Proteosome inhibitors (e.g., bortezomib) represent a new class of chemotherapeutics currently approved to treat multiple myeloma and mantle cell lymphoma but are limited by multiple toxicities and development of resistance during long-term use. Obaidat et al. compared the properties of two novel marine natural product proteosome inhibitors, marizomib (NPI-0052) and NPI-0047 [(1R,4R,5S)-1-[(S)-(1S)-cyclohex-2-en-1-yl(hydroxy)methyl]-4-ethyl-5-methyl-6-oxa-2-azabicyclo[3.2.0]heptane-3,7-dione], to help define differences in their cytotoxic mechanisms. Both marizomib and NPI-0047 covalently bind to the subunits of the proteosome; marizomib is essentially irreversible, whereas NPI-0047 demonstrates a very slow off-rate. Cellular uptake of both inhibitors is essentially identical, and differences are observed only between cell lines, where molecular characteristics of the cell membrane influence uptake. Cellular accumulation and efflux are not mediated through the major ATP-binding cassette (ABC) transporters. Therefore, the greater cytotoxicity of marizomib versus NPI-0047 is due not to differences in cellular transport systems but rather to the high-affinity, irreversible binding of marizomib to the proteosome. These results (i.e., irreversible binding and lack of substrate activity for ABC transporters) also suggest that marizomib might have an advantage relative to current proteosome inhibitors during prolonged administration.
See article at J Pharmacol Exp Ther 2011, 337:479–486
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