Specific and prolonged proteasome inhibition dictates apoptosis induction by marizomib and its analogs

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.

► We use irreversible and reversible analogs of the proteasome inhibitor, marizomib. ► Irreversible leaving group (LG) analogs of marizomib are more potent inducers of apoptosis in leukemia cells. ► Inhibition of two proteasomal activities and the duration of inhibition are key factors in apoptosis induction.