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Cytotoxicity, drug combinability, and biological correlates of ABT-737 against acute lymphoblastic leukemia cells with MLL rearrangement

Authors

  • Aarthi Jayanthan BSc,

    1. Hughes' Children's Cancer Research Centre, University of Calgary, Calgary, Alberta, Canada
    2. Division of Pediatric Oncology, Alberta Children's Hospital, Calgary, Alberta, Canada
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  • Andrea Incoronato MD,

    1. Hughes' Children's Cancer Research Centre, University of Calgary, Calgary, Alberta, Canada
    2. Division of Pediatric Oncology, Alberta Children's Hospital, Calgary, Alberta, Canada
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  • Anjali Singh MSc,

    1. Hughes' Children's Cancer Research Centre, University of Calgary, Calgary, Alberta, Canada
    2. Division of Pediatric Oncology, Alberta Children's Hospital, Calgary, Alberta, Canada
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  • Christopher Blackmore BSc,

    1. Hughes' Children's Cancer Research Centre, University of Calgary, Calgary, Alberta, Canada
    2. Division of Pediatric Oncology, Alberta Children's Hospital, Calgary, Alberta, Canada
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  • Delphine Bernoux MD,

    1. Hughes' Children's Cancer Research Centre, University of Calgary, Calgary, Alberta, Canada
    2. Division of Pediatric Oncology, Alberta Children's Hospital, Calgary, Alberta, Canada
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  • Victor Lewis MD,

    1. Hughes' Children's Cancer Research Centre, University of Calgary, Calgary, Alberta, Canada
    2. Division of Pediatric Oncology, Alberta Children's Hospital, Calgary, Alberta, Canada
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  • Ronald Stam PhD,

    1. Division of Pediatric Oncology/Hematology, Erasmus MC—Sophia Children's Hospital, Rotterdam, The Netherlands
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  • James. A. Whitlock MD,

    1. Vanderbilt University Medical Center, Nashville, Tennessee
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  • Aru Narendran MD, PhD

    Corresponding author
    1. Hughes' Children's Cancer Research Centre, University of Calgary, Calgary, Alberta, Canada
    2. Division of Pediatric Oncology, Alberta Children's Hospital, Calgary, Alberta, Canada
    • Division of Pediatric Oncology, Alberta Children's Hospital, 2888 Shaganappi Trail NW, Calgary, Alberta, Canada T3B 6A8.
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  • Conflict of interest: A.N. and J.A.W. served on the ABT-263 and pediatric malignancies expert panel for Abbott Laboratories.

Abstract

Background

ABT-737 is a BH3 mimetic small-molecule inhibitor that binds with high affinity to Bcl-2 to induce apoptosis in malignant cells and has shown promise as an effective anti-leukemic agent in pediatric preclinical tests. This study focuses on the effects of ABT-737 on leukemia cells with MLL rearrangement and identifies some of the biological correlates of its activity.

Procedure

Cells were cultured in the presence of increasing concentrations of ABT-737 alone or in combination with other agents. After 4 days in culture, cell growth inhibition was measured by Alamar blue assay. The expression and activation of potential intracellular targets of ABT-737 activity were determined by Western blot analysis.

Results

Significant Bcl-2 expression was detected in all infant leukemia cells investigated. ABT-737 induced cell death in all cell lines studied although the IC50 values differed somewhat between cell lines. Western blot analysis identified the effects of ABT-737 on survival and apoptosis-regulatory proteins PARP, caspase-8, and cytochrome-c. Drug combination studies indicated synergy with distinct anti-neoplastic agents, including the multi-tyrosine kinase inhibitor sunitinib. This effective drug synergy appears to be mediated by the combined inhibition of Bcl-2 and intracellular signaling pathways.

Conclusions

We describe the in vitro studies to demonstrate the activity and drug combinability of ABT-737 against MLL rearranged leukemia cells. In addition, identification of the molecular changes that occur in the presence of ABT-737 provides information regarding effective target validation and target modulation analyses in future clinical trials. Pediatr Blood Cancer 2011;56:353–360. © 2010 Wiley-Liss, Inc.

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