|Title||Antileukemic activity and mechanism of drug resistance to the marine Salinispora tropica proteasome inhibitor Salinosporamide A (Marizomib)|
|Publication Type||Journal Article|
|Year of Publication||2014|
|Authors||Niewerth D., Jansen G., Riethoff L.FV, van Meerloo J., Kale A.J, Moore BS, Assaraf Y.G, Anderl J.L, Zweegman S., Kaspers G.JL, Cloos J.|
|Type of Article||Article|
|Keywords||20s proteasome; apoptosis; bortezomib; combination; crystal-structures; leukemia-cells; npi-0052; psmb5; relapsed multiple-myeloma; resistance; vivo synergistic cytotoxicity|
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 beta-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 beta(5)-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. beta-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.
|Short Title||Mol. Pharmacol.|