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

Abstract

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.

• Authors: Claudia P Miller, Christa A Manton, Randal Hale, LaKeisha Debose, Venkat R Macherla, Barbara C Potts, Michael A Palladino, Joya Chandra
• Journal: Chemico-biological interactions (Chem Biol Interact) Vol. 194 Issue 1 Pg. 58-68 (Oct 15 2011) ISSN: 1872-7786 [Electronic] Ireland
• PMID: 21864512 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Published by Elsevier Ireland Ltd.

Chemical References

• Lactones
• Protease Inhibitors
• Pyrroles
• Reactive Oxygen Species
• marizomib
• Caspase 8

Topics

• Apoptosis (drug effects)
• Caspase 8 (metabolism)
• Humans
• Lactones (chemistry, pharmacology)
• Leukemia (drug therapy, metabolism, pathology)
• Oxidative Stress (drug effects)
• Protease Inhibitors (chemistry, pharmacology)
• Pyrroles (chemistry, pharmacology)
• Reactive Oxygen Species (metabolism)
• Tumor Cells, Cultured