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

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.

• Authors: 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
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 86 Issue 1 Pg. 12-9 (Jul 2014) ISSN: 1521-0111 [Electronic] United States
• PMID: 24737138 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

Chemical References

• Boronic Acids
• Lactones
• Proteasome Inhibitors
• Pyrazines
• Pyrroles
• Bortezomib
• marizomib
• PSMB5 protein, human
• Proteasome Endopeptidase Complex

Topics

• Actinobacteria (metabolism)
• Boronic Acids (pharmacology)
• Bortezomib
• Catalysis (drug effects)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (drug effects, genetics)
• Humans
• Lactones (pharmacology)
• Leukemia (drug therapy, genetics, metabolism)
• Mutation (drug effects, genetics)
• Proteasome Endopeptidase Complex (genetics, metabolism)
• Proteasome Inhibitors (pharmacology)
• Pyrazines (pharmacology)
• Pyrroles (pharmacology)
• Up-Regulation (drug effects, genetics)