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

详细信息    查看全文

• 作者：Denise Niewerth^a ; ^{d.niewerth@vumc.nl" class="auth_mail} ; Johan van Meerloo^a ; ^b ; ^{j.vanmeerloo@vumc.nl" class="auth_mail} ; Gerrit Jansen^c ; ^{g.jansen@vumc.nl" class="auth_mail} ; Yehuda G. Assaraf^d ; ^{assaraf@technion.ac.il" class="auth_mail} ; Tessa C. Hendrickx^a ; ^{t_c_hendrickx@hotmail.com" class="auth_mail} ; Christopher J. Kirk^e ; ^{ckirk@onyx.com" class="auth_mail} ; Janet L. Anderl^e ; ^{janderl@onyx.com" class="auth_mail} ; Sonja Zweegman^b ; ^{s.zweegman@vumc.nl" class="auth_mail} ; Gertjan J.L. Kaspers^a ; ^{gjl.kaspers@vumc.nl" class="auth_mail} ; Jacqueline Cloos^a ; ^b ; ^{j.cloos@vumc.nl" class="auth_mail}
• 关键词：Leukemia ; Proteasome ; Immunoproteasome ; Proteasome inhibitor ; PR-924
• 刊名：Biochemical Pharmacology
• 出版年：1 May, 2014
• 年：2014
• 卷：89
• 期：1
• 页码：43-51
• 全文大小：1269 K

文摘

PR-924 is a novel prototypic immunoproteasome inhibitor bearing markedly enhanced specificity for the 尾5i 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 渭M), 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 尾5i 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 渭M 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 尾5i), but acquired Met45Ile mutation in the PSMB5 gene (encoding constitutive 尾5), consistent with 尾5 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 尾5i immunoproteasome subunit, its anti-leukemic effect required concentrations that blocked both 尾5 and 尾5i subunits. This is underscored by the emergence of mutations in PSMB5 rather than in PSMB8.