Antileukemic activity and mechanism of drug resistance to the marine Salinispora tropica proteasome inhibitor Salinosporamide A (Marizomib)

TitleAntileukemic activity and mechanism of drug resistance to the marine Salinispora tropica proteasome inhibitor Salinosporamide A (Marizomib)
Publication TypeJournal Article
Year of Publication2014
AuthorsNiewerth D., Jansen G., Riethoff L.FV, van Meerloo J., Kale A.J, Moore BS, Assaraf Y.G, Anderl J.L, Zweegman S., Kaspers G.JL, Cloos J.
JournalMolecular Pharmacology
Volume86
Pagination12-19
Date Published2014/07
Type of ArticleArticle
ISBN Number0026-895X
Accession NumberWOS:000337242100002
Keywords20s proteasome; apoptosis; bortezomib; combination; crystal-structures; leukemia-cells; npi-0052; psmb5; relapsed multiple-myeloma; resistance; vivo synergistic cytotoxicity
Abstract

Salinosporamide A (NPI-0052, marizomib) is a naturally occurring proteasome inhibitor derived from the marine actinobacterium Salinispora tropica, and represents a promising clinical agent in the treatment of hematologic malignancies. Recently, these actinobacteria were shown to harbor self-resistance properties to salinosporamide A by expressing redundant catalytically active mutants of the 20S proteasome beta-subunit, reminiscent of PSMB5 mutations identified in cancer cells with acquired resistance to the founding proteasome inhibitor bortezomib (BTZ). Here, we assessed the growth inhibitory potential of salinosporamide A in human acute lymphocytic leukemia CCRF-CEM cells, and its 10-fold (CEM/BTZ7) and 123-fold (CEM/BTZ200) bortezomib-resistant sublines harboring PSMB5 mutations. Parental cells displayed sensitivity to salinosporamide A (IC50=5.1 nM), whereas their bortezomib-resistant sublines were 9-and 17-fold cross-resistant to salinosporamide A, respectively. Notably, combination experiments of salinosporamide A and bortezomib showed synergistic activity in CEM/BTZ200 cells. CEM cells gradually exposed to 20 nM salinosporamide A (CEM/S20) displayed stable 5-fold acquired resistance to salinosporamide A and were 3-fold cross-resistant to bortezomib. Consistent with the acquisition of a PSMB5 point mutation (M45V) in CEM/S20 cells, salinosporamide A displayed a markedly impaired capacity to inhibit beta(5)-associated catalytic activity. Last, compared with parental CEM cells, CEM/S20 cells exhibited up to 2.5-fold upregulation of constitutive proteasome subunits, while retaining unaltered immunoproteasome subunit expression. In conclusion, salinosporamide A displayed potent antileukemic activity against bortezomib-resistant leukemia cells. beta-Subunit point mutations as a common feature of acquired resistance to salinosporamide A and bortezomib in hematologic cells and S. tropica suggest an evolutionarily conservedmechanism of resistance to proteasome inhibitors.

DOI10.1124/mol.114.092114
Short TitleMol. Pharmacol.
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