A stapled BIM peptide overcomes apoptotic resistance in hematologic cancers
Open Access
- 1 June 2012
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 122 (6), 2018-2031
- https://doi.org/10.1172/jci46231
Abstract
Cancer cells subvert the natural balance between cellular life and death, achieving immortality through pathologic enforcement of survival pathways and blockade of cell death mechanisms. Pro-apoptotic BCL-2 family proteins are frequently disarmed in relapsed and refractory cancer through genetic deletion or interaction-based neutralization by overexpressed antiapoptotic proteins, resulting in resistance to chemotherapy and radiation treatments. New pharmacologic strategies are urgently needed to overcome these formidable apoptotic blockades. We harnessed the natural killing activity of BCL-2–interacting mediator of cell death (BIM), which contains one of the most potent BH3 death domains of the BCL-2 protein family, to restore BH3-dependent cell death in resistant hematologic cancers. A hydrocarbon-stapled peptide modeled after the BIM BH3 helix broadly targeted BCL-2 family proteins with high affinity, blocked inhibitory antiapoptotic interactions, directly triggered proapoptotic activity, and induced dose-responsive and BH3 sequence–specific cell death of hematologic cancer cells. The therapeutic potential of stapled BIM BH3 was highlighted by the selective activation of cell death in the aberrant lymphoid infiltrates of mice reconstituted with BIM-deficient bone marrow and in a human AML xenograft model. Thus, we found that broad and multimodal targeting of the BCL-2 family pathway can overcome pathologic barriers to cell death.Keywords
This publication has 50 references indexed in Scilit:
- Mitochondria in Apoptosis: Bcl-2 Family Members and Mitochondrial DynamicsDevelopmental Cell, 2011
- BH3-Triggered Structural Reorganization Drives the Activation of Proapoptotic BAXMolecular Cell, 2010
- Mitochondria and cell death: outer membrane permeabilization and beyondNature Reviews Molecular Cell Biology, 2010
- The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizerNature Chemical Biology, 2010
- Effective targeting of STAT5-mediated survival in myeloproliferative neoplasms using ABT-737 combined with rapamycinLeukemia, 2010
- Mcl‐1–Bim complexes accommodate surprising point mutations via minor structural changesProtein Science, 2010
- BAX activation is initiated at a novel interaction siteNature, 2008
- The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralizedCancer Cell, 2006
- Essential role of BAX,BAK in B cell homeostasis and prevention of autoimmune diseaseProceedings of the National Academy of Sciences of the United States of America, 2005
- Cell DeathCell, 2004