrackChangesCaputietal.2020Bioch Pharmrev28920(1).pdf

Open Access dal 02/10/2021

Tipo: Postprint
Licenza: Licenza per Accesso Aperto. Creative Commons Attribuzione - Non commerciale - Non opere derivate (CCBYNCND)
Dimensione 2.37 MB
Formato Adobe PDF
2.37 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/796273
Citazioni
  • ???jsp.display-item.citation.pmc??? 8
  • Scopus 11
  • ???jsp.display-item.citation.isi??? 11
social impact