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

Aarthi Jayanthan, Andrea Incoronato, Anjali Singh, Christopher Blackmore, Delphine Bernoux, Victor Lewis, Ronald Stam, James A. Whitlock, Aru Narendran

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

18 Citaten (Scopus)


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.

Originele taal-2Engels
Pagina's (van-tot)353-360
Aantal pagina's8
TijdschriftPediatric Blood and Cancer
Nummer van het tijdschrift3
StatusGepubliceerd - mrt. 2011
Extern gepubliceerdJa


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