RT Journal Article SR Electronic T1 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 JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 483 OP 494 DO 10.1124/mol.109.060780 VO 77 IS 3 A1 Laura M. High A1 Barbara Szymanska A1 Urszula Wilczynska-Kalak A1 Nicole Barber A1 Rosemary O'Brien A1 Seong Lin Khaw A1 Ingela B. Vikstrom A1 Andrew W. Roberts A1 Richard B. Lock YR 2010 UL http://molpharm.aspetjournals.org/content/77/3/483.abstract AB 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-XL, 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 antiapoptotic Bcl-2 family members) caused profound synergistic antileukemic efficacy both in vitro and in vivo. Rational targeting of specific components of the apoptotic pathway may be a useful approach to improve the treatment of refractory or relapsed pediatric ALL. Overall, this study supports the inclusion of the clinical derivative of ABT-737, ABT-263 (for structure, see Cancer Res 68:3421–3428, 2008), into clinical trials against relapsed/refractory pediatric ALL.Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics