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

Denise Niewerth, Gerrit Jansen, Lesley F.V. Riethoff, Johan Van Meerloo, Andrew J. Kale, Bradley S. Moore, Yehuda G. Assaraf, Janet L. Anderl, Sonja Zweegman, Gertjan J.L. Kaspers, Jacqueline Cloos

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

40 Citaten (Scopus)


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 β-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 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 β5-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. β-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.

Originele taal-2Engels
Pagina's (van-tot)12-19
Aantal pagina's8
TijdschriftMolecular Pharmacology
Nummer van het tijdschrift1
StatusGepubliceerd - jul. 2014
Extern gepubliceerdJa


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