Cancer cell, 2006-11, Vol.10 (5), p.375-388
- Konopleva, Marina
- Contractor, Rooha
- Tsao, Twee
- Samudio, Ismael
- Ruvolo, Peter P.
- Kitada, Shinichi
- Deng, Xingming
- Zhai, Dayong
- Shi, Yue-Xi
- Sneed, Thomas
- Verhaegen, Monique
- Soengas, Maria
- Ruvolo, Vivian R.
- McQueen, Teresa
- Schober, Wendy D.
- Watt, Julie C.
- Jiffar, Tilahun
- Ling, Xiaoyang
- Marini, Frank C.
- Harris, David
- Dietrich, Martin
- Estrov, Zeev
- McCubrey, James
- May, W. Stratford
- Reed, John C.
- Andreeff, Michael
2006
Details
- Autor(en) / Beteiligte
- Konopleva, Marina
- Contractor, Rooha
- Tsao, Twee
- Samudio, Ismael
- Ruvolo, Peter P.
- Kitada, Shinichi
- Deng, Xingming
- Zhai, Dayong
- Shi, Yue-Xi
- Sneed, Thomas
- Verhaegen, Monique
- Soengas, Maria
- Ruvolo, Vivian R.
- McQueen, Teresa
- Schober, Wendy D.
- Watt, Julie C.
- Jiffar, Tilahun
- Ling, Xiaoyang
- Marini, Frank C.
- Harris, David
- Dietrich, Martin
- Estrov, Zeev
- McCubrey, James
- May, W. Stratford
- Reed, John C.
- Andreeff, Michael
- Titel
- Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia
- Ist Teil von
- Cancer cell, 2006-11, Vol.10 (5), p.375-388
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2006
- Link zum Volltext
- Quelle
- EZB Electronic Journals Library
- Beschreibungen/Notizen
- BCL-2 proteins are critical for cell survival and are overexpressed in many tumors. ABT-737 is a small-molecule BH3 mimetic that exhibits single-agent activity against lymphoma and small-cell lung cancer in preclinical studies. We here report that ABT-737 effectively kills acute myeloid leukemia blast, progenitor, and stem cells without affecting normal hematopoietic cells. ABT-737 induced the disruption of the BCL-2/BAX complex and BAK-dependent but BIM-independent activation of the intrinsic apoptotic pathway. In cells with phosphorylated BCL-2 or increased MCL-1, ABT-737 was inactive. Inhibition of BCL-2 phosphorylation and reduction of MCL-1 expression restored sensitivity to ABT-737. These data suggest that ABT-737 could be a highly effective antileukemia agent when the mechanisms of resistance identified here are considered.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1535-6108eISSN: 1878-3686DOI: 10.1016/j.ccr.2006.10.006Titel-ID: cdi_proquest_miscellaneous_68136839
- Format
- –
- Schlagworte
- Animals, Apoptosis - physiology, bcl-2 Homologous Antagonist-Killer Protein - genetics, bcl-2 Homologous Antagonist-Killer Protein - metabolism, bcl-2-Associated X Protein - chemistry, bcl-2-Associated X Protein - genetics, bcl-2-Associated X Protein - metabolism, Biphenyl Compounds - metabolism, Biphenyl Compounds - therapeutic use, Cell Line, CELLCYCLE, Dimerization, Drug Resistance, Neoplasm - physiology, Hematopoietic Stem Cells - physiology, Humans, Leukemia, Myeloid, Acute - drug therapy, Leukemia, Myeloid, Acute - metabolism, Mice, Myeloid Cell Leukemia Sequence 1 Protein, Neoplasm Proteins - metabolism, Nitrophenols - metabolism, Nitrophenols - therapeutic use, Piperazines - metabolism, Piperazines - therapeutic use, Protein Conformation, Protein Structure, Tertiary, Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors, Proto-Oncogene Proteins c-bcl-2 - chemistry, Proto-Oncogene Proteins c-bcl-2 - genetics, Proto-Oncogene Proteins c-bcl-2 - metabolism, Recombinant Fusion Proteins - genetics, Recombinant Fusion Proteins - metabolism, RNA, Small Interfering - genetics, RNA, Small Interfering - metabolism, Sulfonamides - metabolism, Sulfonamides - therapeutic use