ABT‐737 Inhibits Full Length And Cleaved Pro‐Apoptotic Bcl‐xL, Resulting in Differential Effects on Death And Survival

Abstract

ABT-737 is a pharmacological inhibitor of the anti-apoptotic Bcl-2 family protein, Bcl-xL. ABT-737 occupies the BH3-binding domain, supporting apoptosis of cancer cells. We have shown that ABT-737 lowers neuronal metabolic efficiency by inhibiting ATP synthase activity. However, we unexpectedly found that ABT-737 protects brains from ischemic injury in vivo. In our recent study, ABT-737 inhibited formation and function of the cleavage product of full length Bcl-xL, pro-apoptotic ΔN-Bcl-xL. In the current study, we find that high concentration ABT-737 blocks the effects of full length Bcl-xL but low concentration ABT-737 inhibits ΔN-Bcl-xL; this suggests that cleavage of full length Bcl-xL during cell death stimuli exposes the ABT-737 binding site. We tested whether ABT-737 exerts neuroprotective properties by altering mitochondrial membrane permeability. We found that pre-treatment of neurons with 1μM ABT-737 aggravated death induced by glutamate. We observed a loss of mitochondrial potential and a decline in ATP production in ABT-737 and glutamate treated cells. In contrast, pre-treatment with 10nM ABT-737, a hundred fold lower concentration, rescued neurons from death and augmented mitochondrial potential and ATP production during glutamate challenge. Incubation of recombinant ΔN-Bcl-xL protein with isolated mitochondria significantly reduced mitochondrial potential, rescued by CsA and low dose ABT-737, suggesting involvement of mitochondrial permeability transition pore. Our findings suggest that low concentrations of Bcl-xL inhibitors may promote survival by preferentially binding to the pro-apoptotic form of Bcl-xL even as high concentrations potentiate cell death in malignant cells.