Differential Targeting of Pro-Survival Bcl-2 Proteins by Their Pro-Apoptotic BH3-Only Ligands: Implications for Targeted Therapies.

Chemoresistance is a significant barrier in the management of hematological malignancies. Despite some striking successes, many malignancies remain incurable. The efficacy of cytotoxic drugs is often blunted by loss of p53 or overexpression of pro-survival proteins like Bcl-2 or its functional homologs Bcl-xL and Mcl-1. Bcl-2-like proteins promote cell survival until antagonized by BH3-only proteins such as Bim. A potential way of overcoming tumor resistance is to engineer BH3-only mimetics to trigger cell death. Although such drugs may have a useful role in overcoming chemoresistance, a serious concern is the potential deleterious effects on normal cells. To assess the feasibility of such an approach, we studied the binding of mammalian pro-apoptotic BH3-only proteins to their pro-survival Bcl-2-like targets. The targeting of pro-survival Bcl-2-like proteins has been considered to be promiscuous, but unexpected selectivity emerged from our analysis. The interactions varied over 10,000-fold in affinity and, accordingly, certain protein pairs associated selectively inside cells. Some death ligands that bound promiscuously were potent killers when overexpressed, whereas Noxa which only targets some pro-survival proteins, but not Bcl-2, had weak activity. Importantly, although expression of Noxa by itself caused limited cytotoxicity, it markedly enhanced sensitivity to cytotoxic drugs such as etoposide, even in those cells normally highly chemoresistant because of Bcl-2 overexpression. Thus, selective targeting of key pro-survival proteins in a malignancy may improve the efficacy of currently used cytotoxic agents with reduced undesirable side effects. In particular, our results suggest that it should be feasible to discover BH3 mimetic drugs with better therapeutic profiles and with the potential to overcome chemoresistant cancers overexpressing pro-survival proteins.