TY - JOUR T1 - Antileukemic Activity and Mechanism of Drug Resistance to the Marine <em>Salinispora tropica</em> Proteasome Inhibitor Salinosporamide A (Marizomib) JF - Molecular Pharmacology JO - Mol Pharmacol SP - 12 LP - 19 DO - 10.1124/mol.114.092114 VL - 86 IS - 1 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 - 2014/07/01 UR - http://molpharm.aspetjournals.org/content/86/1/12.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 (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. ER -