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A stapled BIM peptide overcomes apoptotic resistance in hematologic cancers
James L. LaBelle, … , Andrew L. Kung, Loren D. Walensky
James L. LaBelle, … , Andrew L. Kung, Loren D. Walensky
Published May 24, 2012
Citation Information: J Clin Invest. 2012;122(6):2018-2031. https://doi.org/10.1172/JCI46231.
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Research Article

A stapled BIM peptide overcomes apoptotic resistance in hematologic cancers

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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.

Authors

James L. LaBelle, Samuel G. Katz, Gregory H. Bird, Evripidis Gavathiotis, Michelle L. Stewart, Chelsea Lawrence, Jill K. Fisher, Marina Godes, Kenneth Pitter, Andrew L. Kung, Loren D. Walensky

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Figure 6

BIM SAHBA treatment induces biochemical and morphological changes that reflect a proapoptotic mechanism of action.

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BIM SAHBA treatment induces biochemical and morphological changes that r...
(A) OCI-AML3 cells treated with BIM SAHBA (0–10 μM) manifest dose-responsive dissociation of the native BAK/MCL-1 complex, as assessed by MCL-1 immunoprecipitation and anti-BAK Western analysis. No effect is observed upon treatment with BIM SAHBA(R153D). (B) BIM SAHBA (0–10 μM) likewise triggers BAX activation, as monitored by BAX immunoprecipitation using the 6A7 antibody, which selectively recognizes BAX’s N-terminal activation epitope. R153D mutagenesis abrogates the effect. (C) A Wright-Giemsa stain of BIM SAHBA–treated OCI-AML3 cells (5 μM) revealed cellular shrinkage, chromatin condensation and marginalization, and nuclear fragmentation, all hallmark morphological features of apoptosis induction (arrowheads). Vehicle- and BIM SAHBA(R153D)–treated cells showed no such effects. Original magnification, ×100; third column, additional ×15 zoom. (D) BIM SAHBA (25 mg/kg/d i.v.) suppressed tumor growth compared with vehicle (n = 7 per arm; 2-way ANOVA, P = 0.018), as assessed by in vivo bioluminescence imaging of a subcutaneous OCI-AML3 tumor xenograft model. Data are mean ± SEM. *P < 0.05.

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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