BH3 peptidomimetics potently activate apoptosis and demonstrate single agent efficacy in neuroblastoma
1Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
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.
Insights
BH3 peptides, designed to re-engage apoptosis pathways, effectively induce cancer cell death. These compounds show promise in overcoming therapy resistance and treating refractory malignancies.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Therapy resistance and tumor progression are major challenges in cancer treatment.
- Defects in apoptosis pathways, particularly involving Bcl-2 family proteins, contribute significantly to treatment failure.
- Neuroblastoma (NB) is a pediatric cancer often characterized by therapy resistance.
Purpose of the Study:
- To investigate the efficacy of BH3 peptidomimetics in inducing apoptosis in neuroblastoma cells.
- To explore the mechanism of action of these BH3 peptides.
- To evaluate the therapeutic potential of BH3 peptides in preclinical cancer models.
Main Methods:
- Synthesized modified BH3 peptides (r8-BidBH3, r8-BadBH3) for enhanced cell membrane transduction.
- Assessed apoptosis induction in neuroblastoma cell lines, including those with MYCN amplification.
- Investigated the dependence on caspase 9 and the role of specific BH domain interactions.
- Evaluated synergistic effects of combined BH3 peptide treatment.
- Tested antitumor efficacy in a neuroblastoma xenograft model.
Main Results:
- r8-BidBH3 and r8-BadBH3 potently induced apoptosis in neuroblastoma cells.
- Apoptosis was dependent on caspase 9, indicating activation of the intrinsic mitochondrial pathway.
- Specific residue substitutions in r8-BidBH3 abolished efficacy, confirming targeted BH domain interactions.
- Sublethal doses of r8-BadBH3 and r8-BidBH3 showed synergistic apoptosis induction.
- BH3 peptides demonstrated significant antitumor efficacy in a neuroblastoma xenograft model.
Conclusions:
- Targeted re-engagement of apoptosis pathways using BH3 peptidomimetics is a viable therapeutic strategy.
- BH3 peptides are promising lead agents for re-establishing apoptosis in therapy-resistant cancers.
- These findings support the development of BH3-like compounds for treating refractory malignancies.
