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.