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

AbstractBACKGROUND:
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 IC(50) 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.
AuthorsAarthi Jayanthan, Andrea Incoronato, Anjali Singh, Christopher Blackmore, Delphine Bernoux, Victor Lewis, Ronald Stam, James A Whitlock, Aru Narendran
JournalPediatric blood & cancer (Pediatr Blood Cancer) Vol. 56 Issue 3 Pg. 353-60 (Mar 2011) ISSN: 1545-5017 [Electronic] United States
PMID21225911 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2010 Wiley-Liss, Inc.
Chemical References
  • ABT-737
  • Antineoplastic Agents
  • Biphenyl Compounds
  • Drug Combinations
  • KMT2A protein, human
  • Nitrophenols
  • Piperazines
  • Proto-Oncogene Proteins c-bcl-2
  • Sulfonamides
  • Myeloid-Lymphoid Leukemia Protein
  • Cytochromes c
  • Histone-Lysine N-Methyltransferase
  • Poly(ADP-ribose) Polymerases
  • Caspase 8
Topics
  • Antineoplastic Agents (pharmacology)
  • Apoptosis (drug effects)
  • Biphenyl Compounds (pharmacology)
  • Blotting, Western
  • Caspase 8 (metabolism)
  • Cell Line, Tumor
  • Cytochromes c (metabolism)
  • Drug Combinations
  • Gene Rearrangement
  • Histone-Lysine N-Methyltransferase
  • Humans
  • Infant
  • Male
  • Myeloid-Lymphoid Leukemia Protein (genetics)
  • Nitrophenols (pharmacology)
  • Piperazines (pharmacology)
  • Poly(ADP-ribose) Polymerases (metabolism)
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, genetics, pathology)
  • Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, metabolism)
  • Sulfonamides (pharmacology)

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