Higher proteotoxic stress rather than mitochondrial damage is involved in higher neurotoxicity of bortezomib compared to carfilzomib.
Bortezomib
Carfilzomib
Mitotoxicity
Neurotoxicity
Peripheral neuropathy
Journal
Redox biology
ISSN: 2213-2317
Titre abrégé: Redox Biol
Pays: Netherlands
ID NLM: 101605639
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
05
12
2019
revised:
02
03
2020
accepted:
07
03
2020
pubmed:
4
4
2020
medline:
22
6
2021
entrez:
4
4
2020
Statut:
ppublish
Résumé
Proteasome inhibitors have great success for their therapeutic potential against hematologic malignancies. First generation proteasome inhibitor bortezomib induced peripheral neuropathy is considered as a limiting factor in chemotherapy and its second-generation counterpart carfilzomib is associated with lower rates of neurotoxicity. The mitochondrial toxicity (mitotoxicity) hypothesis arises from studies with animal models of bortezomib induced peripheral neuropathy. However, molecular mechanisms are not fully elucidated and the role of mitotoxicity in bortezomib and carfilzomib induced neurotoxicity has not been investigated comparatively. Herein, we characterized the neurotoxic effects of bortezomib and carfilzomib at the molecular level in human neuronal cells using LC-MS/MS analysis, flow cytometry, RT-qPCR, confocal microscopy and western blotting. We showed that bortezomib and carfilzomib affected the human neuronal proteome differently, and bortezomib caused higher proteotoxic stress via protein oxidation, protein K48-ubiquitination, heat shock protein expression upregulation and reduction of mitochondria membrane potential. Bortezomib and carfilzomib did not affect the gene expression levels related to mitochondrial dynamics (optic atrophy 1; OPA1, mitofusin 1; MFN1, mitofusin 2; MFN2, fission 1; FIS1, dynamin-related protein 1; DRP1) and overall mitophagy rate whereas, PINK1/Parkin mediated mitophagy gene expressions were altered with both drugs. Bortezomib and carfilzomib caused downregulation of the contents of mitochondrial oxidative phosphorylation complexes, voltage-dependent anion channel 1 (VDAC1) and uncoupling protein 2 (UCP2) similarly. Our findings suggest that, both drugs induce mitotoxicity besides proteotoxic stress in human neuronal cells and the higher incidence of neurotoxicity with bortezomib than carfilzomib is not directly related to mitochondrial pathways.
Identifiants
pubmed: 32244176
pii: S2213-2317(19)31437-5
doi: 10.1016/j.redox.2020.101502
pmc: PMC7115161
pii:
doi:
Substances chimiques
Oligopeptides
0
Bortezomib
69G8BD63PP
carfilzomib
72X6E3J5AR
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
101502Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors declare no conflict of interest.
Références
Nat Rev Mol Cell Biol. 2005 Mar;6(3):248-61
pubmed: 15738989
Exp Neurol. 2011 Dec;232(2):154-61
pubmed: 21907196
Endocrinology. 2003 Nov;144(11):5014-21
pubmed: 12960023
Blood. 2013 Feb 7;121(6):893-7
pubmed: 23393020
Neuron. 2017 Nov 1;96(3):651-666
pubmed: 29096078
Acta Histochem. 2017 Apr;119(3):315-326
pubmed: 28314612
J Adv Pract Oncol. 2013 Sep;4(5):307-21
pubmed: 25032010
Nat Commun. 2013;4:2428
pubmed: 24013556
Free Radic Biol Med. 2014 Dec;77:195-209
pubmed: 25236750
Nat Med. 2003 Aug;9(8):1062-8
pubmed: 12858170
