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-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.
Footnotes
↵ The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
This work was supported by the University of Southern California-Childrens Hospital Los Angeles (USC-CHLA) Institute for Pediatric Clinical Research (IPCR); Children's Cancer Institute Australia for Medical Research; the Leukemia Foundation of Australia; the Anthony Rothe Memorial Trust [Grant 0594]; The Australian National Health and Medical Research Council Program Grant [Grant 461221]; Leukemia and Lymphoma Society Specialized Centre for Research Grant [Grant 7015-02]; and the Hematology Society of Australia and New Zealand (HOTT Fellowship to S.L.K.).
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.109.060780
-
ABBREVIATIONS:
- 4-HPR
- fenretinide
- A1
- Bcl-2-related protein A1a
- ALL
- acute lymphoblastic leukemia
- Bad
- Bcl-2-associated death promoter
- Bak
- Bcl-2 homologous antagonist/killer
- Bax
- Bcl-2-associated X protein
- Bcl-2
- B-cell lymphoma-leukemia gene 2
- BCP
- B-cell precursor
- BH
- Bcl-2 homology
- BH3
- Bcl-2 homology domain 3
- Bid
- BH3-interacting domain death agonist
- Bik
- Bcl-2-interacting killer
- Bim
- Bcl-2 interacting mediator of cell death
- Bmf
- Bcl-2 modifying factor
- CI
- combination index
- DEX
- dexamethasone
- EFS
- event-free survival
- ETO
- etoposide
- ETO
- etoposide
- FBS
- fetal bovine serum
- Hrk
- harakiri
- huCD45+
- human CD45-positive
- l-asp
- l-asparaginase
- %huCD45+
- proportion of huCD45+ cells versus total murine CD45+ and huCD45+ cells in the murine peripheral blood
- LGD
- leukemia growth delay
- Mcl-1
- myeloid cell leukemia sequence 1
- MTD
- maximal tolerated dose
- MTP
- mitochondrial transmembrane potential
- MT-PBS
- mouse tonicity-phosphate-buffered saline
- NOD
- nonobese diabetic
- PI
- propidium iodide
- pNA
- para-nitroaniline
- PS
- phosphatidylserine
- Puma
- p53 up-regulated modulator of apoptosis
- SCID
- severe combined immunodeficient
- TPT
- topotecan
- VCR
- vincristine
- z-VAD-fmk
- benzyloxycarbonyl-Val-Ala-Asp fluoromethyl ketone.
- Received September 3, 2009.
- Accepted December 11, 2009.
- Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|