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BH3 peptidomimetics potently activate apoptosis and demonstrate single agent efficacy in neuroblastoma

Oncogene volume 25, pages 4525–4533 (2006)Cite this article

Abstract

The major impediment to cure for many malignancies is the development of therapy resistance with resultant tumor progression. Genetic alterations leading to subversion of inherent apoptosis pathways are common themes in therapy resistance. Bcl-2 family proteins play a critical role in regulating mitochondrial apoptosis that governs chemotherapeutic effects, and defective engagement of these pathways contributes to treatment failure. We have studied the efficacy of BH3 peptidomimetics consisting of the minimal death, or BH3, domains of the proapoptotic BH3-only proteins Bid and Bad to induce apoptosis using neuroblastoma (NB) as a model system. We demonstrate that BH3 peptides, modified with an arginine homopolymer for membrane transduction (called r8-BidBH3 and r8-BadBH3, respectively), potently induce apoptosis in NB cells, including those with MYCN amplification. Cell death is caspase 9 dependent, consistent with a requirement for the intrinsic mitochondrial pathway. Substitutions at highly conserved residues within the r8-BidBH3 peptide abolish apoptotic efficacy supporting activity through specific BH domain interactions. Concomitant exposure to r8-BadBH3 and r8-BidBH3 at sublethal monotherapy doses revealed potent synergy consistent with a competitive displacement model, whereby BH3 peptides displace sequestered BH3 proteins to induce cell death. Further, BH3 peptides demonstrate antitumor efficacy in a xenograft model of NB in the absence of additional genotoxic or trophic stressors. These data provide proof of principle that targeted re-engagement of apoptosis pathways may be of therapeutic utility, and BH3-like compounds are attractive lead agents to re-establish therapy-induced apoptosis in refractory malignancies.

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Abbreviations

BH:

Bcl-2 homology domain

DISC:

death-inducing signaling complex

PTD:

peptide transduction domain

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Acknowledgements

This work is dedicated to the memory of Stanley J Korsmeyer. We thank Al Knudson, Garrett Brodeur, Audrey Evans and John Maris for manuscript review and commentary, Michael Rosenblatt for assistance with circular dichroism analyses and Rosalind Barr and Agueda Lin for technical assistance. This work was supported by NIH CA97323, a Career Development Award in the Biomedical Sciences from the Burroughs Wellcome Fund, and the Richard and Sheila Sanford Chair in Pediatric Oncology (M.D.H.); and The Caitlin Robb Foundation (K.C.G.).

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Authors and Affiliations

  1. Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA

    K C Goldsmith, X Liu, V Dam, B T Morgan & M D Hogarty

  2. Division of Biostatistics and Epidemiology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA

    M Shabbout & A Cnaan

  3. Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    A Cnaan & M D Hogarty

  4. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    A Letai

  5. Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA, USA

    S J Korsmeyer

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  1. K C Goldsmith
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  2. X Liu
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Correspondence to M D Hogarty.

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Goldsmith, K., Liu, X., Dam, V. et al. BH3 peptidomimetics potently activate apoptosis and demonstrate single agent efficacy in neuroblastoma. Oncogene 25, 4525–4533 (2006). https://doi.org/10.1038/sj.onc.1209489

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Keywords

  • apoptosis
  • neuroblastoma
  • Bcl-2 homologues
  • programmed cell death
  • MYCN

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