The Bcl-2 homology domain 3 mimetic ABT-737 targets the apoptotic machinery in acute lymphoblastic leukemia resulting in synergistic in vitro and in vivo interactions with established drugs

Molecular Pharmacology
Laura HighRichard B Lock

Abstract

Antiapoptotic Bcl-2 proteins are overexpressed in a number of cancers, including leukemias, and are frequently associated with resistance to conventional chemotherapeutic drugs. ABT-737, a Bcl-2 homology domain 3 mimetic (for structure, see Nature 435:677-681, 2005) inhibits the prosurvival function of Bcl-2, Bcl-X(L), and Bcl-w. We show that ABT-737 was effective as a single agent against a panel of pediatric acute lymphoblastic leukemia (ALL) xenografts, previously established, from patient biopsies, in immunodeficient mice. Although in vitro resistance of leukemia cell lines correlated with expression of the prosurvival protein Mcl-1, there was no relationship between Mcl-1 expression and in vivo xenograft response to ABT-737. However, expression of the pro-apoptotic protein Bim, and the extent of its association with Bcl-2, significantly correlated with in vivo ABT-737 sensitivity. ABT-737 potentiated the antileukemic effects of L-asparaginase, topotecan, vincristine, and etoposide against drug-resistant xenografts in vitro and in vivo. Finally, we show that the combination of L-asparaginase (by specifically down-regulating Mcl-1 protein levels), topotecan (by activating p53 via DNA damage), and ABT-737 (by inhibiting antia...Continue Reading

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