Zhonghua Xue Ye Xue Za Zhi. 2011 Feb;32(2):107-11
pubmed: 21429377
Neuron. 2008 Dec 10;60(5):748-66
pubmed: 19081372
J Peripher Nerv Syst. 2008 Mar;13(1):27-46
pubmed: 18346229
Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10925-30
pubmed: 9380736
Mol Cell. 2013 Jan 10;49(1):121-32
pubmed: 23201127
Ann Neurol. 2017 Jun;81(6):772-781
pubmed: 28486769
Curr Neuropharmacol. 2016;14(6):593-609
pubmed: 26818748
Nucleic Acids Res. 2019 Jan 8;47(D1):D590-D595
pubmed: 30321428
Redox Biol. 2014 Jan 18;2:289-95
pubmed: 24494204
Exp Neurol. 2008 Dec;214(2):276-84
pubmed: 18809400
Nat Cell Biol. 2002 Sep;4(9):674-80
pubmed: 12198491
Int J Biochem Mol Biol. 2013 Mar 31;4(1):1-26
pubmed: 23638318
Proc Natl Acad Sci U S A. 2006 Apr 11;103(15):5787-92
pubmed: 16585511
Biochim Biophys Acta. 2014 Jan;1843(1):182-96
pubmed: 23850760
Free Radic Biol Med. 2017 Feb;103:1-13
pubmed: 27940347
Science. 2012 Aug 31;337(6098):1062-5
pubmed: 22936770
J Biol Chem. 2004 May 14;279(20):20699-707
pubmed: 14742431
Sci Rep. 2014 Jul 31;4:5896
pubmed: 25077633
Antioxid Redox Signal. 2012 Sep 1;17(5):786-93
pubmed: 22074114
Lancet Oncol. 2017 Oct;18(10):1327-1337
pubmed: 28843768
Biochimie. 2001 Mar-Apr;83(3-4):301-10
pubmed: 11295490
Biochim Biophys Acta. 2011 Jun;1812(6):674-84
pubmed: 21421046
Free Radic Biol Med. 2007 Nov 15;43(10):1351-71
pubmed: 17936181
Clin Cancer Res. 2011 May 1;17(9):2734-43
pubmed: 21364033
Ann Neurol. 2003 Jun;53(6):711-7
pubmed: 12783416
Nature. 2006 Jun 29;441(7097):1162-6
pubmed: 16672981
J Cell Sci. 2004 Jun 1;117(Pt 13):2641-51
pubmed: 15169835
Leukemia. 2019 Oct;33(10):2343-2357
pubmed: 31455853
Lancet Oncol. 2016 Jan;17(1):27-38
pubmed: 26671818
Biochim Biophys Acta. 2008 Dec;1782(12):691-9
pubmed: 18930136
Nat Cell Biol. 2010 Feb;12(2):119-31
pubmed: 20098416
Front Physiol. 2013 Apr 22;4:82
pubmed: 23630499
Nature. 2000 Apr 13;404(6779):770-4
pubmed: 10783891
Einstein (Sao Paulo). 2011 Dec;9(4):538-44
pubmed: 26761262
Trends Biochem Sci. 1999 Apr;24(4):136-41
pubmed: 10322418
Sci Rep. 2017 Dec 19;7(1):17802
pubmed: 29259189
Exp Neurol. 2012 Dec;238(2):225-34
pubmed: 22947198
Drug Discov Today. 2007 Sep;12(17-18):777-85
pubmed: 17826691
Sci Rep. 2018 Nov 5;8(1):16318
pubmed: 30397214
Hum Mol Genet. 2011 May 1;20(9):1726-37
pubmed: 21296869
Neurotoxicology. 2014 Jul;43:28-35
pubmed: 24525285
Nucleic Acids Res. 2013 Jan;41(Database issue):D793-800
pubmed: 23143270
J Bioenerg Biomembr. 2008 Jun;40(3):183-91
pubmed: 18651212
Biosci Rep. 2017 May 17;37(3):
pubmed: 28465355
Nat Rev Neurol. 2014 Jun;10(6):326-36
pubmed: 24840972
Annu Rev Cell Dev Biol. 2006;22:79-99
pubmed: 16704336
Arch Biochem Biophys. 2000 May 1;377(1):65-8
pubmed: 10775442
J Cell Biol. 2010 Dec 27;191(7):1367-80
pubmed: 21173115
Cell Mol Life Sci. 2016 Sep;73(17):3221-47
pubmed: 27100828
J Cell Commun Signal. 2011 Jun;5(2):101-10
pubmed: 21484190
Free Radic Biol Med. 2011 Oct 1;51(7):1355-64
pubmed: 21767633
Genes Cells. 2010 Aug;15(8):887-900
pubmed: 20604804
Biochim Biophys Acta. 2006 May-Jun;1757(5-6):692-9
pubmed: 16729962
Clin Cancer Res. 2013 Sep 1;19(17):4559-63
pubmed: 23775332
Mol Cells. 2017 Jul 31;40(7):441-449
pubmed: 28743182
Neurotox Res. 2015 May;27(4):430-40
pubmed: 25588865
J Cell Sci. 2010 Feb 15;123(Pt 4):578-85
pubmed: 20103532
Dis Model Mech. 2014 Apr;7(4):421-34
pubmed: 24719117