Chem Biol Interact 2011 Oct 16;194(1):58-68. Epub 2011 Aug 16.
Department of Pediatrics Research, Children's Cancer Hospital at M.D. Anderson, University of Texas M.D. Anderson Cancer Center, Houston, United States.
Marizomib (NPI-0052) is a naturally derived irreversible proteasome inhibitor that potently induces apoptosis via a caspase-8 and ROS-dependent mechanism in leukemia cells. We aim to understand the relationship between the irreversible inhibition of the proteasome and induction of cell death in leukemia cells by using analogs of marizomib that display reversible and irreversible properties. We highlight the importance of sustained inhibition of at least two proteasome activities as being key permissive events for the induction of the apoptotic process in leukemia cells. These data provide the basis for the development of new approaches to generate more effective anti-proteasome therapies.