title: 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.
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 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.
authors.affiliation: Children's Cancer Institute Australia for Medical Research, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Laura M
authors.initials: LM
authors.lastname: High
authors.forename: Barbara
authors.initials: B
authors.lastname: Szymanska
authors.forename: Urszula
authors.initials: U
authors.lastname: Wilczynska-Kalak
authors.forename: Nicole
authors.initials: N
authors.lastname: Barber
authors.forename: Rosemary
authors.initials: R
authors.lastname: O'Brien
authors.forename: Seong Lin
authors.initials: SL
authors.lastname: Khaw
authors.forename: Ingela B
authors.initials: IB
authors.lastname: Vikstrom
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Roberts
authors.forename: Richard B
authors.initials: RB
authors.lastname: Lock
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001713:Biphenyl Compounds / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D004357:Drug Synergism; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D020014:K562 Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D018716:Molecular Mimicry; D009596:Nitrophenols / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism*; D010879:Piperazines / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: C501332:ABT-737; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D009596:Nitrophenols; D004364:Pharmaceutical Preparations; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides