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Mol Pharmacol. 2014 Jul;86(1):12-9. doi: 10.1124/mol.114.092114. Epub 2014 Apr 15.

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

Author information

1
Department of Pediatric Oncology/Hematology (D.N., L.F.V.R., J.v.M., G.J.L.K., J.C.), Department of Rheumatology (G.J.), and Department of Hematology (J.v.M., S.Z., J.C.), VU University Medical Center, Amsterdam, The Netherlands; Scripps Institution of Oceanography and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, San Diego, California (A.J.K., B.S.M.); The Fred Wyszkowski Cancer Research Laboratory, Technion-Israel Institute of Technology, Haifa, Israel (Y.G.A.); and Research Department, Onyx Pharmaceuticals Inc., South San Francisco, California (J.L.A.).
2
Department of Pediatric Oncology/Hematology (D.N., L.F.V.R., J.v.M., G.J.L.K., J.C.), Department of Rheumatology (G.J.), and Department of Hematology (J.v.M., S.Z., J.C.), VU University Medical Center, Amsterdam, The Netherlands; Scripps Institution of Oceanography and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, San Diego, California (A.J.K., B.S.M.); The Fred Wyszkowski Cancer Research Laboratory, Technion-Israel Institute of Technology, Haifa, Israel (Y.G.A.); and Research Department, Onyx Pharmaceuticals Inc., South San Francisco, California (J.L.A.) j.cloos@vumc.nl.

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 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 = 5.1 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 conserved mechanism of resistance to proteasome inhibitors.

PMID:
24737138
PMCID:
PMC4054006
DOI:
10.1124/mol.114.092114
[Indexed for MEDLINE]
Free PMC Article
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