TY - JOUR T1 - Antileukemic Activity and Mechanism of Drug Resistance to the Marine Salinispora Tropica Proteasome Inhibitor Salinosporamide A (marizomib) JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.114.092114 SP - mol.114.092114 AU - Denise Niewerth AU - Gerrit Jansen AU - Lesley F V Riethoff AU - Johan van Meerloo AU - Andrew J Kale AU - Bradley S Moore AU - Yehuda G Assaraf AU - Janet L Anderl AU - Sonja Zweegman AU - Gertjan J L Kaspers AU - Jacqueline Cloos Y1 - 2014/01/01 UR - http://molpharm.aspetjournals.org/content/early/2014/04/15/mol.114.092114.abstract N2 - 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. 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 (Met45Val) in CEM/S20 cells, salinosporamide A displayed a markedly impaired capacity to inhibit β5-associated catalytic activity. Lastly, compared to 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 Salinispora tropica suggest an evolutionarily conserved mechanism of resistance to proteasome inhibitors. ER -