Effect of proteasome inhibitors with different chemical structures on the ubiquitin-proteasome system in vitro

Veterinary Pathology
Vilmos CsizmadiaCarl L Alden

Abstract

Proteasome inhibitor therapeutics (PITs) have the potential to cause peripheral neuropathy. In a mouse model of PIT-induced peripheral neuropathy, the authors demonstrated that ubiquitin-positive multifocal protein aggregates with nuclear displacement appear in dorsal root ganglion cells of animals that subsequently develop nerve injuries. This peripheral-nerve effect in nonclinical models has generally been recognized as the correlate of grade 3 neuropathy in clinical testing. In differentiated PC12 cells, the authors demonstrated perturbations correlative with the development of neuropathy in vivo, including ubiquitinated protein aggregate (UPA) formation and/or nuclear displacement associated with the degree of proteasome inhibition. They compared 7 proteasome inhibitors of 3 chemical scaffolds (peptide boronate, peptide epoxyketone, and lactacystin analog) to determine if PIT-induced peripheral neuropathy is modulated by inhibition of the proteasome (ie, a mechanism-based effect) or due to effects independent of proteasome inhibition (ie, an off target or chemical-structure-based effect). The appearance of UPAs was assayed at IC(90) +/- 5% (90% inhibition concentration +/- 5%) for 20S proteasome inhibition. Results show tha...Continue Reading

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Citations

Feb 15, 2014·Neurotoxicology·Albert AléEsther Udina
Jan 16, 2015·Neurotoxicity Research·Albert AléEsther Udina
Jun 25, 2016·The Biochemical Journal·Sanghamitra SinghAleksandar M Jeremic
Mar 3, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Shirin Arastu-KapurChristopher J Kirk

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Methods Mentioned

BETA
Protein Assay
electrophoresis
light microscopy

Software Mentioned

XL fit

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