Anti-leukemic activity and mechanisms underlying resistance to the novel immunoproteasome inhibitor PR-924

Denise Niewerth, Johan Van Meerloo, Gerrit Jansen, Yehuda G. Assaraf, Tessa C. Hendrickx, Christopher J. Kirk, Janet L. Anderl, Sonja Zweegman, Gertjan J.L. Kaspers, Jacqueline Cloos

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

35 Citaten (Scopus)

Samenvatting

PR-924 is a novel prototypic immunoproteasome inhibitor bearing markedly enhanced specificity for the β5i immunoproteasome subunit, compared to the classical proteasome inhibitor bortezomib. Here, we assessed the growth inhibitory potential of PR-924 in three human hematologic malignancy cell lines (CCRF-CEM, THP1, and 8226) and their bortezomib-resistant sublines. Parental cells displayed equal sensitivity to PR-924 (IC50: 1.5-2.8 μM), whereas their bortezomib-resistant tumor lines displayed a 10-12 fold cross-resistance to PR-924. However, PR-924 cross-resistance factors for bortezomib-resistant sublines were markedly lower compared to the resistance factors to bortezomib. Proteasome inhibition experiments confirmed that PR-924 specifically inhibited β5i activity, even far below concentrations that exerted anti-proliferative activity. We further determined whether PR-924 activity might be compromised by acquisition of drug resistance phenomena. Indeed, CEM cells rendered stepwise resistant to 20 μM PR-924 (CEM/PR20) displayed 13-fold PR-924-resistance and 10-fold cross-resistance to bortezomib. CEM/PR20 cells were devoid of mutations in the PSMB8 gene (encoding β5i), but acquired Met45Ile mutation in the PSMB5 gene (encoding constitutive β5), consistent with β5 mutations observed in bortezomib-resistant cells. Furthermore, compared to parental CEM cells, CEM/PR20 cells exhibited 2.5-fold upregulation of constitutive proteasome subunit expression, whereas immunoproteasome subunit expression was 2-fold decreased. In conclusion, PR-924 displayed potent anti-leukemic activity including toward bortezomib-resistant leukemia cells. Despite the specificity of PR-924 to the β5i immunoproteasome subunit, its anti-leukemic effect required concentrations that blocked both β5 and β5i subunits. This is underscored by the emergence of mutations in PSMB5 rather than in PSMB8.

Originele taal-2Engels
Pagina's (van-tot)43-51
Aantal pagina's9
TijdschriftBiochemical Pharmacology
Volume89
Nummer van het tijdschrift1
DOI's
StatusGepubliceerd - 1 mei 2014
Extern gepubliceerdJa

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